Vitamins: Important Dietary Constituents and Supplements

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Introduction to Vitamins and Minerals

What are vitamins?

Vitamins are organic molecules that function in a wide variety of capacities within the body. The most prominent function of the vitamins is to serve as cofactors (co-enzymes) for enzymatic reactions that serve to utilize the energy in the food we eat. For details on the structures of the vitamins please visit The Medical Biochemistry Page.

What exactly defines something as a vitamin?











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.

The minerals 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.

Water Soluble Vitamins Fat Soluble Vitamins
Thiamin (B1)
B1 Deficiency and Disease

Riboflavin (B2)
B2 Deficiency and Disease

Niacin (B3)
B3 Deficiency and Disease
Pantothenic Acid (B5)
Pyridoxal, Pyridoxamine, Pyridoxine (B6)
B6 Deficiency and Disease
B6 Deficiency and Related Anemias
Clinical Significance of Biotin
Cobalamin (B12)
B12 Deficiency and Disease

Folic Acid
Folate Deficiency and Disease

Ascorbic Acid
Vitamin A
Role of Vitamin A in Vision
Clinical Significances of Vitamin A

Vitamin D
Clinical Significances of Vitamin D

Vitamin E
Clinical Significances of Vitamin E

Vitamin K
Clinical Significance of Vitamin K


RDA Values for Vitamins and Minerals

Thiamin: Vitamin B1

Thiamin is derived from a substituted pyrimidine and a thiazole which are coupled by a methylene bridge. Thiamin is rapidly converted to its active form, thiamin pyrophosphate, TPP, in the brain and liver by a specific enzyme, thiamin diphosphotransferase. TPP is necessary as a cofactor for the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase catalyzed reactions which are required for the generation of energy from the metabolism of carbohydrates and fatty acids. TPP is also required for the transketolase catalyzed reactions of the pentose phosphate pathway which is required for metabolism of some dietary sugars but is most important in the production of an intermediate sugar  (ribose) used for the synthesis of the nucleotides which are the building blocks of DNA and RNA.

A deficiency in thiamin intake leads to a severely reduced capacity of cells to generate energy as a result of its role in these reactions. The dietary requirement for thiamin 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  thiamin intake will be required.

Where do I get vitamin B1?

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

Thiamin 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
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Clinical Significances of B1 Deficiency

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 are 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.

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Riboflavin: Vitamin B2

Riboflavin is the precursor for the coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). 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 enzymes are involved in a wide range of redox reactions, e.g. succinate dehydrogenase and xanthine oxidase. 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.

Where do I get vitamin B2?

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
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Clinical Significances of B2 Deficiency

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 hyperbilirubinemia by phototherapy requiring dietary supplementation in these infants.

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Niacin: Vitamin B3

Nicotinic acid and nicotinamide constitute the dietary forms of vitamin B3. Niacin is required for the synthesis of the active forms of vitamin B3, nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+). Both NAD+ and NADP+ function as cofactors for numerous dehydrogenases, e.g., lactate dehydrogenase and malate dehydrogenase.

Niacin is not a true vitamin in the strictest definition since it can be derived from the amino acid tryptophan. However, the ability to utilize tryptophan for niacin synthesis is inefficient (60 mg of tryptophan are required to synthesize 1 mg of niacin). Also, synthesis of niacin 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).

Where do I get vitamin B3?

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
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Clinical Significances of Vitamin B3

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. Hartnup disorder and malignant carcinoid syndrome) as well as certain drug therapies (e.g. isoniazid whicxh was commonly used to treat tuberculosis) 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. The major action of nicotinic acid in this capacity is a reduction in fatty acid mobilization from adipose tissue. 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 gout.

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Pantothenic Acid: Vitamin B5

Pantothenic acid is formed from β-alanine and pantoic acid. Pantothenate is required for synthesis of coenzyme A (CoA) and is a component of the acyl carrier protein (ACP) domain of fatty acid synthase. 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.

The normal dietary intake for adults is 4–7 mg/day. 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.

Where do I get vitamin B5?

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 
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Vitamin B6

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 phosphate functions as a cofactor in enzymes involved in transamination reactions required for the synthesis and catabolism of the amino acids as well as in breakdown of glycogen as a cofactor for glycogen phosphorylase. Glycogen is a polymeric compound that is used as the reservoir of glucose with the primary tissues of storage being the the liver and  skeletal muscle. PLP is also a co-factor for the synthesis of the inhibitory neurotransmitter γ(gamma)-aminobutyric acid (GABA).

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. Although vitamin B6 is water soluble, consuming megadoses may be toxic. Symptoms of toxicity are mainly neurological and include weakness and numbness and tingling of peripheral nerves. These symptoms are thought to be related to excess levels of PLP, which inhibits GABA synthesis by negative feedback inhibition.

Deficiencies of vitamin B6 are rare and usually are related to an overall deficiency of all the B-complex vitamins. Isoniazid (see niacin deficiencies above) and penicillamine (used to treat rheumatoid arthritis and cystinurias) 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. 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.

Where do I get vitamin B6?

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
Avacado, 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 tbls 0.29 
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B6 Deficiency and Disease

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 cystinurias) 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 metabolism of methionine to cysteine. 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 The Medical Biochemistry 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.

Differential Diagnosis: Several Causes of Microcytic Anemia

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 poisoning

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Biotin is the cofactor required of enzymes that are involved in carboxylation reactions, e.g. acetyl-CoA carboxylase and pyruvate carboxylase. Biotin is found in numerous foods and also is synthesized by intestinal bacteria and as such deficiencies of the vitamin are rare. Deficiencies are generally seen only after long antibiotic therapies which deplete the intestinal fauna 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. Symptoms that may appear if biotin is deficient are extreme exhaustion, drowsiness, muscle pain, loss of appetite, depression, and grayish skin color.

Where do I get biotin?

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.

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Clinical Significance of Biotin

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 fauna 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.

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Cobalamin: Vitamin B12

Vitamin B12 is composed of a complex tetrapyrrol ring structure (corrin ring) and a cobalt ion in the center. Vitamin B12 is synthesized exclusively by microorganisms and is found in the liver of animals bound to protein as methycobalamin or 5'-deoxyadenosylcobalamin. The vitamin must be hydrolyzed from protein in order to be active. Hydrolysis occurs in the stomach by gastric acids or the intestines by trypsin digestion following consumption of animal meat. The vitamin is then bound by intrinsic factor, a protein secreted by parietal cells of the stomach, and carried to the ileum where it is absorbed. Following absorption the vitamin is transported to the liver in the blood bound to transcobalamin II.

There are only two clinically significant reactions in the body that require vitamin B12 as a cofactor. During the catabolism of fatty acids with an odd number of carbon atoms and the amino acids valine, isoleucine and threonine the resultant propionyl-CoA is converted to succinyl-CoA for oxidation in the TCA cycle. One of the enzymes in this pathway, methylmalonyl-CoA mutase, requires vitamin B12 as a cofactor in the conversion of methylmalonyl-CoA to succinyl-CoA. The 5'-deoxyadenosine derivative of cobalamin is required for this reaction.

The second reaction requiring vitamin B12 catalyzes the conversion of homocysteine to methionine and is catalyzed by methionine synthase. This reaction results in the transfer of the methyl group from N5-methyltetrahydrofolate to hydroxycobalamin generating tetrahydrofolate (THF) and methylcobalamin during the process of the conversion. The significance of this latter reaction are described below in the Clinical Significances of B12.

Where do I get vitamin B12?

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
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Clinical Significances of B12 Deficiency

The liver can store up to six 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 a lack of intrinsic factor in the stomach leading to malabsorption of the vitamin. The anemia results from impaired DNA synthesis due to a block in the biosynthesis of the building blocks used to make DNA. 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 derivative as a result of the loss of functional methionine synthase. 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 result from vitamin B12 deficiency. 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 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.

Deficiencies in B12 can also lead to elevations in the level of circulating homocysteine. 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. The detrimental effects of homocysteine are thought to be due to its' binding to lysyl oxidase, an enzyme responsible for proper maturation of the extracellular matrix (the glue that holds cells together to form tissues) 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 blood clots and cardiovascular disease.

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Folic Acid (Folate)

Folic acid is a conjugated molecule consisting of a pteridine ring structure linked to para-aminobenzoic acid (PABA) that forms pteroic acid. Folic acid itself is then generated through the conjugation of glutamic acid residues to pteroic acid. Folic acid is obtained primarily from yeasts and leafy vegetables as well as animal liver. Animal cannot synthesize PABA nor attach glutamate residues to pteroic acid, thus, requiring folate intake in the diet.

When stored in the liver or ingested folic acid exists in a polyglutamate form. Intestinal mucosal cells remove some of the glutamate residues through the action of the lysosomal enzyme, conjugase. The removal of glutamate residues makes folate less negatively charged (from the polyglutamic acids) and therefore more capable of passing through the basal lamenal membrane of the epithelial cells of the intestine and into the bloodstream. Folic acid is reduced within cells (principally the liver where it is stored) to tetrahydrofolate (THF also H4folate) through the action of dihydrofolate reductase (DHFR), an NADPH-requiring enzyme.

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.

These one carbon transfer reactions are required in the biosynthesis of serine, methionine, glycine, choline and the purine nucleotides and dTMP.

The ability to acquire choline and amino acids from the diet and to salvage the purine nucleotides makes the role of N5,N10-methylene-THF in dTMP synthesis the most metabolically significant function for this vitamin. The role of vitamin B12 and N5-methyl-THF in the conversion of homocysteine to methionine also can have a significant impact on the ability of cells to regenerate needed THF.

Where do I get folate? 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.

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Clinical Significances of Folate Deficiency

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 the synthesis of a critical building block (thymidine nucleotides) of DNA 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 (red blood cells) maturation leads to abnormally large erythrocytes termed macrocytic anemia.

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.

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Ascorbic Acid: Vitamin C

The active form of vitamin C is ascorbate acid itself. The main function of ascorbate is as a reducing agent in a number of different reactions. Vitamin C has the potential to reduce cytochromes a and c of the respiratory chain (oxidative phosphorylation: the pathway for ATP synthesis) as well as molecular oxygen. The most important reaction requiring ascorbate as a cofactor is the hydroxylation of 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 and the synthesis of epinephrine from tyrosine and the synthesis of the 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.

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. 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.

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.

Where do I get vitamin C? 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.

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Vitamin A

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 compounds are 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.

Ingested β-carotene is cleaved in the lumen of the intestine by β-carotene dioxygenase to yield retinal. Retinal is reduced to retinol by retinaldehyde reductase, an NADPH requiring enzyme within the intestines. Retinol is esterified to palmitic acid and delivered to the blood via chylomicrons. The uptake of chylomicron remnants by the liver results in delivery of retinol to this organ for storage as a lipid ester within lipocytes. Transport of retinol from the liver to extrahepatic tissues occurs by binding of hydrolyzed retinol to aporetinol binding protein (RBP). the retinol-RBP complex is then transported to the cell surface within the Golgi and secreted. Within extrahepatic tissues retinol is bound to cellular retinol binding protein (CRBP). Plasma transport of retinoic acid is accomplished by binding to albumin.

Where do I get vitamin A? 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
Sweetpotato 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

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Vision and the Role of Vitamin A

Photoreception in the eye is the function of two specialized cell types located in the retina; the rod and cone cells. 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 serpentine receptor imbedded in the membrane of the rod cell. 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.

When the rhodopsin is exposed to light it is bleached releasing the 11-cis-retinal from opsin. Absorption of photons by 11-cis-retinal triggers a series of conformational changes on the way to conversion all-trans-retinal. One important conformational intermediate is metarhodopsin II. The release of opsin results in a conformational change in the photoreceptor. This conformational change activates transducin, leading to an increased GTP-binding by the α-subunit of transducin. Binding of GTP releases the α-subunit from the inhibitory β- and γ-subunits. The GTP-activated α-subunit in turn activates an associated phosphodiesterase; an enzyme that hydrolyzes cyclic-GMP (cGMP) to GMP. Cyclic GMP is required to maintain the Na+ channels of the rod cell in the open conformation. The drop in cGMP concentration results in complete closure of the Na+ channels. Metarhodopsin II appears to be responsible for initiating the closure of the channels. The closing of the channels leads to hyperpolarization of the rod cell with concomitant propagation of nerve impulses to the brain.

role of vitamin A in the function of visual signaling via rod cells

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 PDE6B. Cyclic GMP is required to maintain a cyclic nucleotide gated (CNG) ion channel in the open conformation. The CNG ion channel, when opened via cGMP interaction, transports both sodium (Na+) and calcium (Ca2+) ions into the rod cell maintaining the cell in a state of depolarization. In the dark, the continuous influx of calcium ion 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.

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Clinical Significances of Vitamin A Deficiency

Vitamin A is stored in the liver and deficiency of the vitamin occurs only after prolonged lack of dietary intake. 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.

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Vitamin D

Vitamin D is a steroid hormone that functions to regulate specific gene expression following interaction with its intracellular receptor. The biologically active form of the hormone is 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3, also termed calcitriol). Calcitriol functions primarily to regulate calcium and phosphorous homeostasis.

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 (produced in the skin). Ergocalciferol (vitamin D2) is formed by uv irradiation of ergosterol. In the skin 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3) following uv irradiation.

Vitamin D2 and D3 are processed to D2-calcitriol and D3-calcitriol, respectively, by the same enzymatic pathways in the body. Cholecalciferol (or ergocalciferol) are absorbed from the intestine and transported to the liver bound to a specific vitamin D-binding protein. In the liver cholecalciferol is hydroxylated at the 25 position by a specific D3-25-hydroxylase generating 25-hydroxy-D3 [25-(OH)D3] which is the major circulating form of vitamin D. Conversion of 25-(OH)D3 to its biologically active form, calcitriol, occurs through the activity of a specific D3-1-hydroxylase present in the proximal convoluted tubules of the kidneys, and in bone and placenta. 25-(OH)D3 can also be hydroxylated at the 24 position by a specific D3-24-hydroxylase in the kidneys, intestine, placenta and cartilage.

Calcitriol functions in concert with parathyroid hormone (PTH) and calcitonin to regulate serum calcium and phosphorous levels. PTH is released in response to low serum calcium and induces the production of calcitriol. In contrast, reduced levels of PTH stimulate synthesis of the inactive 24,25-(OH)2D3. In the intestinal epithelium, calcitriol functions as a steroid hormone in inducing the expression of calbindinD28K, a protein involved in intestinal calcium absorption. The steroid hormone action of vitamin D occurs via the action of calcitriol binding to a specific intracellular receptor called the vitamin D receptor (VDR).

The increased absorption of calcium ions requires concomitant absorption of a negatively charged counter ion to maintain electrical neutrality. The predominant counter ion is Pi. When plasma calcium levels fall the major sites of action of calcitriol and PTH are bone where they stimulate bone resorption and the kidneys where they inhibit calcium excretion by stimulating reabsorption by the distal tubules. The role of calcitonin in calcium homeostasis is to decrease elevated serum calcium levels by inhibiting bone resorption.

Where do I get vitamin D? 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

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Clinical Significances of Vitamin D Deficiency

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 hyperparathyroidism as a compensatory mechanism. The excess release of parathyroid hormone (PTH) can cause metastatic calcification and peritrabecular fibrosis. 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 neurofibromatosis type 1.

Vitamin D Toxicity

Due to the fat solubility of vitamin D it is possible to consume too much of the vitamin. Excess vitamin D intake results in a very characteristic toxicity profile. The excess vitamin results in and associated excess uptake of intestinal Ca2+ leading to hypercalcemia. This hypercalcemia is essentially indistinguishable from the hypercalcemia caused by secondary hyperparathyroidism in the context of vitamin D deficiency. The earliest tissue affected by the onset of the metastatic calcification with vitamin D toxicity is the kidney. The symptoms of the renal deficit are very similar to those experienced by type 1 diabetics: polydipsia and polyuria. Chronic vitamin D toxicity leads to metastatic calcification of numerous soft tissues and eventually results in permanent renal failure.

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Vitamin E

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.

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.

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. 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.

Where do I get vitamin E? 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

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Clinical Significances of Vitamin E Deficiency

No major disease states have been found to be associated with vitamin E deficiency due to adequate levels in the average American diet. The major symptom of vitamin E deficiency in humans is an increase in red blood cell fragility. Since vitamin E is absorbed from the intestines in chylomicrons, any fat malabsorption diseases can lead to deficiencies in vitamin E intake. Neurological disorders have been associated with vitamin E deficiencies associated with fat malabsorptive disorders. 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.

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Vitamin K

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. The menaquinones contain a variable number (6, 7, or 9) of isoprene units (a chemical structure containing 5 carbon atoms and 8 hydrogen atoms with two of the carbons attached together with a carbon-carbon double bond).

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 blood clotting 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 modification 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 an uncharacterized reductase. This latter reaction is the site of action of the coumarin based anticoagulants such as warfarin (trade name = Coumadin®).

Where do I get vitamin K? 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.

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Clinical Significances of Vitamin K Deficiency

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 malabsorptive diseases can result in vitamin K deficiency. 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.

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Minerals: Critical Micronutrients

Minerals constitute one of two major classes of biologically critical micronutrients required for normal health and development of humans. The other class are the vitamins. Humans must consume both macronutrients (the major sources of calories: fats, carbohydrates, proteins) and micronutrients in order to maintain virtually all metabolic and developmental processes. There is a clear correlation between micronutrient deficit and the development of chronic metabolic disruption. This is quite clear in the Vitamins page which discusses numerous, potentially lethal, consequences of vitamin deficiency. Given the fact that many manufactured foods, consumed by most individuals in the developed world, are now supplemented with vitamins, deficiencies are less and less common. This is somewhat true for minerals these are not as rigorously supplemented in prepared foods to the extent of the vitamins. The functions of the minerals are numerous and either quite broad or highly specific. Minerals serve as ions required for nerve impulse transmission in the central and peripheral nervous systems. Minerals, as ions, serve as activators of complex biochemical reactions in most tissues with the role of calcium ions in the activation of cardiac and skeletal muscle activity being a prime example. Minerals also serve as required cofactors for many different types of enzymes involved in a vast array of critical biochemical reactions. The minerals considered as trace minerals function primarily as cofactors or regulators of enzyme function. The terminology of "trace" relates to the fact that these minerals are effective and necessary in only minute concentration. The following discussions of minerals and their functions is not intended to be exhaustive.

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Macro Minerals

Calcium: Ca2+

Calcium ion (Ca2+) is an extremely critical mineral required for a vast array of biochemical processes. Some of the most wide-spread functions for this ion are its requirements for neural signaling, cell proliferation, bone mineralization, cardiac function, muscle contraction, digestive system function, and secretory processes. In the context of Ca2+ in secretion, the ion is required for neurotransmitter release and hormone release from a number of different tissues. In addition, calcium is necessary for proper activity of a number of proteins involved in blood coagulation. Calcium concentrations in the blood are very tightly regulated within a narrow range. Within the blood over half of the Ca2+ is free while the rest is bound to albumin or complexed with other ions such as bicarbonate and phosphate.

Calcium functions both intracellularly and extracellularly. As an intracellular ion, Ca2+, serves the role of a second messenger. The difference between the Ca2+ concentration outside the cell, within the interstitial fluids, is on the order of 12,000 times that of the free intracellular concentration. This difference creates an inwardly directed electrical gradient as well as allowing for dramatic influxes of the ion in response to a variety of cellular stimuli. Within the cell, most calcium is not free in the cytosol but is stored within the endoplasmic reticulum (ER) and other microsomal (membrane) compartments. This calcium is able to be rapidly mobilized to the cytosol via the activation of ligand-gated ion channels.

Calcium exerts many of its biochemical effects by binding to Ca2+-binding proteins, several of the most significant are outlined in the following Table. The vast majority of proteins, whose activities are controlled by Ca2+ binding, contain a structural motif referred to as the EF-hand. The EF-hand domain consists of two regions of α-helix linked by a short (usually 12 amino acids) loop region. These EF-hand proteins are found both intracellularly and extracellularly. The superfamily of human EF-hand domain containing proteins consists of 222 proteins. The total number of proteins that bind calcium is beyond the scope of this discussion but several important examples of intracellular Ca2+-binding proteins include the calmodulins, calcineurins, calbindins, and troponins, whereas important extracellular Ca2+-binding proteins include the coagulation factors [II (prothrombin), VII, IX, X, protein C, protein S] and the cell-cell communication/adhesion proteins of the cadherin family.

Examples of Important Calcium-Binding and Regulated Proteins

Protein Name Functions / Comments
Calbindins refers to a family of Ca2+-binding proteins; original member identified as vitamin D-dependent calcium-binding protein and then called calbindin-D28K (gene symbol: CALB1); other members include calretinin (29kDa protein encoded by CALB2 gene) and calbindin-D9K (gene symbol: CALB3); all members mediate Ca2+ transport across membranes; CALB1 protein is required for mediating intestinal calcium absorption in response to hormonal action of calcitriol; CALB2 is a neural-specific Ca2+-binding protein; CALB3 is a member of the S100 family of proteins of which there are 24 members each of which function in some capacity related to the regulation of proliferation, differentiation, apoptosis (programmed cell death), Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion
Calcineurins these proteins are components of a Ca2+-dependent serine/threonine phosphatase identified as protein phosphatase 3, PP3 (formerly PP2B); calcineurins consists of a catalytic subunit and a regulatory subunit, and a subunit of calmodulin; the catalytic subunit is encoded by one of three genes: PPP3CA (commonly called calcinuerin A, CALNA), PPP3BB (commonly called calcineurin B, CALNB), and PPP3CC; the regulatory subunit is encoded by one of two genes: PPP3R1 and PPP3R2; major cell types regulated by calcineurin activity are T cells, neural cells, and cardiac cells; within the brain the primary substrates for calcineurin activity are Ca2+ channels, the dephosphorylation of which leads to their inactivation, thereby modulating the release of various neurotransmitters; calcineurin is potently inhibited by the immunosuppressant drugs, cyclosporin A and FK506 (fujimycin)
Calmodulins these proteins are regulatory subunits of numerous enzymes, particularly kinases; humans express three distinct calmodulin genes identified as CALM1, CALM2, and CALM3; the proteins possess four Ca2+-binding sites; several kinase families are known to possess calmodulin subunits: glycogen synthase-glycogen phosphorylase kinase (PHK, composed of six subunits, the δ-subunit is calmodulin), myosin light-chain kinases (four isoforms: MYLK or MLCK in smooth muscle, MYLK2 in skeletal muscle, MYLK3 in cardiac muscle, and MYLK4), and the kinases termed Ca2+/calmodulin (CaM)-dependent protein kinases (CaMK) which includes CaMKI, CaMKII, CaMKIII, and CaMKIV; CaMKIII is more commonly referred to as eEF-2 kinase (eEF-2K) involved in the regulation of protein synthesis; in addition to serving as calcium-sensing regulatory subunits of numerous kinases, calmodulins also regulate the activity of protein phosphatases (particularly PP3 as indicated above) and the nitric oxide synthases, NOS
Troponins the troponins are actually heterotrimeric complexes of three distinct subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT); TnT and TnI exist in tissue specific isoforms with the cardiac muscle forms identified as cTnI and cTnT, whereas the skeletal muscle forms are skTnI and skTnT; TnC is the Ca2+-binding subunit whose role is to effect the Ca2+-dependent regulation of muscle contraction; TnI inhibits the ATPase activity of the actin-myosin complex of the thin filaments that control muscle fiber contraction; TnT binds tropomyosin, thereby regulating troponin complex interaction with thin filaments; measurement of plasma levels of cTnI is now considered the standard for determination of diseases/disorders related to cardiac function such as acute myocardial infarction (AMI)
Protein kinase C (PKC) family the protein kinase C (PKC) family of serine/threonine kinases is composed of several related enzymes (for a more detailed discussion go to the The Medical Biochemistry Page); PKC enzymes are divided into three subfamilies termed conventional (cPKC), novel (nPKC), and atypical (aPKC); it is only the conventional PKC subfamily of enzymes that is regulated by calcium ions

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Chlorine (as chloride ion: Cl) is a major ion necessary for digestive processes as it is required for the formation of gastric acid (HCl) within the lumen of the stomach. The majority of the chloride ion in the body is found in the extracellular fluid compartment. Chloride ion represents approximately 3% of the total electrolyte composition of the human body. Chloride ion functions along with sodium ion (Na+) and potassium ion (K+) in the maintenance of electrolyte balance. Chloride ion is required for the function of several ligand-gated ion channels. Of particular importance is the role of Cl in the function of the inhibitory neurotransmitter, GABA (γ-aminobutyric acid). The GABA-A receptor is a Cl channel that, in response to GABA binding induces an inward flux of Cl into the neuron.

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Magnesium ion (Mg2+) is an activator for more than 300 enzymes. All enzymes that utilize ATP as a substrate or as an allosteric regulator require Mg2+ ion for activity. Magnesium is a highly critical ion in the nucleus where it interacts with DNA, an interaction necessary for stabilization of DNA structure. With respect to the requirement for Mg2+ in ATP functions, essentially all of the ATP in the cell has Mg2+ bound to the phosphates. This Mg2+:ATP complex allows ATP to more readily release the terminal phosphate (the γ-phosphate) when doing so to provide energy for cellular metabolism. Some of the nuclear enzymes that require Mg2+ for activity are DNA repair endonucleases (involved in nucleotide excision repair, NER and mismatch repair, MMR), topoisomerase II, and RNase H. Magnesium is also required for protein synthesis since it is necessary for the stabilization of the ribosomes. Magnesium is a required component of numerous signal transduction pathways as a result of its role as a substrate (activator) of adenylate cyclase leading to the production of cAMP which in turn activates the serine/threonine kinase, PKA. Magnesium is also important in the processes of electrolyte transport across membranes which facilitates, among numerous metabolic processes, glucose uptake and metabolism, ATP production via mitochondrial oxidative phosphorylation, and the functioning of nerve transmission via stabilization of ATP in Na+/K+-ATPases. Another critical role for Mg2+ is in the formation of the mineral matrix of bone.

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Phosphorous is the most important systemic electrolyte acting as a significant buffer in the blood in the form of phosphate ion: PO43–. In the context of biological systems, phosphate ion is commonly referred to as inorganic phosphate and written as Pi. In addition to its role as a critical blood buffer, Pi required in the biosynthesis of cellular components, such as ATP, nucleic acids, phospholipids, and proteins, and is involved in many metabolic pathways, including energy transfer, protein activation, and carbon and amino acid metabolic processes. Phosphate is also required for bone mineralization, and is necessary for energy utilization. One of the most important metabolic reactions that requires Pi is the phosphorolytic cleavage of glucose from glycogen by the enzyme glycogen phosphorylase.

In order to carry out its functions in metabolic processes, serum and intracellular Pi levels are maintained within a narrow range via a complex interplay between intestinal absorption, bone storage, and intracellular exchange. Hormonal control of phosphate levels is exerted primarily via the actions of vitamin D and parathyroid hormone within the proximal tubules of the kidneys.

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Potassium: K+

Potassium ion is a key circulating electrolyte as well as being involved in the regulation of ATP-dependent channels along with sodium ion. These channels are referred to as Na+/K+-ATPases and their primary function is in the transmission of nerve impulses in the brain. Potassium ions represent approximately 5% of the total electrolyte pool in the human body. The majority of potassium ion in the body is found intracellularly.

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Sodium: Na+

Sodium ion is a key circulating electrolyte and also functions in the regulation of Na+/K+-ATPases with potassium ion. Sodium ions represent approximately 2% of the total electrolyte composition in the human body. Along with chloride ion (Cl) and potassium ion (K+), sodium ion is required for normal cellular osmolarity, maintenance of normal water distribution and water balance in the body, and maitenance of normal acid-base balance. The majority of the total body sodium ion is found in the extracellular fluids. The functions of the Na+/K+-ATPases in the body are numerous with primary roles being in the processes of nerve transmission in the central and peripheral bnervous systems and in the functioning of muscle cells, in particular cardiac muscle function.

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Sulfur has a primary function in amino acid metabolism (methionine and cysteine) but is also necessary for the modification of complex carbohydrates present in proteins (glycoproteins) and lipids (glycolipids), however, it should be noted that in this latter function the sulfur is donated from the amino acid methionine.

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Trace Minerals


Copper is involved in the formation of red bloods cells, the synthesis of hemoglobin, and the formation of bone. Additional functions of copper are energy production, wound healing, taste sensation, skin and hair color. Copper is also involved in the proper processing of collagen and elastin via the action of the extracellular matrix-associated enzyme, lysyl oxidase. Thus, copper is critical to the proper production of connective tissue.

Important Copper-Dependent Enzymes

Enzyme Name Gene Functions
Ceruloplasmin CP major ferroxidase in the blood; each enzyme binds 6–7 Cu2+ (cupric) ions; plays a major role in ensuring no free iron in the circulation; oxidizes Fe2+ (ferrous) iron to Fe3+ (ferric) iron which can then be bound to transferrin, the major iron transporting protein in the blood; ceruloplasmin is often misrepresented as the major copper transporting protein of the blood due to the fact that up to 95% of copper in the blood is found in this enzyme, however, the enzyme does not function in any copper transport/carrying capacity; two CP isoforms generated via alternative mRNA splicing, one form is secreted the other is attached to the plasma membrane; secreted CP synthesized exclusively by the liver, the membrane-linked CP is expressed by numerous organs including the brain, liver, kidneys, and lungs; the membrane-linked CP is primarily responsible for iron efflux from tissues; aceruloplasminemia, due to defects in the CP gene, doesn't affect copper homeostasis but manifests with iron overload of a form referred to as hemosiderosis
Cytochrome c oxidase 13 genes composed of 13 subunits that comprise the mitochondrial oxidative phosphorylation complex IV; mitochondrial genome harbors MT-CO1, MT-CO2, and MT-CO3 genes; nuclear genome harbors the other ten genes: COX4, COX5A, COX5B, COX6A, COX6B, COX6C, COX7A, COX7B, COX7C, COX8; functions to re-oxidized reduced cytochrome c while subsequently reducing molecular oxygen to water; the ferric (Fe3+) iron in complex IV is the site of cyanide (CN binding
Dopamine β-hydroxylase
(dopamine β-monooxygenase)
DBH involved in catecholamine synthesis, catalyzes hydroxylation of dopamine to norepinephrine; expression limited to adrenal medulla and post-ganglionic sympathetic neurons
Hephaestin HEPH functions as a ferroxidase (similar to ceruloplasmin); expression is limited to intestinal villi cells; required for iron transport from intestinal enterocytes to the blood; dietary iron is transported from enterocytes to the blood via the action of ferroportin with simultaneous oxidation of Fe2+ (ferrous) iron to Fe3+ (ferric) iron by hephaestin; ensures the iron can be bound to transferrin for delivery to the tissues
Lysyl oxidase LOX catalyzes the oxidative deamination of the ε-amino group of lysine and hydroxylysine residues in collagens and lysine residues of elastin; results in cross-linking of protein forming fibrils
Methionine synthase
(homocysteine methyltransferase)
MTR official name is 5-methyltetrahydrofolate-homocysteine S-methyltransferase; catalyzes the conversion of homocysteine to methionine; is one of only two enzymes that require vitamin B12 (as methylcobalamin); as the name implies the enzyme also requires N5-methyl-THF for activity; defects in the MTR gene, or deficiency in either folate or B12 (or both), result in homocysteinemia/homocystinemia and macrocytic anemia
Cu-Zn Superoxide dismutase SOD1 major cytoplasmic anti-oxidant enzyme; catalyzes conversion of superoxide free radicals to molecular oxygen (O2) and hydrogen peroxide (H2O2); the major mitochondrial superoxide dismutase (SOD2) is a manganese-dependent enzyme

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Iodine is required for the synthesis of the thyroid hormones and thus plays an important role in the regulation of energy metabolism via thyroid hormone functions.

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Iron: Fe2+ and Fe3+

Iron is the most abundant trace metal in the human body. Iron (as the ferrous ion, Fe2+) is a critical micronutrient with a major role in the transport of oxygen. Iron is the functional center of the heme moiety found in each of the protein subunit of hemoglobin. The function of Fe2+ is to coordinate the oxygen molecule into heme of hemoglobin so that it can be transported from the lungs to the tissues. Aside from its role in oxygen transport, iron is critical to the overall process of oxidative phosphorylation where it is also found in the heme of cytochromes and in the Fe-S (iron-sulfur) centers of the various complex of oxidative phosphorylation. Iron is the only metal in the human body that is toxic if allowed to remain free in the plasma or the fluid compartments of cells. The toxicity of free iron is related to its ability to rapidly generate the highly toxic hydroxyl free radical (HO) via the Fenton reaction. For this reason there are extremely tight controls on overall iron homeostasis.

Several Iron-Dependent Enzymes

Enzyme Name Gene Symbol Functions / Comments
Aconitases ACO1, ACO2 the protein encoded by ACO1 functions in the iron-mediated control of translation of the H-ferritin, L-ferritin, transferrin receptor, DMT1, ferroportin, ALAS2, and ACO2 mRNAs; the ACO2 encoded protein is involved in the TCA cycle
Alcohol dehydrogenases 7 different genes belong to medium-chain dehydrogenase/reductase (MDR) superfamily; catalyze the oxidation of various alcohols to their corresponding aldehydes; important in the detoxification/metabolism of ethanol
Catalase CAT primary reaction is to detoxify the reactive oxygen species (ROS) hydrogen peroxide (H2O2) to water; can also oxidize certain alcohols to corresponding aldehydes
Cytochrome c reductase multiple subunits including the Fe-S protein encoded by the UQCRFS1 gene multisubunit component of oxidative phosphorylation Complex III; contains two cytochromes b (b-562 and b-566), cytochrome c1, and the Fe-S protein which is called the Rieske Fe-S protein after its discoverer J.S. Rieske; official name of this enzyme complex is ubiquinol-cytochrome c reductase
Lipoxygenases ALOX5, ALOX12, ALOX15 all three lipoxygenases (5-LOX, 12-LOX, and 15-LOX) are involved in arachidonic acid oxidation during the synthesis of the leukotrienes and the lipoxins
Lysyl hydroxylases PLOD1, PLOD2, PLOD3 official name for these enzymes is procollagen-lysine, 2-oxoglutarate 5-dioxygenase; PLOD1 is the major procollagen lysine hydroxylating enzyme; all 3 enzymes function as homodimers; PLOD2 and PLOD3 carry out hydroxylations in collagen-like proteins; mutations in PLOD1 are associated with Ehlers-Danlos syndrome (EDS) type VI, mutations in PLOD2 or PLOD3 are associated with EDS type VIB
NADH-ubiquinone reductase multiple Fe-S subunit genes multisubunit component of oxidative phosphorylation Complex I
Phenylalanine hydroxylase PAH catalyzes the conversion of phenylalanine to tyrosine; mutations in the PAH gene result in phenylketonuria, PKU
Prolyl 4-hydroxylase (two α, two β subunits) three α subunit genes: P4HA1, P4HA2, P4HA3; β subunit gene: P4HB catalyzes the formation of 4-hydroxyproline residues in procollagen
Ribonucleotide reductase (contains 2 subunits) RRM1, RRM2 catalyzes the conversion of ribonucleoside diphosphates to their corresponding deoxyribonucleotide diphosphates
Stearoyl-CoA desaturase SCD1 one of three fatty acid desaturases in humans; stearoyl-CoA desaturase is the rate-limiting enzyme catalyzing the synthesis of monounsaturated fatty acids (MUFAs), primarily oleate (18:1; a physiologically significant omega-9 fatty acid) and palmitoleate (16:1)
Succinate-ubiquinone reductase multiple Fe-S subunit genes multisubunit component of oxidative phosphorylation Complex II
Thyroid peroxidase TPO exclusively expressed in the thyroid gland; within the thyroid colloid TPO oxidizes I to I+; reaction requires H2O2
Tryptophan hydroxylase TPH2 initial enzyme in the conversion of tryptophan to the neurotransmitters, serotonin and melatonin
Tyrosine hydroxylase TH initial enzyme in the conversion of tyrosine to the catecholamines, dopamine, norepinephrine and epinephrine
Xanthine oxidase (derived from xanthine dehydrogenase) XDH also requires molybdenum for function; xanthine dehydrogenase can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification; catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid in the catabolism and salvage of purine nucleotides

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Manganese is involved in reactions of protein and fat metabolism, promotes a healthy nervous system, and is necessary for digestive function, bone growth, and immune function. Maintenance of blood glucose levels is controlled in large part via the ability of the liver to produce glucose from precursor carbon atoms in the pathway of gluconeogenesis. Two of the enzymes of gluconeogenesis, pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK) require manganese for their activity. Within the liver, kidneys, and brain manganese is critical in the regulation of ammonium ion (NH4+) levels via its role activating glutamine synthetase. Within the liver, manganese plays an additional role in the regulation of NH4+ levels in the body via its activation of the urea cycle enzyme arginase. Manganese also serves as an important anti-oxidant mineral since it is necessary for the proper function of mitochondrial superoxide dismutase (SOD2) which catalyzes the same reaction as that catalyzed by the cytosolic version, SOD1 (see Table above in Copper discussion).

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Molybdenum is primarily involved as a co-factor in oxidase enzymes such as xanthine dehydrogenase/oxidase necessary for purine nucleotide catabolism. Molybdenum is also a necessary cofactor in the detoxification reactions catalyzed by sulfite oxidase. Sulfite oxidase is the terminal enzyme in the pathways of the metabolism of sulfur-containing compounds such as the amino acid cysteine. The product of the sulfite oxidase reaction, sulfate, is then excreted.

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Selenium serves as a modifier of the activity of several enzymes through its incorporation into protein in the form of selenocysteine. Two critical re-dox enzyme familiess that require selenocysteine residues are the glutathione peroxidase and thioredoxin reductase families. Glutathione peroxidase is a critical enzyme involved in the protection of red blood cells from reactive oxygen species (ROS). This enzyme is a component of a re-dox system that also involves the enzyme glutathione reductase and NADPH as the terminal electron donor. This system is required for the continued reduction of oxidized glutathione (GSSG) and represents the single most significant system requiring continued glucose metabolism via the Pentose Phosphate Pathway in erythrocytes as the means for the production of the NADPH. Glutathione (GSH) becomes oxidized in the context of reducing various ROS and peroxides and to continue in this capacity the oxidized form needs to be continously reduced. Humans express eight different glutathione peroxidase genes identified as GPX1 through GPX8.

As the name of the enzyme implies, thioredoxin reductase is involved in the reduction of thioredoxin which itself is principally involved in the reduction of oxidized disulfide bonds in proteins. The reduction of these disulfide bonds results in oxidation of thioredoxin which then is reduced by thioredoxin reductase. The overall process, like the glutathione peroxidase system, requires NADPH as the terminal electron donor for the reduction process. A critically important reaction that is coupled to the thioredoxin system is the formation of deoxynucleotides. Humans contain three thioredoxin reductase genes that encode three distinct enzymes identified as TrxR1, TrxR2, and TrxR3. The TrxR1 enzyme is functional in the cytosol and is primarily involved in the maintenance of the ribonucleotide reductase system. The TrxR2 enzyme is functional in the mitochondria where it is principally involved in the detoxification of reactive oxygen species (ROS) produced in this organelle. TrxR3 is a testes-specific isoform of the enzyme.

The enzymes of the deiodinase family are also important selenocysteine-containing enzymes. Clinically relevant enzymes in this family are the thyroid deiodinases that are critical for the maturation and catabolism of the thyroid hormones. Humans express three different thyroid deiodinase genes identified as DIO1, DIO2, and DIO3. The enzyme encoded by the DIO1 gene, thryroxine deiodinase type I (also called iodothyronine deiodinase type I) is involved in the peripheral tissue conversion of thyroxine (T4) to bioactive form of thyroid hormone, tri-iodothyronine (T3). In addition to its role in the generation of T3, thyroxine deiodinase I is involved in the catabolism of thyroid hormones. The enzyme encoded by the DIO2 gene, iodothyronine deiodinase type II, is also involved in the conversion of T4 to T3 but does so within the thyroid gland itself. The activity of iodothyronine deiodinase II has been associated with the thyrotoxicosis of Graves disease. The enzyme encoded by the DIO3 gene is involved only in the inactivation (catabolism) of T3 and T4. Expression of the DIO3 gene is highest the female uterus during pregnancy and in fetal and neonatal tissue suggesting a role for this enzyme in the regulation of thyroid hormone levels and functions during early development.

Selenium Toxicity

Given the significant role of selenium in the protection against the damaging effects of reactive oxygen and reactive nitrogen species, it might seem logical to consume large quantities of the metal as a protective prophylactic. However, this is definitely not a clinically sound approach. There is a very narrow clinically safe range for selenium intake, too little and there are serious clinical consequences, too much and some overlapping as well as a different set of serious clinical complications occur. Chronic selenium deficiency is associated with lethargy, dizziness, motor weakness and paresthesias, and an excess risk of amyotrophic lateral sclerosis. Selenium toxicity due to excess intake manifests most significantly with neurological impairment evidenced by ataxia, hypotonia, hyperreflexia, dyasthesia, and paralysis. Lethargy and dizziness are also common with selenium intoxication as for selenium deficiency. Additional CNS effects of selenium intoxication include localized or generalized tremors and convulsions. Many individuals suffering from selenium intoxication experience behavioral disturbances that can lead to suicidal ideation. The cardiovascular and respiratory systems are also impaired with selenium toxicity and can result in death due to respiratory failure and cardiac arrest. One characteristic feature associated with selenium intoxication is a garlic odor to the expired breath. This is similar to the consequences oif arsenic poisoning, therefore, in and of itself a garlic odor to the breath is not exclusively diagnostic for selenium intoxication.

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Zinc: Zn2+

After iron, zinc is the second most abundant trace metal in the human body. Zinc ion (Zn2+) is found as a co-factor in over 300 different enzymes and thus is involved in a wide variety of biochemical processes. Zinc interacts with the hormone insulin to ensure proper function, thus, zinc participates in the regulation of blood glucose levels via insulin action. Zinc is necessary for the activity of a number of transcription factors such as those of the nuclear receptor (steroid and thyroid hormone receptor superfamily) family through its role in the formation of the structurally critical zinc finger domain that binds to DNA. Zinc also promotes wound healing, regulates immune function, serves as a co-factor for numerous antioxidant enzymes, and is necessary for protein synthesis and the processing of collagen.

Several Zinc-Dependent Enzymes

Enzyme Name Gene Symbol Functions
ALA dehydratase ALAD is the second enzyme in the pathway of heme biosynthesis, catalyzes the condensation of two molecules of δ-aminolevulinic acid (ALA) forming porphobilinogen
Alcohol dehydrogenases, ADH 7 different genes belong to medium-chain dehydrogenase/reductase (MDR) superfamily; catalyze the oxidation of various alcohols to their corresponding aldehydes; important in the detoxification/metabolism of ethanol
Aldolases ALDOA, ALDOB, ALDOC catalyzes the hydrolysis of fructose-1,6-bisphosphatase (ALDOA) in the pathway of glycolysis; ALDOB is involved in the hepatic metabolism of fructose
Carbonic anhydrases, CA at least 12 different functional members catalyze the formation of carbonic acid (H2CO3) from CO2 and H2O; see the Enzyme Kinetics page for more details
Histone deacetylases, HDACs at least 18 different members of family as the name implies, these enzymes remove acetyl groups from histones; the consequences of histone deacetylation are the silencing of transcription; the sirtuin (SIRT) proteins in humans also possess HDAC activity
Monoamine oxidases MAOA, MAOB catalyze the oxidation of monoamines; critical roles in the regulaiton of the catabolism of dopamine, serotonin, epinephrine, and norepinephrine; given these important functions MAO inhibitors (MAOIs) were used for several years as anti-depressants and anti-anxiety drugs; due to potential for excessive levels of epinephrine and norepinephrine MAOIs can cause hypertensive crisis
Pyridoxal kinase PDXK required for the formation of the cofactor form of vitamin B6: pyridoxal phosphate (PLP; also identified as pyridoxal-5-phosphate)
Pyruvate carboxylase PC first of two enzymes required for bypass 1 step of gluconeogenesis; catalyzes the formation of oxaloacetate from pyruvate and bicarbonate ion
Superoxide dismutase, Cu-Zn SOD1 major cytoplasmic anti-oxidant enzyme; catalyzes conversion of superoxide free radicals to molecular oxygen (O2) or hydrogen peroxide (H2O2); the major mitochondrial superoxide dismutase (SOD2) is a manganese-dependent enzyme

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Last modified: February 12, 2017