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)
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 thiamin deficiency include constipation, appetite suppression, nausea as well as mental depression, peripheral neuropathy and fatigue. Chronic thiamin deficiency leads to more severe neurological symptoms including ataxia, mental confusion and loss of eye coordination. Other clinical symptoms of prolonged thiamin deficiency are related to cardiovascular and musculature defects.

The severe thiamin deficiency disease is known as Beriberi, is the result of a diet that is carbohydrate rich and thiamin deficient. An additional thiamin deficiency related disease is known as Wernicke-Korsakoff syndrome. This disease is most commonly found in chronic alcoholics due to their poor dietetic lifestyles. Wernicke-Korsakoff syndrome is characterized by acute encephalopathy followed by chronic impairment of short-term memory. Persons afflicted with Wernicke-Korsakoff syndrome appear to have an inborn error of metabolism that is clinically important only when the diet is inadequate in thiamin. 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 encoding this enzyme when cloned from patients exhibiting the syndrome.

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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.

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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, are associated with the condition known as pellagra. Several physiological conditions (e.g. Hartnup disease and malignant carcinoid syndrome) as well as certain drug therapies (e.g. isoniazid) can lead to niacin deficiency. In Hartnup disease 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) is a primary drug for chemotherapy 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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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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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 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 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. 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.

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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.

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

As a result of the addition of vitamin D to milk, deficiencies in this vitamin are rare in this country. The main symptom of vitamin D deficiency in children is rickets and in adults is osteomalacia. Rickets is characterized 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.

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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. 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). For information on isoprenes visit the

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 discussed above. 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 following discussion of minerals and their functions is not intended to be exhaustive.

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Macro Minerals

Calcium: 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. These proteins are found both intracellularly and extracellularly. The total number of proteins that bind calcium is beyond the scope of this discussion but several important examples are described in the following Table.

Ca2+-binding protein Functions / Comments
Calbindin 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; 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, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion
Calcineurin (CaN) a Ca2+-dependent serine/threoinine phosphatase; major cell types regulated by calcineurin activity are T cells, neural cells, and cardiac cells; within the brain the primary substrates for CaN activity are Ca2+ channels, the dephosphorylation of which leads to their inactivation, thereby modulating the release of various neurotransmitters; CaN is potently inhibited by immunosuppressant drugs, cyclosporin A and FK506
Calmodulin (CaM) is a subunit of numerous enzymes, particularly kinases; possesses four Ca2+-binding sites; six kinases (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 (4 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
Troponin troponin is actually a heterotrimeric complex of three 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)

Chlorine: Chlorine (as chloride ion: Cl) is a major ion necessary for digestive processes as it is required for the formation of gastric acid (HCl); most of the Cl in the human body is found in the extracellular fluid compartment; Cl 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

Iron: 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.

Magnesium: 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 cell regulatory 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.

Phosphorous: Phosphorous is the most important systemic electrolyte acting as a significant buffer in the blood in the form of phosphate ion: PO43–. Phosphate is also required for bone mineralization, and is necessary for energy utilization.

Potassium: Potassium is a key circulating electrolyte as well as being involved in the regulation of ATP-dependent channels along with sodium. These channels are referred to as Na+/K+-ATPases and their primary function is in the transmission of nerve impulses in the brain.

Sodium: Sodium is a key circulating electrolyte and also functions in the regulation of Na+/K+-ATPases with potassium.

Sulfur: Sulfur has a primary function in amino acid metabolism 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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Micro (Trace) Minerals

The 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.

Copper: 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; often misrepresented as the major copper carrying protein of the blood due to the fact that 90%–95% of copper in the blood is found in this enzyme, however, the enzyme does not function in any copper transport/carrying capacity; aceruloplasminemia, due to defects in the CP gene, can lead to 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 oxidizing 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

Iodine: 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

Manganese: Manganese is involved in reactions of protein and fat metabolism, promotes a healthy nervous system, necessary for digestive function, bone growth, and immune function; in addition, manganese 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).

Molybdenum: Molybdenum is primarily involved as a co-factor in oxidase enzymes such as xanthine oxidase (purine nucleotide metabolism).

Selenium: Selenium serves as a modifier of the activity of glutathione peroxidase through its incorporation into the protein in the form of selenocysteine.

Zinc: 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 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 Functions
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 two genes: MAO-A and MAO-B 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
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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Last modified: January 16, 2017