Found cell phone photos Protection Status

© 1996–2018, LLC | info @

Vitamins are organic molecules that function in a wide variety of capacities within the body. The most prominent function of the vitamins is found cell phone photos to serve as cofactors (co-enzymes) for enzymatic reactions. The distinguishing feature of the vitamins is that they generally cannot be synthesized by mammalian cells and, therefore, must be supplied in the diet. The vitamins are of two distinct types, water soluble and fat soluble. For more information on the food products that are good sources of the individual vitamins visit the page.












The that are considered of dietary significance are those that are necessary to support biochemical reactions by serving both functional and structural roles as well as those serving as electrolytes. The use of the term dietary mineral is considered archaic since the intent of the term "mineral" is to describe ions not actual minerals. There are both quantity elements required by the body and trace elements. The quantity elements are sodium, magnesium, phosphorous, sulfur, chlorine, potassium and calcium. The essential trace elements are manganese, iron, cobalt, nickel, copper, zinc, selenium, molybdenum, and iodine. Additional trace elements (although not considered essential) are boron, chromium, fluoride, and silicon.

Structure of thiamine

Thiamine structure

Thiamine (also written thiamin) is also known as vitamin B1. Thiamine is derived from a substituted pyrimidine and a thiazole which are coupled by a methylene bridge. Thiamine is the form of vitamin B1 that is absorbed from the small intestine. Thiamine uptake from the intestines is a function of the family member encoded by the SLC19A2 gene. Thiamine is rapidly converted to its active form, thiamine pyrophosphate, TPP, by the enzyme thiamine pyrophosphokinase 1, TPK1. The TPK1 gene is located on chromosome 7q34–q35 and is composed of 27 exons that generate two alternatively spliced mRNAs encoding isoforms of 243 amino acids (isoform a) and 194 amino acids (isoform b). Expression of the TPK1 gene is highest in the liver and brain. Uptake of thiamine into cells occurs primarily through the activity of the SLC19A3 encoded transporter. Mitochondrial uptake of TPP occurs via the action of the transporter encoded by the SLC25A19 gene.

Structure of thiamine pyrophosphate

Thiamine pyrophosphate

TPP is necessary as a cofactor for three critical dehydrogenases. These enzymes are the pyruvate dehydrogenase complex (PDHc) and 2-oxoglutarate (α-ketoglutarate) dehydrogenase (OGDH), both of which are associated with the, and necessary for metabolism of the branched-chain amino acids, leucine, isoleucine, and valine. These three dehydrogenases also require the co-factors derived from the vitamins lipoic acid, pantothenic acid (CoA), riboflavin, and niacin. For this reason these three dehydrogenases are often referred to as the Tender (thiamine) Loving (lipoic acid) Care (CoA) For (flavin) Nancy (niacin) enzymes. In addition to these three dehydrogenases, TPP is a required co-factor for the transketolase catalyzed reactions of the and it is required for the catabolism of the methyl-substituted fatty acid () at the 2-hydroxyphytanoyl-CoA lyase reaction. A deficiency in thiamine intake leads to a severely reduced capacity of cells to generate energy and to carry out reductive biosynthetic reactions as well as to synthesize nucleotides because of its role in the three critical dehydrogenase complexes.

The dietary requirement for thiamine is proportional to the caloric intake of the diet and ranges from 1.0–1.5 mg/day for normal adults. If the carbohydrate content of the diet is excessive then an increase in  thiamine intake will be required.

The richest sources of vitamin B1 include yeasts and animal liver. Additional sources include whole-grain cereals, rye and whole-wheat flour, navy beans, kidney beans, wheat germ, as well as pork and fish.

Food source

Thiamine content (mg)

Yeast, brewer's, 2 tbls 2.3 Pork chop, lean, 3.5 oz 0.9 Ham, lean, 3.5 oz 0.7 Catfish, 3.5 oz cooked 0.4 Bagel, 2 oz enriched 0.4 Milk, soy, 1 cup 0.4 Beans, baked, 1 cup 0.34 Oatmeal, 1 cup cooked 0.26 Rice, white, cooked, 1 cup 0.26 Green peas, ½ cup cooked 0.23 Potato, one medium baked 0.22 Orange juice, 1 cup 0.20 Black beans, ½ cup cooked 0.21 Navy beans, ½ cup cooked 0.19 Soy nuts, ½ cup 0.20 Cashews, ½ cup 0.15 Peanuts, ½ cup 0.10

The earliest symptoms of thiamine deficiency include constipation, appetite suppression, and nausea. Progressive deficiency will lead to mental depression, peripheral neuropathy and fatigue. Chronic thiamine deficiency leads to more severe neurological symptoms including ataxia, mental confusion and loss of eye coordination (nystagmus). A highly diagnostic physical test of thiamine deficiency is vertical nystagmus. Vertical nystagmus is characterized by spontaneous upbeating or downbeating of the eyeball. There are numerous causes or horizontal nystagmus but vertical is only seen due to the CNS damage associated with thiamine deficiency or with phencyclidine (PCP) intoxication. Additional clinical symptoms of prolonged thiamine deficiency are related to cardiovascular and musculature defects.

Dietary thiamine deficiency is known as beri beri, is most often the result of a diet that is carbohydrate rich and thiamine deficient. An additional thiamine deficiency related syndrome is known as Wernicke syndrome which is most often associated with chronic alcohol consumption. This disease is most commonly found in chronic alcoholics due to the fact that alcohol impairs thiamine uptake from the small intestine as well as the fact that these individuals generally have poor dietetic lifestyles. Wernicke syndrome is also referred to as dry beri beri. Prolonged dietary deficiency in thiamine leads to wet beri beri. The wet form of the disease is the result the cardiac involvement in the deficiency. At this stage in the deficiency all four chambers of the heart enlarge due to loss of energy generation and fluid retention resulting in what is called dilated cardiomyopathy. The result of the enlarged chambers is that they can't fill completely resulting in systolic failure. Systole relates to the force associated with cardiac contraction expelling blood to arteries. Blood pumped from the left ventricle enters the aorta and is delivered to the body, whereas blood pumped from the right ventricle is sent to the lungs.

When thiamine deficiency manifests with CNS involvement it is called Korsakoff encephalopathy (or Korsakoff psychosis) and is also commonly referred to as Wernicke-Korsakoff syndrome (WKS). WKS is characterized by acute encephalopathy progressing to chronic impairment of short-term memory. Thiamine supplementation can reverse the symptoms of beri beri and Wernicke syndrome, however, the consequences of severe deficiency (WKS) are irreversible. The confabulation of Korsakoff psychosis is due to destruction of the mammillary bodies in the brain. The mammillary bodies are composed of two small round structures at the underside of the brain that are part of the limbic system, specifically they are part of the Papez circuit. This circuit is also called the hippocampal-mammillo-thalamo-cortical pathway. The consequence of destruction of the mammillary bodies is retrograde amnesia.

Persons afflicted with an inherited form of Wernicke-Korsakoff syndrome appear to have an inborn error of metabolism that is clinically important only when the diet is inadequate in thiamine. These individuals were thought to harbor an abnormality in the enzyme, transketolase. Although a variant transketolase enzyme has been proposed to be associated with Wernicke-Korsakoff syndrome, no mutations have been found in the gene (symbol: TKT) encoding this enzyme when cloned from patients exhibiting the syndrome. It has been speculated that the protein encoded by a transketolase-related gene (transketolase-like 1: TKTL1) may be involved in the inherited propensity for the development of WKS. However, the TKTL1 encoded protein lacks 38 amino acids, compared to the TKT protein, in the TPP-binding region. All TPP-dependent enzymes contain a highly similar TPP-binding domain and its lack in the TKTL1 protein strongly suggests that it is unlikely that TKTL1 is a TPP-dependent protein capable of catalyzing the transketolase reaction. Indeed, recent evidence has confirmed that the TKTL1 protein does not catalyze the transketolase reaction of the PPP. Intense interest in the TKTL1 gene, and its encoded protein, was stimulated because it was shown that the level of TKTL1 expression correlated with poor patient outcomes and metastasis in many solid tumours. In addition, specific inhibition of TKTL1 mRNA has been shown to inhibit cancer cell proliferation in functional studies.

A Wernicke-like encephalopathy is associated with mutations in one of the thiamine transporter genes. As indicated above, cellular uptake of thiamine occurs via the transporter encoded by the SLC19A3 gene. Mutations in the SLC19A3 gene have been linked to an inherited Wernicke-like disorder.

Structure of riboflavin

Riboflavin structure

Riboflavin is also known as vitamin B2. Riboflavin is the precursor for the coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Dietary riboflavin is absorbed from the small intestine through the action of the member transporter encoded by the SLC52A3 gene. Cellular uptake of riboflavin occurs through the actions of the SLC transporters encoded by the SLC52A1 and SLC52A2 genes. The SLC52A2 gene is highly expressed in the brain and mutations in this gene result in the autosomal recessive progressive neurological disorder known as Brown-Vialetto-Van Laere syndrome 2.

FMN is synthesized from riboflavin via the ATP-dependent enzyme riboflavin kinase (RFK). RFK introduces a phosphate group onto the terminal hydroxyl of riboflavin. The RFK gene is located on chromosome 9q21.13 and is composed of 4 exons that encode a 155 amino acid protein. FMN is then converted to FAD via the attachment of AMP (derived from ATP) though the action of flavin adenine dinucleotide synthetase 1 which is encoded by the FLAD1 gene. The FLAD1 gene is located on chromosome 1q21.3 and is composed of 7 exons that generate four alternatively spliced mRNAs each of which encode distinct isoforms of the enzyme.

The enzymes that require FMN or FAD as cofactors are termed flavoproteins. Several flavoproteins also contain metal ions and are termed metalloflavoproteins. Both classes of enzyme are involved in a wide range of red-ox reactions and includes the same critical thiamine-dependent enzymes described above, the pyruvate dehydrogenase complex (PDHc), 2-oxoglutarate (α-ketoglutarate) dehydrogenase (OGDH), and branched-chain α-ketoacid dehydrogenase (BCKD). Additional important metabolic regulatory enzymes that require flavin as a co-factor include, succinate dehydrogenase (TCA cycle and complex II of ), glycerol-3-phosphate dehydrogenase (involved in the and ), and xanthine oxidase involved in. During the course of the enzymatic reactions involving the flavoproteins the reduced forms of FMN and FAD are formed, FMNH2 and FADH2, respectively. The hydrogens of FADH2 are on nitrogens 1 and 5 as indicated in the Figure. The normal daily requirement for riboflavin is 1.2–1.7 mg/day for normal adults.

Structure of FAD

Structure of FAD

Riboflavin is found in dairy products, lean meats, poultry, fish, grains, broccoli, turnip greens, asparagus, spinach, and enriched food products.

Food source

Riboflavin content (mg)

Beef liver, 3.5oz cooked 4.14 Mackerel, 3.5 oz canned 0.54 Pork, loin, 3 oz cooked 0.24 Hamburger, lean, 3.5 oz 0.21 Chicken, dark, 3 oz cooked 0.19 Steamed clams, 3.5 oz 0.43 Yogurt, low-fat, 1 cup 0.37 Egg, cooked 0.25 Cheese, cottage, ½ cup 0.21 Milk, nonfat, 1 cup 0.34 Pasta, 1 cup cooked 0.23 Bagel, plain 0.22 Spinach, ½ cup cooked 0.16 Wheat germ, raw, 2 tbls 0.12 Soy nuts, ½ cup 0.65 Almonds, ½ cup 0.78

Riboflavin deficiencies are rare in the United States due to the presence of adequate amounts of the vitamin in eggs, milk, meat and cereals. Riboflavin deficiency is often seen in chronic alcoholics due to their poor dietetic habits.

Symptoms associated with riboflavin deficiency include itching and burning eyes, angular stomatitis and cheilosis (cracks and sores in the mouth and lips), bloodshot eyes, glossitis (inflammation of the tongue leading to purplish discoloration), seborrhea (dandruff, flaking skin on scalp and face), trembling, sluggishness, and photophobia (excessive light sensitivity). Riboflavin decomposes when exposed to visible light. This characteristic can lead to riboflavin deficiencies in newborns treated for by phototherapy requiring dietary supplementation in these infants.

Niacin (nicotinic acid) is also known as vitamin B3. Both nicotinic acid (NA) and nicotinamide (NAM) can serve as the dietary source of the co-factor forms of vitamin B3, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).

Structures of nicotinamide and nicotinic acid

With respect to niacin the designation NAD (and NADP) refers to the chemical backbone of the active form of the vitamin-derived cofactor. The designations, NAD+ and NADH, as well as NADP+ and NADPH, refer to the oxidized and reduced forms of the cofactors, respectively.

Structure of NAD

Structure of NAD+. The –OH phosphorylated in NADP+ is indicated by the red arrow. NADH is shown in the box insert where the "R" represents the adenine dinucleotide portion.

Nicotinamide (NAM) can also be obtained in the diet from the consumption of NAD and NADP, both of which are hydrolyzed to nicotinamide within the lumen of the small intestines. The nicotinamide is then absorbed and delivered to the blood. Nicotinamide can also be hydrolyzed to nicotinic acid (NA) in the lumen of the small intestines and then absorbed. Intestinal uptake of nicotinic acid and nicotinamide is the function of the transporter encoded by the SLC22A13 gene. The SLC22A13 encoded transporter is also involved in high affinity nicotinic acid exchange in the kidneys.

Niacin is not a true vitamin in the strictest definition since NAD can be derived from the amino acid. However, the ability to utilize tryptophan for niacin synthesis is inefficient given that approximately 60 mg of tryptophan are required to synthesize 1 mg of NAD. Also, synthesis of NAD from tryptophan requires vitamins B1, B2 and B6 which would be limiting in themselves on a marginal diet. The recommended daily requirement for niacin is 13–19 niacin equivalents (NE) per day for a normal adult. One NE is equivalent to 1 mg of free niacin).

Niacin is found in liver, meat, peanuts and other nuts, and whole grains. In addition, foods that are rich in protein, with exception of tryptophan-poor grains, can satisfy some of the demand for niacin.

Food source

Niacin content (mg)

Beef liver, 3.5oz cooked 14.4 Chicken, white meat, cooked 13.4 Tuna, canned in water, 3 oz 11.8 Salmon, 3.5 oz cooked 8.0 Ground beef, 3.5 oz cooked 5.3 Peanuts, ½ cup 10.5 Almonds, ½ cup 1.4 Potato, baked with skin 3.3 Mushrooms, raw, ½ cup 1.7 Barley, ½ cup cooked 1.6 Corn, yellow, ½ cup 1.3 Lentils, ½ cup cooked 1.4 Sweet potatoes, ½ cooked 1.2 Carrot, raw, medium 0.7 Peach, raw, medium 0.9 Mango, 1 medium 1.5

Synthesis and Salvage of NAD

With the exception of neurons, human cells cannot transport NAD+ into the cell, therefore, they must synthesize it either de novo or through the pathway involving the amino acid. However, due to the critical need for NAD, most cells recycle the cofactor via salvage pathways as opposed to de novo synthesis. The salvage pathways for NAD synthesis take place in both the nucleus and the mitochondria.

Formation of NAD from nicotinamide (NAM) occurs in a two-step process and from nicotinic acid in a three-step process (referred to as the Preiss-Handler pathway). Both reaction pathways require the activated form of ribose, 5-phosphoribosyl 1-pyrophosphate (PRPP). PRPP is the same activated ribose required for. Nicotinamide is converted to nicotinamide mononucleotide (NMN) in what is a salvage pathway utilizing nicotinamide phosphoribosyltransferase which is encoded by the NAMPT gene. The NAMPT gene is located on chromosome 7q22.3 and is composed of 12 exons that encode a 491 amino acid precursor protein.

Interestingly there was an activity that was identified at high levels in white that was purported to have insulin mimetic effects. This purported activity was originally called visfatin. The protein identified as visfatin was subsequently discovered to be encoded by the NAMPT gene. The level of NAMPT activity changes under different dietary states such as nutrient status, stress, and during exercise. Of clinical significance is the fact that NAMPT levels are reduced in obesity decreasing its role in stress responses. The NAMPT protein is found both intracellularly (identified as iNAMPT) and extracellularly (identified as eNAMPT). Among numerous functions, the activity of NAMPT is required for the regulation NAD+-dependent deacetylases of the sirtuin (SIRT) family. SIRT enzymes are critical in the regulation of gene expression through their ability to, thereby altering chromatin structure.

Following the synthesis of NMN, it is then converted to NAD through the action of the nicotinamide nucleotide adenylyltransferase (NMNAT) enzymes and ATP. Humans express three NMNAT genes identified as NMNAT1, NMNAT2, and NMNAT3. The NMNAT1 gene is located on chromosome 1p36.22 and is composed of 9 exons that generate three alternatively spliced mRNAs that collectively encode two distinct protein isoforms. The NMNAT1 encoded proteins are localized to the nucleus. The NMNAT2 gene is located on chromosome 1q25.3 and is composed of 13 exons that generate two alternatively spliced mRNAs both of which encode distinct protein isoforms. Expression of the NMNAT2 gene is predominantly localized to the brain. The NMNAT2 encoded proteins are found in the cytosol and in the Golgi. The NMNAT3 gene is located on chromosome 3q23 and is composed of 14 exons that generate seven alternatively spliced mRNAs collectively encode six different protein isoforms. The NMNAT3 encoded proteins are localized to the mitochondria. The distinct localization of the various NMNAT enzymes indicates that there are likely to be distinct pools of NAD in the different subcellular organelles and that these pools are independently regulated through the activity of a given NMNAT.

Nicotinic acid (NA) is converted to nicotinate mononucleotide (NAMN) via the action of nicotinate phosphoribosyltransferase encoded by the NAPRT gene. The NAPRT gene is located on chromosome 8q24.3 and is composed of 12 exons that generate two alternatively spliced mRNAs each encoding distinct isoforms of the enzyme. NAMN is then converted to nicotinate adenine dinucleotide (NAAD) by the action of the NMNAT enzymes. NAAD is then converted to NAD via the action of NAD synthetase (also called glutamine-dependent NAD synthetase) which is encoded by the NADSYN1 gene. The NADSYN1 gene is located on chromosome 11q13.4 and is composed of 21 exons that encode a 706 amino acid protein. NAD can be converted to NADP through the action of NAD kinase (NADK). The NADK gene is located on chromosome 1p36.33 and is composed of 19 exons that generate four alternatively spliced mRNAs that collectively generate three distinct isoforms of the enzyme.

Synthesis and salvage of NAD

Pathways of NAD synthesis and salvage.. The conversion of dietary niacin (nicotinic acid) and nicotinamide to bioactive NAD involves the biosynthesis pathway, whereas, resynthesis of NAD following it's consumption in various biological reactions, involves the salvage pathways. Dietary niacin (nicotinic acid: NA) is converted to NAD in a three-step reaction pathway as outlined in the text. Dietary nicotinamide (NAM), as well as NAM resulting from numerous ADP-ribosylation enzymes and SIRT family deacetylases, is converted/savaged to NAD via a two-step reaction pathway as outlined in the text. QPRT: quinolinic acid phosphoribosyltransferase; NAPRT: nicotinic acid phosphoribosyltransferase; NMNAT1: nicotinamide nucleotide adenylyltransferase 1; NADSYN1: NAD synthetase; NADK: NAD kinase; NMRK1: nicotinamide riboside kinase 1; NAMPT: nicotinamide phosphoribosyltransferase

Biological Functions of NAD and NADP

NAD functions as a cofactor for numerous dehydrogenases including the same critical thiamine-dependent enzymes described above [the,, and ] as well as and, for example. NADPH serves as a cofactor for numerous reductive biosynthetic processes including,,, and. In total NAD/NADP is required for over 500 enzymatic reactions and as such plays a critical role in the regulation of almost all major biological processes.

Outside the context of metabolic pathways that utilize NAD or NADP in red-ox reactions, NAD is required for a wide array of biological processes. There are two major cell signaling pathways that utilize NAD+ as a co-substrate. The and the are all NAD+-dependent enzymes that function in processes that include, inflammation, meiosis,,,,,, chromatin remodeling, the, and circadian rhythms. The major function of the SIRT proteins is the NAD+-dependent deacetylation of lysine residues in target proteins, particularly histone proteins. During the course of the deacetylation reaction NAM is released and salvaged for synthesis of NAD. The PARP family of enzymes is encoded by 17 different genes in humans. This family of NAD+-dependent enzymes includes both poly-ADP-ribose polymerases (encoded by the PARP1, 2, and 5 genes) and mono-ADP-ribose transferases (encoded by the PARP3, 4, 6, 10, and 14–16 genes). The reaction catalyzed by PARP enzymes is the cleavage of NAD+ with the subsequent transfer of ADP-ribose to aspartic acid, glutamic acid, and lysine residues on target proteins with the release of NAM. In addition to the PARP family of ADP-ribosylating enzymes, the encoded enzymes and the arginine-specific ecto-enzymes (ARTC) also possess ADP-ribosylating activity. The process of ADP-ribosylation is a reversible post-translational modification and it's presence in a protein is recognized by specific binding proteins termed ADP-ribose "readers".

NAD Degradation

NAD+ is degraded in cells primarily via the actions of two related glycohydrolases. These consumption reactions are distinct from the conversion of NAD+ to NADH or to NADP or the release of NAM in the context of the use of NAD+ by SIRT or PARP enzymes. The two glycohydrolases are encoded by the CD38 and BST1 (bone marrow stromal cell antigen 1) genes. Both of these enzymes convert NAD+ to nicotinamide (NAM) and adenosine diphosphoribose (ADPR). The NAM is then rapidly converted back to NAD through the salvage pathways described above. The CD38 gene is ubiquitously expressed and the encoded enzyme is the major NAD degrading enzyme in mammals. Expression of the BST1 gene is restricted to lymphoid cells and cells of the gut. As humans age the level of CD38 expression increases leading to a concurrent decline in cellular NAD+ levels. Another NAD+ cleaving enzyme is encoded by the SARM1 (sterile alpha and TIR motif containing 1) gene. Expression of SARM1 is enriched in neural tissues.

A diet deficient in niacin (as well as tryptophan) leads to glossitis of the tongue (inflammation of the tongue leading to purplish discoloration), dermatitis, weight loss, diarrhea, depression and dementia. The severe symptoms, depression, dermatitis and diarrhea (referred to as the "3-D's"), are associated with the condition known as pellagra. Several physiological conditions (e.g. and malignant carcinoid syndrome) as well as certain drug therapies (e.g. isoniazid) can lead to niacin deficiency. In Hartnup disorder, tryptophan absorption is impaired and in malignant carcinoid syndrome tryptophan metabolism is altered resulting in excess serotonin synthesis. Isoniazid (the hydrazide derivative of isonicotinic acid) was, at one time, a primary drug for chemotherapeutic treatment of tuberculosis.

Nicotinic acid (but not nicotinamide) when administered in pharmacological doses of 2–4 g/day lowers plasma cholesterol levels and has been shown to be a useful therapeutic for hypercholesterolemia. These effects of nicotinic acid are exerted by it binding to and activating the which was originally identifed as GPR109A. The major action of nicotinic acid in this capacity is a reduction in fatty acid mobilization from adipose tissue. The HCA2 receptor activates an associated Gi-type G-protein which inhibits the production of cAMP, thereby reducing the PKA-mediated phosphorylation and activation of hormone-sensitive lipase, HSL. Although nicotinic acid therapy lowers blood cholesterol it also causes a depletion of glycogen stores and fat reserves in skeletal and cardiac muscle. Additionally, there is an elevation in blood glucose and uric acid production. For these reasons nicotinic acid therapy is not recommended for diabetics or persons who suffer from. One of the side-effects of nicotinic acid therapy, that reduces patient compliance with its use, is cutaneous vasodilation resulting in a burning flush in the face and upper body. This negative effect of nicotinic acid is the result of the activation of HCA2 on macrophages.

Pantothenic Acid

Pantothenic acid is also known as vitamin B5. In humans pantothenic acid is synthesized by colonic bacteria from β-alanine and pantoic acid. The pantothenate is then absorbed from the intestine via the action of a Na+-dependent transporter that is also responsible for biotin absorption from the gut. This vitamin transporter is encoded by the gene. In the synthesis of coenzyme A from pantothenate there are five reaction steps. Pantothenate is phosphorylated on the hydroxyl group via the action of the pantothenate kinases forming 4'-phosphopantethenate. Humans express four pantothenate kinase genes identified as PANK1–PANK4. The PANK1 gene is regulated by the tumor suppressor,. In addition, an intronic gene resides within the PANK1 gene. The PANK1 gene is located on chromosome 10q23.31 and is composed of r12 exons that generate three alternatively spliced mRNAs each of which encode unique isoforms pof the enzyme. The PANK2 enzyme is the only one of the four enzymes to be expressed in the mitochondria. The PANK2 gene is located on chromosome 20p13 and is composed of 13 exons that generate six alternatively spliced mRNAs, three of which encode the same isoform of the enzyme, for a total of three distinct isoforms. Expression of the PANK3 gene is expressed at highest levels in the liver. The PANK3 gene is located on chromosome 5q34 and is composed of 7 exons that encode a 370 amino acid protein. The PANK4 gene is expressed at highest levels in skeletal muscle. The PANK4 gene is located on chromosome 1p36.32 and is composed of 21 exons that encode a 781 amino acid protein.

The reactive sulfhydryl group is added to the carboxylic acid end of 4'-phosphopantothenate from cysteine via the action of phosphopantothenoylcysteine synthetase which is encoded by the PPCS gene. The PPCS gene is located on chromosome 1p34.2 and is composed of 5 exons that generate eight alternatively spliced mRNAs that collectively encode four distinct isoforms of the enzyme. The product of the PPCS reaction is 4'-phosphopantetheine. 4'-Phosphopantetheine is converted to coenzyme A via the action of the bifunctional enzyme, coenzyme A synthase encoded by the COASY gene. The phosphopantetheine adenylyltransferase domain of COASY utilizes ATP to catalyze the conversion of 4'-phosphopantetheine into dephospho-coenzyme A. The dephospho-CoA kinase domain of COASY catalyzes the final step in CoA synthesis by adding the phosphate from ATP to the 2'-hydroxyl of the ribose from the adenine added in the previous reaction. The COASY gene is located on chromosome 17q21.2 and is composed of 9 exons that generate three alternatively spliced mRNAs, two of which encode the same enzyme isoform. The fully functional coenzyme A is shown in the Figure below.

Pantothenate is required for synthesis of coenzyme A (abbreviated CoA or CoASH) and is a component of the acyl carrier protein (ACP) domain of. Pantothenate is, therefore, required for the metabolism of carbohydrate via the TCA cycle and all fats and proteins. At least 70 enzymes have been identified as requiring CoA or ACP derivatives for their function including the same critical thiamine-dependent enzymes described above, the pyruvate dehydrogenase complex (PDHc), 2-oxoglutarate (α-ketoglutarate) dehydrogenase (OGDH), and branched-chain α-ketoacid dehydrogenase (BCKD).

Food source

Vitamin B5 content (mg)

Beef liver, 3.5 oz 5.3 Poultry, dark meat, 3.5 oz 1.3 Poultry, white meat, 3.5 oz 1.0 Salmon, 3.5 oz cooked 1.4 Low fat yogurt, 1 cup 1.5 Milk, nonfat, 1 cup 0.8 Bleu cheese, 1 oz 0.49 Cottage cheese, ½ cup 0.27 Corn, cooked, ½ cup 0.72 Potato, baked, one 0.7 Sweet potato, ½ cup 0.68 Broccoli, boiled, ½ cup 0.4 Wheat germ, raw, ¼ cup 1.2 Mushrooms, cooked, ½ cup 0.84 Peanuts, ½ cup 0.9 Avocado half 1.0 Sunflower seeds, ¼ cup 2.3 Dates, 10 0.65  Papaya, ½ cup 0.33  Strawberries, 1 cup 0.25  Orange juice, 1 cup 0.24 

Deficiency of pantothenic acid is extremely rare due to its widespread distribution in whole grain cereals, legumes and meat. Symptoms specific to pantothenate deficiency are difficult to assess since they are subtle and resemble those of other B vitamin deficiencies. These symptoms include painful and burning feet, skin abnormalities, retarded growth, dizzy spells, digestive disturbances, vomiting, restlessness, stomach stress, and muscle cramps.

Coenzyme A

Pyridoxal, pyridoxamine and pyridoxine are collectively known as vitamin B6. All three compounds are efficiently converted to the biologically active form of vitamin B6, pyridoxal phosphate (PLP). This conversion is catalyzed by the ATP requiring enzyme, pyridoxal kinase. Pyridoxal kinase requires zinc for full activity thus making it a metalloenzyme. Pyridoxal kinase is encoded by the PDXK gene which is located on chromosome 21q22.3 and is composed of 19 exons that generate two alternatively spliced mRNAs encoding isoform 1 (312 amino acids) and isoform 2 (272 amino acids). Any PLP consumed in the diet is acted upon by intestinal alkaline phosphatases that remove the phosphate. All three forms of vitamin B6 are then passively absorbed by intestinal enterocytes of the jejunum. Within intestinal enterocytes the three forms are re-phosphorylated to PLP and then delivered to the blood.

Pyridoxal Phosphate

Pyridoxal phosphate (PLP) functions as a cofactor in all of the enzymes that carry out the transamination reactions required for the synthesis and catabolism of the amino acids.  PLP is a cofactor for the synthesis of several neurotransmitters including, the catecholamines [critical enzyme is aromatic L-amino acid decarboxylase (AADC) which is encoded by the DDC gene and is more commonly referred to as DOPA decarboxylase], and (critical enzyme is glutamic acid decarboxylase, GAD). PLP is required for the via the enzyme catalyzing the initial and regulated step in this pathway, δ-aminolevulinic acid synthase (ALAS). PLP is a cofactor for two enzymes involved in methionine and cysteine metabolism, cystathionine β-synthase (CBS) and cystathionase (cystathionine γ-lyase). As indicated above, PLP is also required for the conversion of tryptophan to nicotinamide adenine dinucleotide (NAD). PLP is also required for as a cofactor for glycogen phosphorylase. This latter reaction is the only PLP-dependent process that is not associated with metabolism of nitrogen containing compounds (principally amino acids).

The requirement for vitamin B6 in the diet is proportional to the level of protein consumption ranging from 1.4–2.0 mg/day for a normal adult. During pregnancy and lactation the requirement for vitamin B6 increases approximately 0.6 mg/day.

Food source

Vitamin B6 content (mg)

Beef liver, 3.5 oz 1.4 Turkey, light meat, 3.5 oz 0.5 Chicken, light meat, 3.5 oz 0.63 Salmon, 3.5 oz cooked 0.65 Halibut, baked, 3.5 oz 0.4 Potatoes, 1 cup 0.48 Sweet potatoes, ½ cup 0.3 Oatmeal, 1 cup cooked 0.74 Rice, brown, cooked, 1 cup 0.28 Brussels sprouts, ½ cup 0.23 Lentils, ½ cup cooked 0.18 Carrots, ½ cup cooked 0.18 Peanuts, ½ cup 0.18 Sunflower seeds, ¼ cup 0.26 Avocado, 1 Haas 0.48 Mango 0.28 Watermelon, 1 cup 0.22 Cantelope, 1 cup 0.18 Prunes, 10 dried 0.22 Blackstrap molasses, 2 tbsp 0.29

Deficiencies of vitamin B6 are rare and usually are related to an overall deficiency of all the B-complex vitamins. Like the role of chronic alcohol consumption and an associated poor diet leading to thiamine deficiency, alcoholism is the leading cause of deficiency in B6. Isoniazid (see niacin deficiencies above) and penicillamine (used to treat rheumatoid arthritis and ) are two drugs that complex with pyridoxal and PLP resulting in a deficiency in this vitamin. Deficiencies in pyridoxal kinase result in reduced synthesis of PLP and are associated with seizure disorders related to a reduction in the synthesis of GABA. Due to its role in heme biosynthesis, deficiency in vitamin B6 can result in microcytic hypochromic anemias that are similar to those caused by iron deficiency or as a result of heavy metal (e.g. lead) poisoning. Two additional critical enzymes requiring PLP are cystathionine β-synthase (CBS) and cystathionine γ-lyase (cystathionase) which are involved in the. Due to the role of B6 in this latter reaction, deficiencies in the vitamin can lead to homocysteinemia/uria due to a resultant blockade in the CBS reaction (see the page for discussion of this effect). Other symptoms that may appear with deficiency in vitamin B6 include nervousness, insomnia, skin eruptions, loss of muscular control, anemia, mouth disorders, muscular weakness, dermatitis, arm and leg cramps, loss of hair, slow learning, and water retention.

Deficiency/Defect Characteristics B6 deficiency PLP required for the rate-limiting enzyme in heme biosynthesis: δ-aminolevulinic acid synthase (ALAS); deficiency results in loss of protoporphyrin IX synthesis, therefore, there will be a significant reduction in measureable ALAS product (δ-aminolevulinic acid, δ-ALA) and protoporphyrin in these patients; loss of heme production leads to hypochromic microcytic anemia; lack of protoporphyrin results in iron deposits on mitochondria in bone marrow erythroblasts resulting in the formation of ringed sideroblasts; loss of iron incorporation into protoporphyrin IX leads to increased serum and intracellular iron concentration; increase in intracellular iron results in increased translation of ferritin as a means to prevent iron toxicity Iron deficiency iron deficiency is the leading cause of microcytic anemia; loss of iron results in reduced production of heme, thus, the result is a hypochromic microcytic anemia; lack of heme production results in loss of feed-back inhibition of ALAS, therefore these patients will have an associated increase in measureable protoporphyrin; loss of iron intake means reduced iron in the serum and reduced intracellular iron, the latter resulting in reduced ferritin translation; loss of iron for incorporation into protoporphyrin IX results in spontaneous, non-enzymatic incorporation of Zn2+ forming Zn-protoporphyrin (ZPP), ZPP causes erythrocytes to fluoresce under ultraviolet illumination and is the basis of the ZPP test for iron deficiency or lead poisoning Heavy metal poisoning heavy metals, such as lead, inhibit several enzymes of heme biosynthesis and metabolism with the most significant toxic effects resulting from inhibition of ferrochelatase, the enzyme that incorporates iron into protoporphyrin IX generating heme; similar to B6 deficiency, lead poisoning leads to increased intracellular iron in bone marrow erythroblasts causing the formation of ringed sideroblasts; because there is no heme, the ALAS reaction is not inhibited, as in the case of iron deficiency, this results in increased production of δ-ALA and protoporphyrin; lack of iron incorporation into protoporphyrin results in increased serum and intracellular iron concentrations, with the latter leading to increased ferritin synthesis as in the case of iron-deficient anemia; loss of iron for incorporation into protoporphyrin IX results in spontaneous, non-enzymatic incorporation of Zn2+ forming ZPP; as in the case of iron-deficient anemia, the ZPP test is diagnostic for lead/heavy metal poisoning

Structure of biotin


Biotin is the cofactor required of enzymes that are involved in carboxylation, decarboxylation, or transcarboxylation reactions in prokaryotes and eukaryotes. Biotin is sometimes referred to as vitamin H. Biotin, produced by intestinal bacteria, as well as that found in the diet, is bound to lysine residues in protein forming a complex that is called biocytin. Removal of biotin from biocytin and recycling of biotin from human biotin-dependent enzymes requires the activity of the enzyme biotinidase. The biotinidase gene (gene symbol: BTD) is located on chromosome 3p25.1 and is composed of 4 exons that encode a 543 amino acid protein. The clinical significance of defects in the BTD gene are described below. When released from protein, or consumed in free form, biotin is absorbed from the lumen of the intestines through the action of the Na+-dependent vitamin transporter encoded by the gene. This is the same transporter involved in pantothenate () absorption.

In humans, the biotin-requiring enzymes include acetyl-CoA carboxylase (ACC: humans express two distinct ACC genes), pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), and 3-methylcrotonyl-CoA carboxylase (3MCC). The critically important biotin-requiring enzymes are ACC, PC, and PCC. All four of these enzymes are referred to as ABC enzymes because they require/utilize ATP, Biotin, and CO2. The biotin-dependent carboxylating enzymes in mammals are multifunctional and contain three distinct enzymatic activities that may be contained in a single protein or in different subunits of the multisubunit enzymes. These three enzymatic activities are the biotin carboxylase (BC), the carboxyltransferase (CT), and the biotin carboxyl carrier protein (BCCP) activities. The ACC enzymes are cytosolic enzymes with the ACC1 gene encoded protein catalyzing the rate-limiting step of. PC is a mitochondrial enzyme that catalyzes the critical first reaction in the pathway of. PCC is a mitochondrial enzyme that catalyzes reactions involved in the metabolism of several amino acids (valine, methionine, isoleucine, and threonine) as well as the with an odd number of carbon atoms. The role of PCC in the metabolism of these compounds is often referred to as the VOMIT pathway (Valine, Odd-chain fats, Methionine, Isoleucine, Threonine) for memorization purposes. 3MCC is a mitochondrial enzyme that catalyzes the fourth step in the catabolism of.

As discussed in detail in the page, humans express two forms of ACC (ACC1 and ACC2) both of which are multifunctional enzymes possessing all three biotin-dependent carboxylating activities.

Pyruvate carboxylase (PC) is also a multifunctional enzyme containing all three activities in a single polypeptide that form an α4 homotetrameric enzyme. The human PC gene is located on chromosome 11q13.2 and contains 32 exons that generate three alternatively spliced mRNAs. These mRNAs differ in the 5'-untranslated region (5'-UTR) but all three encode the same protein of 1178 amino acids.

Propionyl-CoA carboxylase (PCC) functions as a heterododecameric enzyme (subunit composition: α6β6) and the two different subunits are encoded by the PCCA and PCCB genes, respectively. The α-subunit possesses the BC and BCCP activities and the β-subunit possesses the CT activity. The PCCA gene is located on chromosome 13q32.3and is composed of 32 exons that generate eleven alternatively spliced mRNAs but only three of these mRNAs are known to encode the PCCα protein. The PCCB gene is located on 3q22.3 and is composed of 17 exons that generate two alternatively spliced mRNAs both of which encode distinct forms of the PCCβ protein.

3-Methylcrotonyl-CoA carboxylase (3MCC), like PCC, is also a heterododecameric enzyme (subunit composition: α6β6). Similar to the activities of PCC, the α-subunit possesses the BC and BCCP activities and the β-subunit possesses the CT activity.. The α-subunit of 3MCC is encoded by the MCCC1 gene and the β-subunit is encoded by the MCCC2 gene. The MCCC1 gene is located on chromosome 3q27.1 and is composed of 22 exons that generate three alternatively spliced mRNAs, two of which are known to encoded functional protein. MCCC1 isoform 1 is a precursor protein of 725 amino acids and isoform 2 is a precursor protein of 608 amino acids. The MCCC2 gene is located on chromosome 5q13.2 and is composed of 19 exons that generate two alternatively spliced mRNAs that encode MCCβ proteins of 563 and 525 amino acids.

Biotin is found in numerous foods and also is synthesized by intestinal bacteria. Some of the richest sources of biotin are swiss chard, tomatoes, romaine lettuce, and carrots. Additional sources include onions, cabbage, cucumber, cauliflower, mushrooms, peanuts, almonds, walnuts, oat meal, bananas, raspberries, strawberries, soy, egg yolk, and cow and goat milk.

Given that biotin is synthesized by intestinal bacteria deficiencies of the vitamin are rare. Deficiencies are generally seen only after long antibiotic therapies which deplete the intestinal microbiota or following excessive consumption of raw eggs. The latter is due to the affinity of the egg white protein, avidin, for biotin preventing intestinal absorption of the biotin. An important autosomal recessive inherited disorder that leads to biotin deficiency is biotinidase (BTD) deficiency. Profound biotinidase deficiency is characterized by mutations in the gene that result in enzyme activity that is less than 10% of the normal. Partial biotinidase deficiency is characterized by enzyme activity that is 10%–30% of normal. Profound biotinidase deficiency occurs with a frequency of 1 in 60,000 live births. Indeed, the frequency is high enough, and the resultant symptoms severe enough, that current neonatal disease testing includes analysis for defects in the activity of this enzyme. The most severe symptoms associated with biotin deficiency and profound biotinidase gene defects are the result of the accumulation of toxic metabolic intermediates. The symptoms of profound biotinidase deficiency include delayed development, seizures, hypotonia, respiratory difficulties, hearing and vision loss, ataxia, skin rashes, and alopecia. Patients with profound biotinidase deficiency are also highly susceptible the fungal infection, candidiasis. Symptoms associated with partial biotinidase deficiency can be similar to those of the profound deficiency form but often these symptoms do not appear as severe except during infections, illnesses, or stress.

Cobalamin is more commonly known as vitamin B12. Vitamin B12 is composed of a complex tetrapyrrol ring structure (corrin ring) and a cobalt ion in the center. Vitamin B12 (as the hydroxocobalamin form) is synthesized exclusively by microorganisms and is primarily found in the liver of animals bound to protein as methycobalamin or 5'-deoxyadenosylcobalamin. Bioavailable vitamin B12 is also present in cows milk and soybeans. The vitamin must be released from these binding proteins in order to be active and this release occurs in the stomach by the gastric protease, pepsin.

After being released, cobalamin is bound to an endogenous protein called haptocorrin (also known as transcobalamin I, which is encoded by the TCN1 gene). Haptocorrin is a glycoprotein that is produced by oral salivary glands in response to intake of food. The binding of hatocorrin to the cobalamin that is released by the action of pepsin, protects the vitamin while it transits through the stomach into the duodenum. Within the small intestine pancreatic trypsin hydrolyzes the haptocorrin-cobalamin complexes allowing binding of cobalamin to another protein called intrinsic factor, IF. Intrinsic factor is also called gastric intrinsic factor. Intrinsic factor is a heavily glycosylated protein that is homologous to haptocorrin. Intrinsic factor binds cobalamin only within the alkaline pH of the intestines. Haptocorrin and intrinsic factor are two of the three vitamin B12-binding proteins produced in humans. The third is transcobalamin II (encoded by the TCN2 gene; often called simply transcobalamin, TC) which is a plasma globulin that is the primary transport protein for vitamin B12 in the blood.

Intrinsic factor is a 50-kDa glycoprotein produced by the parietal cells of the stomach. Intrinsic factor is encoded by the GIF (gastric intrinsic factor) gene which is located on chromosome 11q12.1 and is composed of 9 exons that encode a 417 amino acid precursor protein. The secretion of intrinsic factor is stimulated by all three of the mechanisms that lead to gastric acid secretion: histamine, acetylcholine, and gastrin. Cobalamin, bound to intrinsic factor, can then bind to a receptor complex called cubilin present on the apical membranes of enterocytes in the distal ileum as well as on renal epithelial cells of the nephron in the kidney. The cubilin protein is encoded by the CUBN gene which is located on chromosome 10p13 and is composed of 71 exons that encode a 3623 amino acid precursor protein.

Interactions of the intrinsic factor-cobalamin complexes with cubilin requires Ca2+ ions. The cubilin protein is a peripheral membrane protein that lacks both transmembrane and cytoplasmic domains. Internalization of the cubilin bound intrinsic factor-cobalamin complex requires that cubilin be colocalized (anchored) with another transmembrane protein Two proteins have been shown to fulfill the role of cubilin anchoring proteins. One of these proteins was originally identified in the mutant mouse called amnionless. The human protein is called amnion-associated transmembrane protein and it is encoded by the AMN gene. The other cubilin anchoring protein is a member of the, specifically LRP2. The AMN protein is required for intestinal uptake of cubilin-intrinsic factor-cobalamin complexes, whereas LRP2 appears to have some role in the uptake of these complexes from the nephron. However, because the disease known as Donnai-Barrow syndrome, which results from inherited mutations in the LRP2 gene, is not associated with vitamin B12 deficiency, the interactions between cubilin and LRP2 is not required for overall vitamin B12 homeostasis. It is suggested that an additional cubilin anchoring protein may yet be identified. Upon intrinsic factor-cobalamin binding to cubilin, the complex is endocytosed. The intrinsic factor in the endocytosed complexes is degraded by lysosomal hydrolases and the cobalamin is released.

Within intestinal enterocytes cobalamin is bound to transcobalamin II (identified as TC-Cbl) for transfer from the apical side to the basolateral side of the cell. Free cobalamin is released from the intestinal enterocytes to the blood via TC-Cbl interaction with a basolateral membrane transporter that is a member of the family of transporters, specifically the ABCC1 transporter. Within the blood free cobalamin binds again to transcobalamin II. The transcobalamin II-cobalamin (TCN2-cobalamin) complexes are taken up, from the blood, by all cells via a plasma membrane transcobalamin receptor (TCBLR) encoded by the CD320 gene. The TCN2-cobalamin-TCBLR complex is internalized via endocytosis. Within the lysosome transcobalamin II is degraded and the free cobalamin is released so that it can be used as an enzyme co-factor within the cell. The release of free cobalamin from the lysosome requires the action of the lysosomal membrane protein identified as (LMBR1 domain containing 1, where LMBR1 refers to the protein identified as limb region 1 protein homolog).

Free within the cytoplasm of the cell cobalamin binds to the protein encoded by the gene [methylmalonic aciduria (cobalamin deficiency) cblC type, with homocystinuria]. The MMACHC encoded protein dealkylates both adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) and also decyanates cyanocobalamin (CN-Cbl). Within the cytosol cobalamin is converted to MeCbl within the context of the reaction as outlined below. Cobalamin is also transported into the mitochondria via the action of the protein encoded by the gene [methylmalonic aciduria (cobalamin deficiency) cblA type]. Within the mitochondrion cobalamin is converted to AdoCbl which is the co-enzyme form of vitamin B12 required by (see below). Conversion of cobalamin to AdoCbl is catalyzed by the protein encoded by the gene [methylmalonic aciduria (cobalamin deficiency) cblB type]. The MMAB encoded protein synthesizes AdoCbl from cobalamin [the cob(I)yrinic acid a,c-diamide form] in an ATP-dependent reaction. Deficiencies in all of the genes responsible for overall metabolism of cobalamin are associated with various forms of.

There are only two clinically significant reactions in the body that require vitamin B12 as a co-factor. During the catabolism of with an odd number of carbon atoms and the amino acids valine, isoleucine, methionine, and threonine the resultant propionyl-CoA is converted to succinyl-CoA for oxidation in the. The catabolism of these compounds into propionyl-CoA is often remembered by the mnemonic VOMIT pathway, where V is for valine, O is for odd number carbon atom fats, M is for methionine, I is for isoleucine, and T is for threonine. The last enzyme in this pathway, methylmalonyl-CoA mutase, requires vitamin B12 as a cofactor in the conversion of methylmalonyl-CoA to succinyl-CoA which then enters the TCA cycle. The 5'-deoxyadenosine derivative of cobalamin (adenosylcobalamin: AdoCbl) is required for this reaction. Methylmalonyl-CoA mutase is a mitochondrial enzyme and the synthesis of the required AdoCbl occurs within the mitochondria and is catalyzed by the MMAB encoded protein as described earlier. The second reaction requiring vitamin B12 catalyzes the conversion of homocysteine to methionine and is catalyzed by (also known as homocysteine methyltransferase). This reaction results in the transfer of the methyl group from N5-methyltetrahydrofolate (5-methylTHF) to hydroxocobalamin generating tetrahydrofolate (THF) and methylcobalamin (MeCbl) during the overall reaction process.

Structure of cobalamin, vitamin B12

Vitamin B12 (cobalamin)

The recommended daily intake (RDA) of vitamin B12 for adults is 2.4 micrograms (μg). Vitamin B12 is found primarily in animal products. Due to the lack of sufficient vitamin B12 in plant foods it is added to breakfast cereals and this serves as a good source of the vitamin for vegetarians. Two plant sources that are useful for obtaining vitamin B12 are alfalfa and comfrey (also written comfry). However, to ensure adequate intake vegans should use a vitamin B12 supplement that contains at least 5–10μg due to the low absorption rate of the vitamin in supplement form.

Food source

Vitamin B12 content (mcg: μg)

Beef liver, 3.5 oz 48 Rainbow trout, wild, 3.0 oz 5.4 Salmon, 3.0 oz 4.9 Beef, 3.0 oz 2.4 Tuna, white, 3.0 oz 1.0 Yogurt, plain, 1 cup 1.4 Fortified cereal, 100% RDA 6.0 Milk, 1 cup 0.9 Swiss cheese, 1 oz 0.9 Egg, 1 whole 0.6

The liver can store up 3-5 years worth of vitamin B12, hence deficiencies in this vitamin are rare. Pernicious anemia is a megaloblastic anemia resulting from vitamin B12 deficiency that develops as a result of a lack of intrinsic factor being released from stomach parietal cells leading to subsequent malabsorption of the vitamin. The major cause of the loss of intrinsic factor is an autoimmune destruction of the parietal cells that secrete it. Surgical removal of a part of the stomach can also result in loss of intrinsic factor resulting in pernicious anemia. In rare cases individuals inherit mutation in the GIF gene that encodes intrinsic factor resulting in pernicious anemia.

The pernicious anemias result from impaired DNA synthesis due to a block in. The block in nucleotide biosynthesis is a consequence of the effect of vitamin B12 on folate metabolism. When vitamin B12 is deficient essentially all of the folate becomes trapped as the N5-methylTHF (5-methylTHF; or simply methylTHF) derivative as a result of the loss of functional methionine synthase (also called homocysteine methyltransferase). This trapping prevents the synthesis of other THF derivatives required for the purine and thymidine nucleotide biosynthesis pathways.

Neurological complications also are associated with vitamin B12 deficiency and result from a progressive demyelination of nerve cells. The demyelination is thought to result from the increase in methylmalonyl-CoA that results from vitamin B12 deficiency that is associated with loss of methylmalonyl-CoA mutase activity. The loss of methylmalonyl-CoA mutase activity with deficiencies in B12 results in an accompanying. Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in fatty acid biosynthesis as well as being able to substitute for malonyl-CoA in any fatty acid biosynthesis that may occur. Since the myelin sheath that protects nerve cells is in continual flux the methylmalonyl-CoA-induced inhibition of fatty acid synthesis results in the eventual destruction of the sheath. The incorporation methylmalonyl-CoA into fatty acid biosynthesis results in branched-chain fatty acids being produced that may severely alter the architecture of the normal membrane structure of nerve cells.

Contributing to the neural degeneration seen in vitamin B12 deficiency is the reduced (SAM; also abbreviated AdoMet) due to loss of the methionine synthase catalyzed reaction. The requires the enzyme phosphatidylethanolamine N-methyltransferase (encoded by the PEMT gene) which carries out three successive SAM-dependent methylation reactions. This reaction is a critically important reaction of membrane lipid homeostasis. Therefore, the reduced capacity to carry out the methionine synthase reaction, due to nutritional or disease mediated deficiency of, results in reduced SAM production and as a consequence contributes to the neural degeneration (i.e. depression, peripheral neuropathy) seen in chronic B12 deficiency.

Deficiencies in B12 can also lead to elevations in the level of circulating homocysteine and elevated excretion of the oxidized dimer of homocysteine called homocystine. Elevated levels of homocysteine are known to lead to cardiovascular dysfunction. Due to its high reactivity to proteins, homocysteine is almost always bound to proteins, thus thiolating them leading to their degradation. Homocysteine also binds to albumin and hemoglobin in the blood. Some of the detrimental effects of homocysteine are due to its' binding to lysyl oxidase, an enzyme responsible for proper maturation of the proteins collagen and elastin. Production of defective collagen and elastin has a negative impact on arteries, bone, and skin and the effects on arteries are believed to be the underlying cause for cardiac dysfunction associated with elevated serum homocysteine. In individuals with homocysteine levels above ≈12μM there is an increased risk of thrombosis and cardiovascular disease. The increased risk for thrombotic episodes, such as deep vein thrombosis (DVT), associated with homocysteinemia is due to homocysteine serving as a contact activation nucleus for activation of the.

Structure of folic acid

Folic Acid: positions 7 and 8 carry hydrogens in dihydrofolate (DHF); positions 5–8 carry hydrogens in tetrahydrofolate (THF). Note the mono-glutamic acid residue N-esterified to the PABA end of the molecule.

Folic acid is sometimes referred to as vitamin B9. The terms folic acid and folate are sometimes used interchangeably but from a dietary perspective they are distinctly different. The term folate should be used to refer only to the bioactive forms of folic acid, namely dihydrofolate (DHF) and tetrahydrofolate (THF) and their derivatives. Folic acid is a conjugated molecule consisting of a pteridine ring structure linked to para-aminobenzoic acid (PABA) that forms pteroic acid. Pteroic acid is then converted to folic acid through the N-esterification of glutamic acid to the carboxylic acid of the PABA portion of pteroic acid. This latter structure is the form of "folate" present in dietary supplements and when used to fortify manufactured food products. Dietary folates (which are predominately the N5-methylTHF form; 5-methyl-THF) are obtained primarily from yeasts and leafy vegetables as well as animal liver. Humans cannot synthesize PABA nor attach glutamate residues to pteroic acid, thus, requiring folic acid or folates (DHF or THF) intake in the diet.

When ingested from natural sources, or when stored in cells (predominantly in the liver and the kidneys), folates exists in a polyglutamate form. Jejunal (small intestine) mucosal cells remove the glutamate residues to the monoglutamate state through the action of the enzyme, folate hydrolase 1 which is encoded by the FOLH1 gene. Folate hydrolase 1 is also commonly called glutamate carboxypeptidase II. Within the intestinal enterocytes, the monoglutamate forms of the folates are less negatively charged (compared to the polyglutamic acids), and are therefore, more capable of being transported across the basolateral membrane (facing the blood) of the jejunal enterocytes and into the bloodstream. Another enzyme, with similar activity, is called γ-glutamyl hydrolase (also known as conjugase or folate conjugase) and is encoded by the GGH gene. The function of the GGH encoded enzyme is to remove polyglutamates from intracellular stores of the folate derivatives that, as indicated, are predominantly stored in the liver and the kidneys. The GGH encoded enzyme is localized to the lysosomes. The function of the GGH encoded enzyme is to release glutamates from stored folates so that the monoglutamate forms can be excreted into the blood to meet systemic needs.

Folates in the diet are predominantly the N5-methyltetrahydrofolate (5-methyl-THF) form. Dietary folates are absorbed by jejunal enterocytes primarily via the encoded transporter which is a proton (H+)-coupled transporter more commonly referred to as the proton-coupled folate transporter, PCFT. Another folate transporter, that was originally thought to be the major intestinal folate uptake transporter, was originally identified as the reduced folate carrier (RFC). The RFC protein is encoded by the gene. Outside the intestine cellular folate uptake, particularly cells in the central nervous system, is carried out by the encoded transporter. The activity of RFC-mediated folate transport is highest for reduced folates (hence the name) such as 5-methyl-THF with very low affinity for folic acid. The RFC is also utilized in the uptake of the anti-folate drugs such as methotrexate and palatrexate. RFC functions as an antiporter with organic phosphate being transported out of the cell in exchange for folate uptake. Both PCFT and RFC are highly specific for the monoglutamate forms of the folates. The critical role of the SLC46A1 encoded transporter in intestinal folate absorption is evident in individuals with an inherited form of folate malnutrition (hereditary folate malabsorption, HFM) that results from mutations in the SLC46A1 gene. The SLC46A1 gene is located on chromosome 17q11.2 and is composed of 6 exons that generate two alternatively spliced mRNAs with the major apical membrane-localized protein being the larger isoform 1 (459 amino acids).

Interestingly there are transporters of the multidrug resistance family that can efflux folates from the intestinal enterocyte back into the lumen of the intestines. Both the multidrug resistance-associated protein 2 (MRP2; encoded by the ABCC2 gene) and the breast cancer resistance protein (BCRP; encoded by the ABCG2 gene) are expressed in the apical membranes of intestinal enterocytes. Both transporters have been shown to efflux folates from intestinal enterocytes and, as such, can compete with the activity of PCFT in folate uptake. Another member of the multidrug resistance protein family, multidrug resistance-associated protein 3 (MRP3; encoded by the ABCC3 gene), is expressed in the basolateral membrane of intestinal enterocytes and transports folic acid and 5-methyl-THF into the blood.

Another important protein involved in folate transport in the adult human is the FOLR1 (folate receptor 1) encoded receptor protein. The FOLR1 gene is located on chromosome 11q13.4 and is composed of 7 exons that generate four different mRNAs either through alternative promoter usage or by alternative splicing which all encode the same 257 amino acid precursor protein. The FOLR1 encoded protein binds folic acid and the reduced folate derivative (5-methyl-THF) facilitating their transport into cells. The FOLR1 protein exists in soluble form as well as bound to membranes via a GPI-linkage. The FOLR1 gene represents one member of a family of folate receptor genes that are clustered at the 11q13.4 locus. This family includes FOLR1, FOLR2, and FOLR3. The FOLR2 gene is referred to as the fetal folate receptor gene given it was originally identified as being expressed in the placenta. The FOLR2 protein is both secreted and GPI anchored like the FOLR1 protein. The FOLR3 gene is expressed in bone marrow, thymus, and spleen, and its expression is elevated in ovarian and uterine cancers. The FOLR3 protein is exclusively secreted.

When monoglutamate folates are taken up into cells, particularly in the liver and kidney where they can be stored (but also in other cells), they are polyglutamated through the action of the enzyme folylpolyglutamate synthetase. Folylpolyglutamate synthetase is encoded by the FPGS gene which is located on chromosome 9q34.11 and is composed of 17 exons that generate three alternatively spliced mRNAs, each of which encode a different isoform of the enzyme. The activity of folylpolyglutamate synthetase is lowest towards 5-methyl-THF and this prevents this form of the vitamin from being trapped within intestinal enterocytes. Folic acid, which is the form found in fortified foods and supplements is also a poor substrate for folylpolyglutamate synthetase accounting for its efficient uptake from the intestines and release to the blood.

Within cells (principally the liver where it is stored) folic acid found in enriched food and in vitamin supplements is converted first to dihydrofolate (DHF) and then to tetrahydrofolate (THF also H4folate) through the action of dihydrofolate reductase (DHFR), an NADPH-requiring enzyme. The level of DHFR activity in the human liver is relatively low such that high levels of folic acid intake (such as by megadosing vitamins) can lead to pathological consequences. Several studies have shown increased rates of colon cancer and prostate cancer associated with the intake of large doses of folic acid. However, the lack of folate in the diet, or the lack of folic acid supplementation, is directly correlated to neural tube defects occurring during fetal development.

The function of THF derivatives is to carry and transfer various forms of one carbon units during biosynthetic reactions. The one carbon units are either methyl, methylene, methenyl, formyl or formimino groups.

Active center of tetrahydrofolate (THF). Only the portion of the tetrahydrofolate (THF) molecule where the one-carbon entities are attached (the N5 and N10 positions) is shown in this Figure. Note that the N5 position (often just written as the 5-position) is the site of attachment of methyl groups, the N10 (often just written as the 10-position) the site for attachment of formyl and formimino groups and that both N5 and N10 bridge the methylene and methenyl groups. The formyl group can be attached to the N5 position but this does not represent a significant THF derivative in human metabolism.

Reactions of Folate Derivative Synthesis

There are two distinct pools of THF molecules, the active pool and the reduced pool. The reduced pool consists solely of N5-methyl-THF (5-methyl-THF) which is also the major form of folate absorbed from the small intestines as well as the major form circulating in the blood for transport to the various tissues. All of the other THF derivatives constitute the active pool. The active pool forms of THF can be converted to 5-methyl-THF but 5-methyl-THF cannot be used, in any significant capacity, tocontribute to the synthesis of the active pool folate derivatives.

N5,N10-methylene-THF (5,10-methylene-THF) is synthesized from THF and serine by the (SHMT1 and SHMT2).

The conversion of 5,10-methylene-THF to 5-methyl-THF is catalyzed by methylene THF reductase (encoded by the MTHFR gene). Mutations in the MTHFR gene results in a form of homocysteinemia referred to as.

The synthesis of N5-formimino-THF (5-formimino-THF) occurs during the and is catalyzed by formimidoyltransferase cyclodeaminase (encoded by the FTCD gene).

Synthesis of N10-formyl-THF (10-formyl-THF) can occur by two distinct pathways, both of which utilize the same multifunctional enzyme encoded by the MTHFD1 gene. The activities of the MTHFD1 encoded enzyme include: N5,N10-methenyl-THF (5,10-methenyl-THF) cyclohydrolase: 5,10-methylene-THF dehydrogenase: and 10-formyl-THF synthetase. In one pathway 5,10-methenyl-THF is converted to 10-formyl-THF and in the other pathway 10-formyl-THF is formed from ATP, formate, and THF.

The 5,10-methylene dehydrogenase activity of the MTHFD1 encoded enzyme converts 5,10-methylene-THF to 5,10-methenyl-THF.

Humans express additional genes that encode enzymes with activities similar the MTHFD1 encoded enzyme. The MTFHD2 gene encodes a bifunctional enzyme localized to the mitochondria. The MTHFD2 encoded enzyme is an NADP+-dependent enzyme that possesses 5,10-methylene-THF dehydrogenase and 5,10-methenyl-THF cyclohydrolase activities. Two additional genes, MTHFD1L and MTHFD2L encoded NADP+-dependent methylenetetrahydrofolate dehydrogenases.

One-Carbon Transfer Reactions

The one carbon transfer reactions involving the various THF derivatives are required in the biosynthesis of serine, methionine, glycine, choline, the purine nucleotides, and dTMP. Indeed, the interconversion of, via the involvement of THF, represents a major pathway for the generation of 5,10-methylene-THF which of a member of the active folate pool. The active folate pool includes 10-formyl-, 5,10-methenyl-, and 5,10-methylene-THF. Methyl-THF is referred to as the reduced folate pool. All of the active folate pool molecules can be converted to 5-methyl-THF but the reverse process does not occur. For this reason, the inability to convert 5-methyl-THF to THF (as occurs via the B12- and folate-dependent enzyme, ; also known as homocysteine methyltransferase) and then to any other THF derivative leads to trapping of folate in the "reduced" form. The ability to acquire choline and amino acids from the diet and to salvage the purine nucleotides makes the role of 5,10-methylene-THF, in, one of the most significant metabolic function for this vitamin. The role of vitamin B12 and 5-methyl-THF in the conversion of homocysteine to methionine also can have a significant impact on the ability of cells to regenerate needed active pool THF derivatives and as such represents the physiologically most significant reaction involving folate. Deficiencies in B12 or defects in methionine synthase will result in methyl-THF trapping with the result being the development of megaloblastic anemia due to the block in nucleotide production.

Folate RDA

The recommended daily allowance for folic acid is 400 micrograms (μg) for both men and women except that pregnant women should increase their intake to at least 600 μg/day. The best sources for folic acid are cereals that have been fortified with 100% of the RDA of folic acid. Beef liver (3 oz) contains 45% of the RDA of folic acid. Excellent vegetarian sources for folic acid are baked beans, raw spinach, asparagus, green peas, broccoli, lentils, turnip greens, egg noodles, avocado, peanuts, lettuce, wheat germ, tomato juice and orange juice.

Folate deficiency results in complications nearly identical to those described for vitamin B12 deficiency. The most pronounced effect of folate deficiency on cellular processes is upon DNA synthesis. This is due to an impairment in which leads to cell cycle arrest in S-phase of rapidly proliferating cells, in particular hematopoietic cells. The result is megaloblastic anemia as for vitamin B12 deficiency. The inability to synthesize DNA during erythrocyte maturation leads to abnormally large erythrocytes termed macrocytic (megaloblastic) anemia. Since both folate and vitamin B12 deficiencies result in megaloblastic anemias, it is necessary to be able to clinically distinguish the cause as it relates to vitamin deficiency. Since B12 is required for both the methionine synthase reaction and the methylmalonyl-CoA mutase reaction a megaloblastic anemia resulting from B12 deficiency is also associated with an accompanying, whereas megaloblastic anemias caused by folate deficiency are not. An additional critical diagnostic is related to the onset of symptoms. Because human cells cannot store any significant amount of folate but the liver can store 3-6 years worth of B12, folate deficient megaloblastic anemias manifest very quickly, whereas B12 deficient anemias take considerably longer to manifest.

Folate deficiencies are rare due to the adequate presence of folate in food. Poor dietary habits as those of chronic alcoholics can lead to folate deficiency. The predominant causes of folate deficiency in non-alcoholics are impaired absorption or metabolism or an increased demand for the vitamin. The predominant condition requiring an increase in the daily intake of folate is pregnancy. This is due to an increased number of rapidly proliferating cells present in the blood. The need for folate will nearly double by the third trimester of pregnancy. Certain drugs such as anticonvulsants and oral contraceptives can impair the absorption of folate. Anticonvulsants also increase the rate of folate metabolism.

Inherited Defects in Folate Metabolizing Enzymes

Mutations in the methylene THF reductase gene (MTHFR) are associated with a disorder referred to as hyperhomocysteinemia. Characteristic features of hyperhomocysteinemia are a high plasma homocysteine level and an associated early onset of coronary artery disease (CAD). Additional symptoms of hyperhomocysteinemia include mild cognitive impairment and the potential for dementia. Indeed, there is evidence that links elevated serum homocysteine levels with Alzheimer disease. The most common mutation in the MTHFR gene resulting in this disorder is a C to T change at nucleotide position 677 (C677T).

Deficiency/Defect Characteristics B12 deficiency B12 is required for the methionine synthase and methylmalonyl-CoA mutase catalyzed reactions; deficiency in this vitamin is associated with both homocysteinemia and megaloblastic (macrocytic) anemia; the megaloblastic anemia associated with B12 deficiency is the result of folate (as N5-methyl-THF) trapping at the methionine synthase reaction; homocysteinemia results from the resultant inhibition of the methionine synthase reaction which leads to increased production of homocysteine which cannot be adequately accommodated in the catabolic direction at the cystathionine β-synthase (CBS) reaction; because methionine synthase is inhibited there will be a reduction in measureable methionine in the blood and urine; the resultant homocysteinemia is associated with a significant increase in the risk for cardiovascular disease such as deep vein thrombosis (DVT) and atherosclerosis; both the homocysteinemia and the megaloblastic anemia that result from B12 deficiency will be accompanied by dramatic increases in measurable methylmalonic acid in the serum which is NOT seen in folate deficiency; because the liver can store B12 for up to 6 years it takes a considerable amount of time for a dietary (or other cause) deficiency in B12 to manifest Folate deficiency folate is also required for the methionine synthase reaction and, therefore, as for B12 deficiency, there will be both homocysteinemia and megaloblastic anemia with deficiency in this vitamin; in the case of folate deficiency, the megaloblastic anemia results from a direct loss of and ; folate deficiency is associated with reduction in measureable serum and urine methionine as for B12 deficiency; the resultant homocysteinemia results in a significant increase in the risk for cardiovascular disease such as DVT and atherosclerosis as for B12 deficiency; since there is no associated inhibition of the methylmalonyl-CoA mutase reaction, there is no associated methylmalonic acidemia with the folate deficiency-associated homocysteinemia and megaloblastic anemia; because the human body cannot store folate, and the active folate pool is very small, the onset of symptoms associated with folate deficiency is very rapid

Structure of ascorbic acid

Ascorbic Acid

Ascorbic acid is more commonly known as vitamin C. Ascorbic acid is derived from glucose via the uronic acid pathway, however, the enzyme L-gulono-γ-lactone oxidase responsible for the conversion of gulonolactone to ascorbic acid is absent in primates making ascorbic acid required in the diet. The gene encoding the enzyme (symbol: GULO) is present in the human genome but it lacks five of the twelve exons required to make a function protein. Therefore, the gene is considered a pseudogene and the designation for the gene in humans is GULOP.

The active form of vitamin C is ascorbic acid itself. The main function of ascorbate is as a reducing agent in a number of different reactions. Ascorbate is the cofactor for Cu+–dependent monooxygenases and Fe2+–dependent dioxygenases. Several critical enzymes that require ascorbate as a cofactor include the enzymes, the lysyl hydroxylases and the prolyl hydroxylases as well as the enzyme dopamine β-hydroxylase. Dietary ascorbate is also involved in non-heme iron absorption in the small intestine and in the overall regulation of iron homeostasis. In addition to its role in the regulation of the redox state of iron, ascorbate has the potential to reduce cytochromes a and c of the respiratory chain as well as molecular oxygen.

The most important reactions requiring ascorbate as a cofactor are the hydroxylations of lysine and proline residues in collagen. Vitamin C is, therefore, required for the maintenance of normal connective tissue as well as for wound healing since synthesis of connective tissue is the first event in wound tissue remodeling. Vitamin C also is necessary for bone remodeling due to the presence of collagen in the organic matrix of bones. Several other metabolic reactions require vitamin C as a cofactor. These include the catabolism of tyrosine, the synthesis of epinephrine from tyrosine (critical enzyme is dopamine β-hydroxylase), the synthesis of carnitine, peptide hormone amidation, and the synthesis of bile acids. It is also believed that vitamin C is involved in the process of steroidogenesis since the adrenal cortex contains high levels of vitamin C which are depleted upon adrenocorticotropic hormone (ACTH) stimulation of the gland.

Ascorbic acid also serves as a reducing agent and as an antioxidant. A critical anti-oxidant function of ascorbate is in the plasma membrane reduction of oxidized α-tocopherol (vitamin E). When functioning as an antioxidant, ascorbic acid itself becomes oxidized to semidehydroascorbate and then dehydroascorbate. Semidehydroascorbate is reconverted to ascorbate in the cytosol by cytochrome b5 reductase and thioredoxin reductase in reactions involving NADH and NADPH, respectively. Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH.

Ascorbate is found at highest concentrations within nucleated cells with the intracellular concentration being found on the order of 30-100 times the concentration found in the plasma. The uptake on ascorbate from the lumen of the small intestine as well as its transport into cells is the function of two Na+-dependent vitamin C co-transporters identified as SVCT1 and SVCT2. Expression of SVCT1 is predominantly in intestinal epithelial cells and renal tubular cells where the transporter is found in the apical plasma membrane. Expression of SVCT2 is found in almost all nucleated cells. Expression of the SVCT2 transporter in the brain is critical for normal brain function and for ascorbate homeostasis within the brain. Both SVCT1 and SVCT2 are members of the of solute carriers and as such the gene encoding SVCT1 is SLC23A1 and that encoding SVCT2 is SLC23A2. Although the SVCTs are the primary transporters for ascorbate, cells are also capable of ascorbate uptake via the activity of the facilitative, GLUT1, GLUT3, and GLUT4. Indeed, erythrocyte accumulation of ascorbate occurs primarily through the action of GLUT1.

The amount of vitamin C that is recommended to consume each day (the RDA) depends upon the age and sex of the individual. Infants less than 1 year old should get 50 milligrams (mg) per day. children 1–3 years old need 15mg, 4–8 years old need 25mg, and 9–13 years old need 45mg. Adolescent girls should get 65mg per day and adolescent boys should get 75mg per day. Adult males need 90mg per day and adult women should get 75mg per day. Women who are breastfeeding should increase their intake to at least 120mg per day. Individuals who smoke should increase their daily intake by at least 35mg since smoking depletes vitamin C levels. The recommended daily intake of vitamin C to prevent conditions such as the cardiovascular disorders indicated above is reported to be between 500mg and 1000mg.

Excellent sources of vitamin C are fruits and vegetables such as oranges, watermelon, papaya, grapefruit, cantaloupe, strawberries, raspberries, blueberries, cranberries, pineapple, kiwi, mango, green peppers, broccoli, turnip greens, spinach, red and green peppers, canned and fresh tomatoes, potatoes, Brussels sprouts, cauliflower, and cabbage. Citrus juices or juices fortified with vitamin C are also excellent sources of the vitamin.

Vitamin C is sensitive to light, air, and heat, so the most vitamin C is available in fruits and vegetables that are eaten raw or lightly cooked. Natural or synthetic vitamin C can be found in a variety of forms. Tablets, capsules, and chewables are probably the most popular forms, but vitamin C also comes in powdered crystalline, effervescent, and liquid forms. An esterified form of vitamin C is also available, which may be easier on the stomach for those who are prone to heartburn. The best way to take vitamin C supplements is 2–3 times per day, with meals, depending on the dosage.

Iron homeostasis is critical for cell survival. Indeed, iron-depletion rapidly results in cellular death. The details of dietary uptake and cellular storage and utilization of iron are presented in the page, thus, this discussion will be limited to the role of ascorbate in the overall processes. As a brief overview, the adult human body contains 3–5 grams of iron. Of this, greater than 80% is utilized by red blood cells and is found within the hemoglobin in these cells. The vast majority of the remainder, approximately 20% of the total, is transiently stored within the liver and macrophages, with the liver being the major storage location. When inside cells, the bulk of iron is stored bound within complexes of the protein ferritin. The remainder of the iron is in the heme of cytochromes, iron-sulfur center (ISC)-containing proteins, and in non-heme and non-ISC iron-containing proteins.

When contained in proteins, iron is involved in redox reactions that are one-electron transfers between its ferric (Fe3+) and ferrous (Fe2+) forms. These electron transfers involving iron are vital for cell survival, but must be limited to the context of reactions directed by specific enzymatic reactions. Iron that is not bound in a redox-inert form is capable of generating highly deleterious reactive oxygen species (ROS) via a reaction known as the Fenton reaction. The product of this process is primarily the hydroxy free radical, the most poisonous of all ROS. Thus, as might be expected, iron homeostasis is tightly controlled through processes that regulate its import, storage and cellular efflux. Ascorbate is an essential co-factor in the overall process of iron homeostasis. Ascorbate stimulates dietary iron absorption, contributes to plasma transferrin-bound iron uptake following binding of the transferrin-iron complexes to the plasma membrane transferrin receptor, stimulates the synthesis of the iron storage protein ferritin, inhibits lysosomal ferritin degradation, and inhibits cellular iron efflux.

The absorption of non-heme iron, from the lumen of the small intestine, requires that the dietary iron, which is predominantly in the oxidized state (Fe3+), be reduced to the ferrous (Fe2+) state. Ferrous iron is then taken up into intestinal enterocytes via the action of the divalent metal transporter 1 (DMT1) protein. There are at least three mechanisms known to exist that contribute to the process of dietary iron reduction, all of which involve ascorbic acid. The major mechanism for intestinal iron reduction involves a ferrireductase that is a member of the cytochrome b561 class of transmembrane redox enzymes. This intestinal ferrireductase is known as duodenal cytochrome b561 (DCYTB) which is encoded by the CYBRD1 (cytochrome b reductase 1) gene. During the process of DCYTB-mediated reduction of lumenal ferric iron, intracellular ascorbate is oxidized to an ascorbyl radical and then to dehydroascorbate. Ascorbic acid, as an ascorbyl radical within the lumen of the gut is also capable of reducing ferric iron to ferrous iron which can then be absorbed via DMT1. A third mechanism for intestinal ferric iron reduction involves ascorbic acid being oxidized to dehydroascorbate in the lumen of the intestine concomitant with reduction of ferric to ferrous iron. The resulting ferrous iron is absorbed by the enterocyte via DMT1 while the dehydroascorbate is transported into the enterocyte most likely via the action of GLUT1.

When stored within cells, iron is complexed with a heteromeric protein called ferritin. Ferritin, that stores iron is composed of 24 subunits, that include heavy ferritin (H-ferritin) and light ferritin (L-ferritin). When stored inside ferritin, the ferrous iron that was transported into the cell is oxidized back to the ferric state. The ferroxidase activity of ferritin is associated with H-ferritin. When ferritin stored iron is released it is reduced back to the ferrous state. This intracellular reduction process involves ascorbic acid. Ferrous iron can be transported into the circulation from intestina enterocytes and from hepatocytes which represent the major iron storage cells in the body. This transport involves the transmembrane transporter identified as ferroportin. Associated with ferroportin in the membrane of intestinal enterocytes is the ferroxidase called hepheastin which oxidizes the ferrous iron to the ferric state. When iron is transported from heptocytes to the blood via ferroportin action, the ferrous iron is oxidized by the major plasma copper-dependent ferroxidase, ceruloplasmin. The oxidation of ferrous iron to ferric is required for plasma transport as the major plasma iron transport protein, transferrin, only binds the ferric state iron. The iron bound to trasnferrin is taken up by most cells after binding of the transferrin-iron complexes to the plasma membrane transferrin receptor followed by endocytosis of the ligand-receptor complex. The internalization and release of iron and its reduction to the ferrous state within the cell involves intracellular ascorbic acid.

Deficiency in vitamin C leads to the disease scurvy due to the role of the vitamin in the post-translational modification of collagens. Scurvy is characterized by easily bruised skin, muscle fatigue, soft swollen gums, decreased wound healing and hemorrhaging, osteoporosis, and anemia. Due to its role in collagen processing, the bleeding dysfunction associated with vitamin C deficiency is characterized by the lack of effect on prothrombin time (PT) but with a prolonged bleeding time. The latter effect is the result of the reduced ability for platelets to adhere to exposed sub-endothelial extracellular matrix collagen which is required for their activation.

Vitamin C is readily absorbed and so the primary cause of vitamin C deficiency is poor diet and/or an increased requirement. The primary physiological state leading to an increased requirement for vitamin C is severe stress (or trauma). This is due to a rapid depletion in the adrenal stores of the vitamin. The reason for the decrease in adrenal vitamin C levels is unclear but may be due either to redistribution of the vitamin to areas that need it or an overall increased utilization.

Inefficient intake of vitamin C has also been associated with a number of conditions, such as high blood pressure, gallbladder disease, stroke, some cancers, and atherosclerosis (plaque in blood vessels that can lead to heart attack and stroke). Sufficient vitamin C in the diet may help reduce the risk of developing some of these conditions, however, the evidence that taking vitamin C supplements will help or prevent any of these conditions is still lacking.

Vitamin A consists of three biologically active molecules, retinol, retinal (retinaldehyde) and retinoic acid.

Structures of major forms of vitamin A

Structures of the major vitamin A compounds. The retinaldehyde forms of vitamin A are also commonly referred to as retinals. Both all-trans-retinaldehyde (all-trans-retinal) and 11-cis-retinaldehyde (11-cis-retinal) function in the process of vision. Retinoic acid is a major developmental regulating growth factor.

Each of these vitamin A compounds is derived from the plant precursor molecule, β-carotene (a member of a family of molecules known as carotenoids). Beta-carotene, which consists of two molecules of retinal linked at their aldehyde ends, is also referred to as the provitamin form of vitamin A. Additional provitamin A carotenoids are α-carotene and β-cryptoxanthin. Wheras β-carotene is a source of two moles of retinaldehyde (and thus two moles of retinol), α-carotene and β-cryptoxanthin provide only a single mole each of retinol. Thus, β-carotene represents the most potent provitamin A molecule. Humans also acquire vitamin A from animal-derived foods in the form of long-chain acyl esters of retinol

Dietary retinol from animal-derived foods is released from the fatty acid esters through the actions of pancreatic lipases and the retinol is then taken up into intestinal enterocytes. Within the intestinal enterocytes retinol is re-esterified to saturated fatty acids (principally palmitic acid) via the action of the enzyme known as lecithin:retinol acyltransferase (LRAT). The retinyl esters are then packaged into chylomicrons which, via the intestinal lymphatic system, are eventually delivered to the blood. Retinyl esters can also be transported from enterocytes into the portal circulation via the action of the. The ABCA1 transporter is also involved in the efflux of cholesterol from cells to.

Ingested β-carotene can be cleaved in the lumen of the intestine by either of two β-carotene oxygenases (β-carotene-15,15'-monooxygenases) encoded by the BCO1 and BCO2 genes to yield two molecules of retinaldehyde (retinal). Retinaldehyde is reduced to retinol by one of a family of enzymes called retinol dehydrogenases. The originally identified activity was called retinaldehyde reductase. Retinol dehydrogenases use NADPH as a cofactor in the reduction of retinaldehyde to retinol and use NAD+ as cofactor when oxidizing retinol to retinaldehyde. Humans express over 20 genes that encode proteins exhibiting all trans- or cis-retinol dehydrogenase activity. However, not all are involved in the conversion of retinaldehyde to retinol or the reverse reaction. The retinol dehydrogenases that have been shown to be involved in retinaldehyde and retinol interconversions are members of the short-chain dehydrogenase/reductase (SDR) superfamily of enzymes. Several members of the alcohol dehydrogenase family of enzymes can also interconvert retinaldehyde and retinol. Around 50% of ingested carotenoids are converted to retinol in this way within the lumen of the duodenum. The remainder of ingested carotenoids is transported into intestinal enterocytes through the action of the scavenger receptor identified as SR-BI. SR-BI is also the receptor, on the surface of hepatocytes, for. Beta-carotene taken up into enterocytes in this way is then cleaved into retinaldehyde through the action of the β-carotene oxygenase encoded by the BCO1 gene. The released retinaldehyde is then reduced to retinol via one of the retinol dehydrogenases. As indicated earlier, retinol within the enterocytes is esterified to saturated fatty acids and packaged into chylomicrons.

The uptake of chylomicron remnants by the liver results in delivery of retinol to this organ for storage as a lipid ester within lipid droplets in hepatocytes. Transport of retinol from the liver to extrahepatic tissues occurs by binding of hydrolyzed retinol to retinol binding proteins, RBPs. The predominant plasma carrier of hepatic retinol is retinol binding protein 4 (RBP4). The retinol-RBP4 complex is then transported to the cell surface within the Golgi and secreted. While in the vasculature, the RBP4-retinol complexes interact with the protein transthyretin which prevents loss of retinol via renal glomerular filtration. The uptake of retinol, from the blood, occurs in response to the binding of RBP4-retinol complexes to the plasma membrane receptor identified as STRA6 (stimulated by retinoic acid 6). When bound to STRA6 the retinol is removed from RBP4 and transported across the membrane into the cell. Within extrahepatic tissues retinol is bound, primarily, to one of two RBPs, identified as RBP1 and RBP2. Within the eye, the major retinol binding protein is RBP3.

Vitamin A is found in dark green and yellow vegetables and yellow fruits, such as broccoli, spinach, turnip greens, carrots, squash, sweet potatoes, pumpkin, cantaloupe, and apricots, and in animal sources such as liver, milk, butter, cheese, and whole eggs. When determining the amount of vitamin A to consumw each day the RDA is expressed as retinol activity equivalents (RAE).

Food source

Vitamin A content (mcg: μg RAE)

Organ meats, cooked, 3 oz 1490–9126 Sweet potato with peel (1 medium), baked 1096 Carrots, cooked from fresh, ½ cup 671 Spinach, cooked from frozen, ½ cup 573 Kale, cooked from frozen, ½ cup 478 Beet greens, cooked, ½ cup 276 Dandelion greens, cooked, ½ cup 260 Cantaloupe, raw, ¼ medium melon 233 Mustard greens, cooked, ½ cup 221 Red sweet pepper, cooked, ½ cup 186 Chinese cabbage, cooked, ½ cup 180

Retinol is converted to retinaldehyde via the action of two classes of oxidizing enzymes, cytoplasmic and microsomal. The cytoplasmic enzymes are alcohol dehydrogenases (ADHs) of the medium-chain dehydrogenase/reductase (MDR) family. The microsomal enzymes are retinol dehydrogenases (RDHs) of the short-chain dehydrogenase/reductase (SDR) family. Conversion of retinaldehyde to retinoic acid is catalyzed by a family of retinaldehyde dehydrogenases (RALDHs) that are members of the aldehyde dehydrogenase 1 family of enzymes. The retinoic acid producing enzymes are RALDH1 (gene symbol: ALDH1A1), RALDH2 (gene symbol: ALDH1A2), and RALDH3 (gene symbol: ALDH1A3). All three RALDHs are expressed in tissue specific and developmental stage specific patterns. The degradation of retinoic acid is catalyzed by enzymes of the, specifically CYP26A1, CYP26B1, and CYP26C1.

Within cells retinoic acid (as well as the related compound 9-cis-retinoic acid) binds to specific receptor proteins that are members of the of lipid hormone receptors. Prior to interaction with retinoic acid, the receptor protein is bound to retinoic acid response elements (RARE) in retinoic acid responsive genes. Following binding, the receptor-retinoic acid complex alters the transcriptional activity of the associated genes. Retinoic acid responsive genes are involved in growth and differentiation pathways during embryogenesis that control organogenesis, cranio-facial development, central nervous system patterning and axial patterning. In this capacity retinoic acid is considered a hormone of the steroid/thyroid hormone superfamily. The retinoic acid receptors are abbreviated RAR and the related retinoid X receptors (RXRs) bind 9-cis-retinoic acid. Several genes, whose patterns of expression are altered by retinoic acid, are involved in the earliest processes of embryogenesis including the differentiation of the three germ layers, organogenesis and limb development. Within the adult retinoic acid is involved in processes of reproduction, immunity, memory, and learning. To date, there are more than 530 genes that have been shown to be directly regulated (either positive or negative) via interaction with retinoic acid bound RAR or RXR. The canonical retinoic acid response element (RARE) in retinoic acid target genes is the direct repeat 5'–PuG(G/T)(T/A)CA–3' separated by a spacer of five nucleotides. This response element is referred to as the DR5 element.

Photoreception in the eye is the function of two specialized neuron types located in the retina; the rod and cone cells. The rod cells are utilized only for seeing at night During the day rod cells continuously release the excitatory neurotransmitter glutamate. The released glutamate binds to the synaptic membranes of specialized cells called bipolar cells. The glutamate receptor on bipolar cells is the mGluR6 metabotropic receptor. For more information on the glutamate receptors go to the page. Activation of bipolar cells induces them to release the inhibitory neurotransmitter, GABA. Release of GABA, thus leads to inhibition of the optic nerve.

Both rod and cone cells contain a photoreceptor pigment in their membranes. The photosensitive compound of most mammalian eyes is a protein called opsin to which is covalently coupled an aldehyde of vitamin A. The opsin of rod cells is called scotopsin. The photoreceptor of rod cells is specifically called rhodopsin or visual purple. This compound is a complex between scotopsin and the 11-cis-retinal (also called 11-cis-retinene) form of vitamin A. Rhodopsin is a G-protein coupled receptor (GPCR) embedded in the membrane of the discs inside the outer segment of rod cells. Coupling of 11-cis-retinal occurs at three of the transmembrane domains of rhodopsin. Intracellularly, rhodopsin is coupled to a specific G-protein called transducin. The specific Gα-subunit of transduction is identified as Gαt.

Vitamin A and visual signaling in rod cells: When the rhodopsin is exposed to light, the associated 11-cis-retinal is converted to all-trans-retinal, a process referred to as photobleaching. The conformational change in retinal converts rhodopsin to metarhodopsin II. The change to metarhodopsin II in turn activates the associated G-protein, tranducin. Activated transducin exhibits an increased GTP-binding by the α-subunit. Binding of GTP releases the α-subunit from the inhibitory βγ subunits. The GTP-activated α-subunit in turn activates an associated cGMP phosphodiesterase (PDE); an enzyme that hydrolyzes cyclic-GMP (cGMP) to GMP. This PDE is specifically identified as. Cyclic GMP is required to maintain a cyclic nucleotide gated (CNG) in the open conformation. The rod cGMP-gated ion channel is a heterotetramer consisting of three α subunits and one β subunit (α3β). These subunits are encoded by the CNGA1 and CNGB1 genes, respectively. The CNG ion channel, when opened via cGMP interaction, transports both Na+ and Ca2+ ions into the rod cell maintaining the cell in a state of depolarization. The CNG ion channel is tightly associated with a member of the Na+/Ca2+–K+ exchanger (NCKX) family of transporters encoded by the family of genes. The rod cell NCKX transporter (NCKX1) is encoded by the SCL24A1 gene and is associated with the CNGA1/CNGA2 heterotetramer as a homodimer. The primary function of the NCKX1 transporter is to ensure ionic balance in the rod cell in the dark state by transporting one Ca2+ ion and one K+ ion out of the rod cell in exchange for four Na+ ions transported into the cell. The reciprocal Ca2+ and Na+ transport via NCKX1 is referred to as the dark current and resets the rod cell following photon activation. In the dark, the continuous influx of Ca2+ through the CNG ion channel allows the rod cell to release glutamate which then binds to its receptor (mGluR6) on the bipolar cell activating the bipolar cell to release GABA which in turn inhibits the activity of the optic nerve. The PDE6B-mediated drop in cGMP concentration results in closure of the CNGA1/CNGA2 channel resulting in reduced uptake of Ca2+ ion. Since Ca2+ ions are required for the release of glutamate from rod cell pre-synaptic vesicles, the release of glutamate is inhibited. The loss of glutamate release results in less activation of the mGluR6 receptor on bipolar cells with the consequences that these cells are no longer depolarized by glutamate binding. The release of the inhibitory neurotransmitter, GABA, by the bipolar cells requires the glutamate-mediated depolarization. Therefore, in the absence of glutamate stimulation the bipolar cell no longer releases GABA. The net result is that the optic nerve become disinhibited enabling visual signaling under low light conditions.

Vitamin A is stored in the liver and deficiency of the vitamin occurs only after prolonged lack of dietary intake. As a fat soluble vitamin any lipid absorption disorder can be associated with deficiency in the vitamin. Patients with cystic fibrosis are particularly prone to deficiencies in the fat soluble vitamins due to defective pancreatic enzyme secretion and function. The earliest symptoms of vitamin A deficiency are night blindness. Additional early symptoms include follicular hyperkeratinosis, increased susceptibility to infection and cancer and anemia equivalent to iron deficient anemia. Prolonged lack of vitamin A leads to deterioration of the eye tissue through progressive keratinization of the cornea, a condition known as xerophthalmia.

The increased risk of cancer in vitamin deficiency is thought to be the result of a depletion in β-carotene. Beta-carotene is a very effective antioxidant and is suspected to reduce the risk of cancers known to be initiated by the production of free radicals. Of particular interest is the potential benefit of increased β-carotene intake to reduce the risk of lung cancer in smokers. However, caution needs to be taken when increasing the intake of any of the lipid soluble vitamins. Excess accumulation of vitamin A in the liver can lead to toxicity which manifests as bone pain, hepatosplenomegaly, nausea and diarrhea.

Biologically active vitamin D is a member of the steroid and thyroid hormone superfamily of lipophilic hormones. Vitamin D functions to regulate specific gene expression following interaction with its intracellular receptor, the vitamin D receptor (VDR). The VDR is a member of the steroid and thyroid hormone superfamily of. The hormonally active form of vitamin D is 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3, also called 1,25-dihydroxycholecalciferol or more commonly calcitriol). Calcitriol functions primarily to regulate calcium and phosphorous homeostasis. The transcriptional activity of the VDR is regulated not only by binding calcitriol but via the formation of heterodimers with the other nuclear receptors, specifically members of the RXR family. At sufficient concentration calcidiol, an intermediate in calcitriol synthesis, can also activate the VDR.

Structures of major forms of vitamin D

Structures of the major vitamin D compounds. Ergosterol is the plant-derived precursor to vitamin D2, whereas, 7-dehydrocholesterol is the naturally produced precursor to vitamin D3.

Active calcitriol is derived from ergosterol (produced in plants) and from 7-dehydrocholesterol which is an intermediate in the that accumulates in the skin. Upon exposure to ultraviolet B wavelength light (UVB: 280nm–315nm) from the sun (or from UVA wavelength light from tanning beds), 7-dehydrocholesterol is non-enzymatically (thermal isomerization) converted first to pre-vitamin D3 and then to vitamin D3. Ergocalciferol (vitamin D2) is formed by UVB irradiation of ergosterol. Both vitamin D2 and D3 enter the bloodstream and are taken up by the liver. Within the liver vitamins D2 and D3 undergo the first of two activating hydroxylation reactions. Vitamin D2 and D3, obtained from the diet (e.g. from fortified milk), are processed to D2-calcitriol and D3-calcitriol, respectively, by the same enzymatic pathways in the body as those that convert 7-dehydrocholesterol and ergosterol to their respective calcitriol forms.

Dietary vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) are absorbed from the intestine and transported to the liver bound to a specific vitamin D-binding protein which is a glycosylated α-globulin encoded by the GC gene (originally called group-specific component globulin). In the liver cholecalciferols are hydroxylated at the 25 position by a specific vitamin D 25-hydroxylase generating 25-hydroxy-D3 [25-(OH)D3: more commonly called calcidiol]. The vitamin D 25-hydroxylase enzyme is a microsomal membrane localized enzyme encoded by the CYP2R1 (cytochrome P450 2R1) gene. The CYP2R1 gene is located on chromosome 11p15.2 and is composed of 9 exons that encode a 501 amino acid protein. Conversion of cholecalciferols to calcidiol is dependent solely upon substrate availability as there is no regulatory mechanism to control the formation of calcidiol. Calcidiol is the major form of vitamin D found in the circulation and is transported in the blood bound to the vitamin D-binding protein. Calcidiol is absorbed from the blood by numerous cells of the body with the cells being the most significant for the biological activity of vitamin D.

Conversion of calcidiol to its biologically active form, calcitriol, occurs through the activity of a specific 25-hydroxyvitamin D3 1-α-hydroxylase (commonly just called 1-α-hydroxylase) present in the inner mitochondrial membrane of cells of the proximal convoluted tubules of the kidneys, and in several extrarenal sites such as in keratinocytes, macrophages, and placenta. All of the regulation in the formation of biologically active vitamin D occurs at the reaction catalyzing the synthesis of calcitriol from calcidiol. The 25-hydroxyvitamin D3 1-α-hydroxylase enzyme is encoded by the CYP27B1 (cytochrome P450 27B1) gene. The CYP27B1 gene is located on chromosome 12q14.1 and is composed of 9 exons that encode a 508 amino acid protein. Calcidiol can also be hydroxylated at the 24 position by a specific vitamin D3-24-hydroxylase (encoded by the CYP24A1 gene) in the kidneys, intestine, placenta and cartilage.

Structures of the major hormonal forms of vitamin D

Structures of 25-hydroxyitamin D3 and 1,25-dihydroxyvitamin D3. Formation of 25-hydroxyvitamin D3 occurs within the liver. Coversion of 25-hydroxyvitamin D3 to the hormonally active compound, calcitriol (1,25-dihydroxyvitamin D3 occurs within the kidneys.

The primary functions of calcitriol are exerted in concert with and involve the regulation whole body calcium and phosphorous homeostasis. PTH is released from the parathyroid gland in response to low serum calcium and induces the production of calcitriol by activating the expression of the renal CYP27B1 gene. Circulating calcium levels activate the calcium sensing receptor (CaSR) present in the parathyroid gland. Activation of the CaSR, when there are normal levels of serum calcium, results in increased proteolysis of PTH resulting in little secretion. However, in conditions of hypocalcemia, parathyroid gland PTH is stable and secreted into the circulation. When there are reduced levels of PTH in the circulation the CYP24A1 gene is active leading to the stimulated synthesis of the inactive 24,25-(OH)2D3.

When PTH levels rise in the blood the hormone binds to its receptor on the surface of cells. There are two PTH receptors identified as PTH-1 and PTH-2. Within the kidney the PTH receptor is the PTH-1 isoform. When PTH-1 is activated by PTH binding there is enhanced synthesis and activity of the 25-hydroxyvitamin D3 1-α-hydroxylase enzyme. Activation of the 25-hydroxyvitamin D3 1-α-hydroxylase enzyme results in increased synthesis of calcitriol which is then released into the blood.

When taken up by cells, calcitriol functions as a steroid hormone inducing the expression of calcium-binding proteins called that facilitate calcium transport within cells. The original calcitriol induced calcium-binding protein was identified in chicken duodenal tissues and was later called calbindin-D28K. In humans, and other mammals, the intestinal calcitriol-induced gene is the S100G (also known as CALB3) gene which encodes calbindin-D9K. In humans, calbindin-D28K is encoded by the CALB1 gene which is expressed in the and is responsible for participating in renal Ca2+ reabsorption. Like avian intestinal calbindin-D28K, mammalian intestinal calbindin-D9K binds the absorbed calcium at the apical membrane and transports it across the cell to the basolateral membrane where it can be transported into the blood. In addition to activating expression of the S100G (CALB3) gene in the intestine, calcitriol also enhances the expression of several intestinal calcium transporter genes including the (encoding the transient receptor potential vanilloid 6 transporter), the (encoding the Na+-Ca2+ exchanger; NCX1), and the (encoding the plasma membrane Ca2+ transporter 1b; PCMA1b). As indicated above, the steroid hormone action of vitamin D occurs via the action of calcitriol binding to a specific intracellular receptor that is a member of the of hormone receptors called the vitamin D receptor (VDR).

The overall effects of calcitriol on intestinal calcium absorption are of several different modes. This is due to the fact that intestinal calcium absorption occurs via both paracellular (between cells) and transcellular (through cells) mechanisms. Intestinal concentrations of calclium are much higher in the lumen than in the enterocyte which establishes a gradient favoring passive transcellular movement of calcium. Transcellular calcium movement from the apical membrane to the basolateral involves the calmodulin-actin-myosin complex I. When the intracellular concentration of calcium rises this transport process is less favorable since the calcium gradient is reduced. The transcellular transport of intestinal calcium under these conditions is enhanced by calcitriol activating the expression of the genes just described.

The paracellular transport of intestinal calcium is indirectly influenced by calcitriol activating which phosphorylates tight junction proteins making them more permeable to calcium. The increased absorption of calcium ions requires concomitant absorption of a negatively charged counter ion to maintain electrical neutrality. The predominant counter ion is inorganic phosphate (Pi) which is also taken up from the intestine by both paracellular and transcellular mechanisms. When plasma ionized calcium (Ca2+) levels fall the levels of PTH and calcitriol rise and their major sites of action are bone, where they stimulate bone reabsorption, and the kidneys where they inhibit calcium excretion by stimulating reabsorption at the and the.

Intestinal phosphate ion uptake from the lumen is the function of the SLC34A2 gene encoded transporter identified as NPT2b (Na+-phosphate cotransporter 2b). Hormonally active vitamin D also plays a role in intestinal phosphate uptake through calcitriol regulation of the expression of the SLC34A2 gene. Within the kidneys calcitriol increases phosphate reabsorption in the which counters the effects of PTH. Due to the fact that changes in calcitriol levels alter plasma calcium and PTH levels it is not clear what the exact mode of action is for calcitriol relative to renal phosphate retention.

Due to the critical role of vitamin D in the development of growing bone as well as the maintenance of healthy bone it has been added to milk since the 1930's. In the US all milk is fortified with 100 IU/cup. Fatty fishes such as salmon, sardines and tuna are also an excellent source of vitamin D. Cod liver oil is also very high in vitamin D. For vegetarians and vegans ultraviolet (uv) light irradiated mushrooms and yeast are the only sources of vitamin D that are not animal in origin. The irradiation of yeasts and mushrooms produces vitamin D2. Vitamin D content is listed as the amount in International Units (IU).

Food source

Vitamin D content (IU)

Cod liver oil, 1Tbs (15ml) 1360 Salmon, cooked, 3.5 oz 447 Sardines, canned in oil, 1.75 oz 250 Tuna, canned in water, 3 oz 154 Egg, 1 large 41 Swiss cheese 6

Although calcitriol is a major hormone involved in, primarily, calcium and phosphorous homeostasis the VDR is found widely distributed in numerous different cells throughout the body. Many of the tissues that express the VDR gene have no role in calcium and phosphate homeostasis. Therefore, the presence of the VDR in these tissues indicates that calcitriol has functions in more cellular processes or that there are ligands other than calcitriol that can bind to and activate the VDR. Indeed, there are a large number of humans genes that possess vitamin D-response elements (VDRE) that can bind the VDR and, therefore be responsive to calcitriol. Calcitriol is, thus, capable of being involved in the processes such as the regulation of cell proliferation, cell differentiation, and apoptosis. Several lines of evidence demonstrate that calcitriol exerts immunomodulatory and anti-proliferative effects and these effects have been hypothesized to demonstrate a role for calcitriol as a potential preventative or therapeutic chronic auto-immune conditions such as.

Vitamin D Deficiency

As a result of the addition of vitamin D to milk, deficiencies in this vitamin are rare in most developed countries. As a fat soluble vitamin, any lipid absorption disorder can be associated with deficiency in the vitamin. Patients with cystic fibrosis are particularly prone to deficiencies in the fat soluble vitamins due to defective pancreatic enzyme secretion and function. The main symptom of vitamin D deficiency in children is rickets and in adults is osteomalacia. Rickets is characterized by improper mineralization during the development of the bones resulting in soft bones. Osteomalacia is characterized by demineralization of previously formed bone leading to increased softness and susceptibility to fracture. The resultant decrease in Ca2+ uptake due to vitamin D deficiency leads to hypocalcemia leading to excess parathyroid hormone release (referred to as secondary hyperparathyroidism) as a compensatory mechanism. The excess release of can lead to over resorption of renal calcium leading to hypercalcemia. This hypercalcemia can cause calcification in soft tissues and peritrabecular fibrosis in bones. The peritrabecular fibrosis, associated with hyperparathyroidism, is quite distinct and is clinically called osteitis fibrosa cystica (OFC). OFC is also called von Recklinghausen disease of bone. This latter name is distinct from von Recklinghausen disease which is.

Vitamin D Toxicity

Although vitamin D is critical to the regulation of calcium and phosphorous homeostasis it is possible to consume too much of the vitamin which results in vitamin D toxicity. Although supraphysiological dosing of vitamin D [considered to be any dose above 50,000 IU (2,500μg) per day for a duration of at least 1 month; normal adult RDA for vitmain D is 600 IU/day], and the associated toxicities are rare, it is a valid consideration in the context of the diagnosis of the causes of hypercalcemia. Both vitamin D2 and D3 (the cholecalciferols) are lipophilic and are rapidly taken up into skeletal muscle and adipose tissue where they can remain for several months. Given that the cholecalciferols are converted to calcidiol in the liver based solely on substrate availability, calcidiol will also accumulate under conditions of excess vitamin D intake. Calcidiol is also lipophilic and can be stored within adipose tissue for several months. Due to the storage of cholecalciferols and calcidiol in adipose tissue, vitamin D intoxication can take several weeks to resolve.

In the event of excessive vitamin D intake there is a very characteristic toxicity profile. The excess vitamin results in an associated hypercalcemia. The hypercalcemia caused by vitamin D toxicity is primarily due to the significant increases in circulating levels of calcidiol which when it enters cells can bind to and activate the VDR. In addition, at high concentrations calcidiol can displace calcitriol from vitamin D binding protein resulting in increased free calcitriol that can then activate the VDR. Both of these pathophysiological phenomena result in increased intestinal calcium absorption and increased bone calcium resorption. The resultant hypercalcemia can lead to pathologies that are similar to those caused by the hypercalcemia that results from the secondary hyperparathyroidism in the context of vitamin D deficiency. One of the earliest tissues affected by the onset of the soft tissue calcification with vitamin D toxicity is the kidney. The symptoms that result from the damage to the renal tissue include polydipsia and polyuria. Additional symptoms of vitamin D toxicity include fatigue, nausea, vomiting, and diminished mental capacity. Chronic vitamin D toxicity can lead calcification of numerous soft tissues and may ultimately result in permanent renal failure.

Structure of the tocopherols

Structures of the four tocopherols. The biologically active forms of vitamin E constitute a family of four related compounds called tocopherols. The most abundant tocopherol in non-hepatic tissues in humans is the α-tocopherol form.

Vitamin E is a mixture of several related compounds known as tocopherols and tocotrienols. The tocopherols are the major sources of vitamin E in the U.S. diet. The tocopherols differ by the number and position of methyl (–CH3–) groups present on the ring system of the chemical structure. The different tocopherols are designated α-, β-, γ-, and δ-tocopherol. Most vitamin E in U.S. diets is in the form of γ-tocopherol from soybean, canola, corn, and other vegetable oils. All four tocopherols are able to act as free radical scavengers thus they all have potent antioxidant properties. Vitamin E is absorbed from the intestines packaged in chylomicrons. It is delivered to the tissues via chylomicron transport and then to the liver through chylomicron remnant uptake. The liver can export vitamin E in very low density lipoproteins (VLDLs). Within the liver α-tocopherol transfer protein preferentially transfers α-tocopherol to VLDLs, thus α-tocopherol is the most abundant tocopherol in nonhepatic (liver) tissues. Due to its lipophilic nature, vitamin E accumulates in cellular membranes, fat deposits and other circulating lipoproteins. The major site of vitamin E storage is in adipose tissue.

The major function of vitamin E is to act as a natural antioxidant by scavenging free radicals and molecular oxygen. In particular vitamin E is important for preventing peroxidation of polyunsaturated membrane fatty acids. The vitamins E and C are interrelated in their antioxidant capabilities. Active α-tocopherol can be regenerated by interaction with vitamin C following scavenge of a peroxy free radical. Alternatively, α-tocopherol can scavenge two peroxy free radicals and then be conjugated to glucuronate for excretion in the bile.

Although α-tocopherol is the most abundant tocopherol in tissues outside of the liver, it is not the most potent antioxidant form of the vitamin. Because of the unmethylated carbons in the ring structure of γ- and δ-tocopherol, these two forms of vitamin E are much more active at trapping free radicals, in particular reactive nitrogen species. In addition, research has recently shown that the anticancer effects of vitamin E are due to the γ- and δ-tocopherol forms and is not associated with α-tocopherol.

Recommended daily intake amounts for vitamin E (as α-tocopherol) are listed in milligram (mg) amounts and also in International Units (IU). To convert from mg to IU: 1 mg of α-tocopherol is equivalent to 1.49 IU of the natural form or 2.22 IU of the synthetic form. Nuts, seeds, and vegetable oils are among the best sources of α-tocopherol, and significant amounts are available in green leafy vegetables and fortified cereals. Most vitamin E in US diets is in the form of γ-tocopherol from soybean, canola, corn, and other vegetable oils.

Food source

Vitamin E content (mg)

Wheat germ oil, 1 tablespoon 20.3 Almonds, dry roasted, 1 ounce 7.4 Sunflower oil, 1 tablespoon 5.6 Safflower oil, 1 tablespoon 4.6 Peanut butter, 2 tablespoons 2.9 Peanuts, dry roasted, 1 ounce 2.2 Corn oil, 1 tablespoon 1.9 Broccoli, chopped, boiled, ½ cup 1.2 Soybean oil, 1 tablespoon 1.1 Kiwifruit, 1 medium 1.1 Spinach, raw, 1 cup 0.6

Due to adequate vitamin E intake in the average American diet, no major deficiency syndromes are common. However, conditions that result from vitamin E deficiency are related to disturbances in nerve cell membrane lipid homeostasis. These conditions include cerebellar ataxias, myopathies, retinopathy, loss of deep tendon reflexes, and dysarthria (speech problem associated with difficulty articulating due to defects in the motor component of speech). Another major symptom of vitamin E deficiency in humans is an increase in red blood cell fragility due to the increased level of erythrocyte membrane lipid peroxidation in the absence of tocopherols. Since vitamin E is absorbed from the intestines in chylomicrons, any fat absorption disorder can lead to deficiencies in vitamin E intake. Patients with cystic fibrosis are particularly prone to deficiencies in the fat soluble vitamins due to the defective pancreatic enzyme secretion and function. Increased intake of vitamin E is recommended in premature infants fed formulas that are low in the vitamin as well as in persons consuming a diet high in polyunsaturated fatty acids. Polyunsaturated fatty acids tend to form free radicals upon exposure to oxygen and this may lead to an increased risk of certain cancers.

The K vitamins exist naturally as K1 (phylloquinone) in green vegetables and K2 (menaquinone) produced by intestinal bacteria and K3 is synthetic menadione. When administered, vitamin K3 is alkylated to one of the vitamin K2 forms of menaquinone.

Structures of vitamin K molecules

Structures of the three major vitamin K molecules. The biologically active forms of vitamin K constitute a family of three related compounds, two of which are naturally produced (K1 and K2) and one of which is manufactured as a food additive (K3). The "n" after the isoprene structure in vitamin K2 represents the fact that 6, 7, or 9 isoprene groups are found in the most commonly derived forms of the vitamin.

The major function of the K vitamins is in the maintenance of normal levels of the proteins, factors II, VII, IX, X and protein C and protein S, which are synthesized in the liver as inactive precursor proteins. Conversion from inactive to active clotting factor requires a of specific glutamate (E) residues. This modification is a carboxylation and the enzyme responsible requires vitamin K as a cofactor. The resultant modified E residues are γ-carboxyglutamate (gla). This process is most clearly understood for factor II, also called preprothrombin. Prothrombin is modified preprothrombin. The gla residues are effective calcium ion chelators. Upon chelation of calcium, prothrombin interacts with phospholipids in membranes and is proteolysed to thrombin through the action of activated factor X (Xa).

During the carboxylation reaction reduced hydroquinone form of vitamin K is converted to a 2,3-epoxide form. The regeneration of the hydroquinone form requires the action of the enzyme vitamin K epoxide reductase (VKORC1) which involves a two-step reaction. These latter reactions are the site of action of the coumarin based anticoagulants such as warfarin (trade name: Coumadin®).

Incorporation of a gla-residue into prothrombin: The incorporation of a gla-residue into a protein such as prothrombin requires the hydroquinone (KH2) form of vitamin K (either K1, K2, or synthetic K3). The utilization and regeneration of the KH2 form in the overall process of the γ-glutamyl carboxylase (GGCX) reaction is referred to as the vitamin K cycle. Either following the carboxylation, or directly from dietary quinone forms of vitamin K, the action of vitamin K epoxide reductase (VKORC1) is to provide a continuous source of the KH2 form. An addition enzyme, vitamin K quinone reductase (VKQR) can catalyze the conversion of the quinone form to the hydroquinone form using NADH as a cofactor.

In the average U.S. diet, meats and eggs are the most common food sources of the menaquinone form of vitamin K. Excellent sources of vitamin K include spinach, Brussels sprouts, Swiss chard, green beans, asparagus, broccoli, kale, mustard greens, green peas and carrots. Fermentation of foods can increase their vitamin K content. Fermented soy foods play a unique role in supplying vitamin K in certain traditional cuisines (like that of Japan). Sometimes you will see the word "natto" being used to refer to these fermented soy foods since Bacillus natto are bacteria that can convert vitamin K1 into K2 and are often used in the production of fermented soy products. Some cheeses are also fermented in a way that optimizes their vitamin K content.

Naturally occurring vitamin K is absorbed from the intestines only in the presence of bile salts and other lipids through interaction with chylomicrons. Therefore, fat absorption disorders can result in vitamin K deficiency. Patients with cystic fibrosis are particularly prone to deficiencies in the fat soluble vitamins due to defective pancreatic enzyme secretion and function. The synthetic vitamin K3 is water soluble and absorbed irrespective of the presence of intestinal lipids and bile. Since the vitamin K2 form is synthesized by intestinal bacteria, deficiency of the vitamin in adults is rare. However, long term antibiotic treatment can lead to deficiency in adults. The intestine of newborn infants is sterile, therefore, vitamin K deficiency in infants is possible if lacking from the early diet. The primary symptom of a deficiency in infants is a hemorrhagic syndrome. Since vitamin K is critical for the generation of gla residues in clotting factors, as described above, deficiency in this vitamin results in dysfunction in the processes of blood coagulation. Since the defect will be at the level of factors II, VII, IX, X and protein C and protein S, the effects of vitamin K deficiency can be seen in the context of the. Whereas, vitamin C deficiency is associated with bleeding dysfunction at the level of platelet adhesion to collagen and is, therefore, measurable with an associated increase in bleeding time, vitamin K deficiency has no effect on bleeding time.

Alpha-lipoic acid, LA, (chemical name: 1,2-dithiolane-3-pentanoic acid; also known as thioctic acid), is a naturally occurring dithiol compound synthesized enzymatically in the mitochondrion from the medium-chain fatty acid octanoic acid. Because LA can be synthesized in the body it is not technically considered a vitamin but because of its vital role in overall cellular metabolism it is considered as an important, but not necessary,  dietary supplement. Lipoic acid has one chiral center and therefore exists in both R- and S-enantiomeric forms (see the Figure below). However, only R-LA is conjugated to conserved lysine residues in an amide linkage (forming a lipoamide), thus making this isoform essential as a cofactor in biological systems. Enzymes containing lipoamide are typically mitochondrial multi-enzyme complexes that catalyze the oxidative decarboxylation of α-keto acids such as the (PDHc), (also known as α-ketoglutarate dehydrogenase), and (BCKD), and the (GCC).

Given that LA is a necessary cofactor for mitochondrial α-ketoacid dehydrogenases, it thus serves a critical role in mitochondrial energy metabolism. In addition to de novo synthesis, LA is also absorbed intact from dietary sources, and it transiently accumulates in many tissues. LA has been described as a potent biological antioxidant, a detoxification agent, and a diabetes medicine. LA has been used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits, and has been implicated as a modulator of various inflammatory signaling pathways. Accumulating evidence indicates that LA, supplied as a supplement in the diet, may not be used as a metabolic cofactor but instead, elicits a unique set of biochemical activities with potential therapeutic value against a host of pathophysiological insults.

Structure of α-Lipoic Acid

Lipoic acid, either as a dietary supplement or a therapeutic agent, modulates distinct redox circuits because of its ability to equilibrate between different subcellular compartments as well as extracellularly. Because of its role in regulating redox states, LA is a critical component of the antioxidant network. It is important in the regeneration of other antioxidants, such as vitamins E and C, it increases the intracellular levels of glutathione (GSH), and provides redox regulation of numerous proteins and transcription factors. The extracellular thiol/disulfide red-ox environment (determined by the interconversion between cysteine and cystine) is able to modulate cell proliferation,,, and proinflammatory signaling. Lipoic acid may play an important role in the modulation of the extracellular red-ox state via the involvement of dihydrolipoic acid (DHLA) in the reduction of cystine to cysteine. This reduction facilitates a rapid uptake of the cysteine into the cell making it available to stimulate GSH synthesis. Cellular uptake of LA has been shown to occur via several systems including the medium chain fatty acid transporter, a Na+-dependent vitamin transport system, and a H+-linked monocarboxylate transporter for intestinal uptake. The cellular reduction of LA to DHLA is accomplished by NAD(P)H-driven enzymes, thioredoxin reductase, lipoamide dehydrogenase, and glutathione reductase.

Interconversions of α-lipoic acid (LA) and dihydrolipoic acid (DHLA)

Lipoic acid is an essential cofactor for the E2 component of α-ketoacid dehydrogenase complexes that are exclusively located in mitochondria. These complexes include the pyruvate dehydrogenase complex (PDHc), 2-oxoglutarate (α-ketoglutarate) dehydrogenase (OGDH), and branched chain α-ketoacid dehydrogenase (BCKD) complexes. The PDHc catalyzes the oxidative carboxylation of pyruvate which serves as the entry point for carbohydrates into the as acetyl-CoA. OGDH catalyzes the conversion of 2-oxoglutarate (α-ketoglutarate) to succinyl-CoA in the TCA cycle. Evidence demonstrates that the activities of both PDH and OGDH are substantially decreased during aging and in neurodegenerative disorders.

Extensive evidence suggests that LA may have therapeutic usefulness in lowering blood glucose levels in diabetic conditions and that the intracellular redox status plays a role in the modulation of insulin resistance. Lipoic acid has been shown to stimulate glucose uptake by affecting components of the. The signaling networks of insulin receptor activation include the insulin receptor substrates (IRS1, IRS2, and IRS4),, and PKB/AKT. There are three members of the PKB/AKT family of serine/threonine kinases identified as AKT1 (PKB, also PKBα), AKT2 (PKBβ), and AKT3 (PKBγ). Insulin-mediated activation of PI3K and PKB/AKT is necessary for the translocation of GLUT4 from an intracellular pool to the plasma membrane to allow for uptake of plasma glucose. Lipoic acid has been shown to augment tyrosine phosphorylation and the activity of components of insulin signaling including the insulin receptor, IRS1, PI3K, PKB/AKT, and p38MAPK. In addition, LA stimulated glucose uptake upon translocation and regulation of the intrinsic activity of GLUT4, an effect that is likely mediated by p38 MAPK. R-LA, as well as oxidized isoforms have been shown to stimulate glucose transport in differentiated 3T3-L1 adipocytes by a mechanism entailing changes in the intracellular redox status. These effects of LA are in agreement with an alteration of the thiol reactivity of redox components of the insulin signaling pathway caused by a thiol/disulfide exchange mechanism.

The stress-activated MAPK and JNK pathways play a central role in the progression of insulin resistance and diabetic neuropathies. The activation of these kinases results in the phosphorylation of IRS1 on serine 307 resulting in inhibition of the insulin-stimulated tyrosine phosphorylation of IRS1 leading to inhibition of insulin signaling. Lipoic acid has been shown to inhibit the JNK pathway and IRS1 serine phosphorylation, resulting in improved insulin sensitivity. The precise mechanism by which LA inhibits the JNK pathway remains unclear. Nevertheless, these effects place LA at the cross-road of insulin- and JNK signaling favoring glucose uptake and metabolism, thus ameliorating insulin resistance and improving the status of.

Click the following link to open a PDF file containing the recommended daily intake values for various vitamins and minerals:

Michael W King, PhD | © 1996–2018, LLC | info @

Last modified: October 18, 2018

Related News

Dramatic eye makeup photos
Patriots team photo 2018
Mengunggah foto di twitter
Veronica dela cruz photos
Color photo laser printer
Sangeeta ghosh hot photos