Vitamins-1: Water-soluble vitamins.

Q01. What are vitamins?

A01.

• Vitamins are organic compounds found in foods and are essential in small quantities for the normal health and growth of the body.
• 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 most prominent function is as cofactors for enzymatic reactions.
• There are thirteen organic compounds known to function as vitamins in humans.
• Vitamins are classified into two categories: Fat-soluble Vitamins (A, D, E, K) and Water-soluble Vitamins (All B, Biotin, Folic acid and Ascorbic acid).
• There is minimal tissue storage of water soluble vitamins in the body, therefore, water soluble vitamins are less likely to accumulate to toxic levels than are fat-soluble vitamins. In the case of an overdose of vitamins, fat-soluble vitamins are potentially more toxic than water-soluble vitamins.
• The absence of one or more vitamins from the diet or poor absorption of vitamins can cause vitamin deficiency diseases.

Q02. How chemical structures of water-soluble vitamins are related to their functions?

Q02. In general, the water soluble vitamins consists of:

o Derivatives or substituted derivatives of sugars (vit-C),

o Derivatives of pyridine (niacin, B6),

o Derivatives of purines and pyrimidines (folic acid, B2, B1),

o Amino acid-organic acid complex (folic acid, biotin, pantothenic acid) and

o A porphyrin-nucleotide complex (B12).

These structurally diverse water-soluble vitamins act:

o As enzyme activators and coenzymes (B1, B2, B6, B12, pantothenic acid, folic acid, biotin, niacin)

o As redox agent on enzyme reactions (Vit-C, B2, B12, folic acid, niacin)

• As nuclear agent (folic acid, B12, Vit-C, biotin)
• As mitochondrial agent (B2, Vit-C, niacin)

Q03. Describe briefly the structure of thiamine and its active form.

A03.

· Thiamine is also known as 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 and a-ketoglutarate dehydrogenase catalyzed reactions as well as the transketolase catalyzed reactions of the pentose phosphate pathway.

Q04. What is dietary requirement of Thiamine (Vitamin B1)?

A04. The dietary requirement for thiamine is proportional to the caloric intake of the diet and ranges from 1.0 - 1.5 mg/day for normal adults. If the carbohydrate content of the diet is excessive then an increased thiamine intake will be required. Requirement is increased in pregnancy and lactation. It also depends of intestinal synthesis and absorption and fat content of diet (increased Pyruvate).

Q05. What are dietary sources of Vitamin B1?

A05. Following are the dietary sources of Vitamin B1:

High: 1000-10,000microgram/100g

Wheat germ, rice bran, soybean flour yeast and ham.

Medium: 100-1000microgram/100g

Peanuts, pecan, walnut, almonds etc. sprouts,

Broccoli, cauliflower, potatoes, beans,

Eggs, milk and beef whole grain cereals and breads.

Low: 10-100microgram/100g

Apples, berries, banana, oranges, dates

Beet, cabbage, carrot, radish, spinach etc.

Q06. Describe biochemical role of thiamine.

A06.

• Active form of thiamine, that is thiamine pyrophosphate (TPP) is required for the key reactions catalyzed by Pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex (TCA cycle).
• Thiamine deficiency results in inhibition of carbohydrate metabolism causing accumulation of Pyruvate.
• TPP is also required for transketolase reaction of the pentose phosphate pathway.
• TPP functions in transmission of nerve impulses and is localized in peripheral nerve membranes.
• It is required for acetylcholine synthesis.
• It is required for ion translocation reactions in stimulated neural tissue.

Q07. Describe clinical manifestations of thiamine deficiency.

A07:

· Vitamin B1 is necessary to breakdown & release energy from carbohydrates. It is also necessary for the structure of the nerve membranes.

• 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 earliest symptoms of thiamin deficiency include constipation, loss of appetite, 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 deficiency of thiamine produces the disease called Beriberi, which affects the brain, heart, and nerves. This disease is prevalent in the Orient because of the abundance of rice they consume. The rice has been milled which strips the rice of thiamine.
• An alcohol-related thiamine deficiency, Wernicke-Korsakoff Syndrome, is caused by inadequate intake of thiamine as well as impaired absorption and storage, and is the common cause of dementia.
• Branched-chain ketoaciduria (commonly known as Maple Syrup Urine Disease; MSUD) is another ailment that may be caused by thiamine deficiency. In MSUD, the oxidative decarboxylation of alpha-keto acids derived from, i.e. valine, isoleucine, and leucine, is blocked due to an inadequate supply of the coenzyme thiamine pyrophosphate (TPP). Clinical symptoms of MSUD include mental and physical retardation.

Q08. Describe briefly the structure of Riboflavin (Vitamin B-2) and its biochemical role.

A08.

• 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 flavin coenzymes are essential for energy production and cellular respiration.

Q09. What is dietary requirement of Riboflavin (Vitamin B-2) and what are dietary sources of it?

A09. The normal daily requirement for riboflavin is 1.2 - 1.7 mg/day for normal adults.

Following are the dietary sources of Vitamin B-2:

High: 1000-10,000microgram/100g

Beef, chicken, pork, yeast.

Medium: 100-1000microgram/100g

Avocados, currents, asparagus, beans, sprouts, egg, milk, nuts.

Low: 10-100microgram/100g

Apples, banana, oranges, dates, carrot, rice

Q10. Describe clinical manifestations of riboflavin deficiency.

A10. Symptoms associated with riboflavin deficiency include: inflammation or open sores at the corners of the mouth or lips, a purple -red inflamed tongue, angular stomatitis, glossitis, cheilosis, photophobia & seborrheic dermatitis (dandruff).

Riboflavin decomposes when exposed to visible light. This characteristic can lead to riboflavin deficiencies in newborns treated for hyperbilirubinemia by phototherapy.

Riboflavin deficiency is often seen in chronic alcoholics due to their poor dietetic habits.

Q11. Describe briefly the structure of Niacin and its biochemical role.

A11.

• Niacin (nicotinic acid and nicotinamide) is also known as vitamin B₃. Both nicotinic acid and nicotinamide can serve as the dietary source 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 and oxidases class of enzymes.
• In anabolic role it maintains microsomal reductive biosynthesis and photolsynthesis.
• In catabolic role furnishes coenzymes for lipid catabolism, oxidative deamination and key reactions in TCA cycle.
• It acts as hydrogen and electron transfer agent and maintains respiratory chain in mitochondria.
• 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 them on a marginal diet.

Q12. What is dietary requirement of Niacin and what are dietary sources of it?

A12. 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).

Following are the dietary sources of Vitamin B-2:

High: 10-100mg/100g

Peanut, rice bran, liver, heart, Beef, chicken, tuna, yeast.

Medium: 1-10mg/100g

Avocados, dates, figs, beans, sprouts, nuts.

Low: 0.1-1.0mg/100g

Apples, banana, berries, melon, peach, oranges, sprouts, tomato

Q13. Describe clinical manifestations of Niacin deficiency.

A13.

· A diet deficient in niacin (as well as tryptophan) leads to glossitis of the tongue, dermatitis, weight loss, diarrhea, depression and dementia.

· Deficiency in niacin causes pellagra (rough skin). Pellagra involves the skin and digestive and nervous system. Symptoms are the 4 D's: Dermatitis, Diarrhea, Dementia, & Death. Niacin also has vasodilating activity.

· Several physiological conditions (e.g. Hartnup disease and malignant carcinoid syndrome) 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.

· Certain drug therapies (e.g. isoniazid) can lead to niacin deficiency. Isoniazid (the hydrazide derivative of isonicotinic acid) is the 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.

Q14. Describe briefly the structure of Vitamin B-6 and its biochemical role.

A14.

• 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. The ATP requiring enzyme, pyridoxal kinase, catalyzes this conversion.

· Vitamin B6 is a component of a coenzyme.

• Pyridoxal phosphate is essential for energy production from amino acids and can be considered an energy-releasing vitamin.
• It is active in converting important amino acids to ketoacids.
• Pyridoxal phosphate functions as a cofactor in enzymes involved in transamination reactions required for the synthesis and catabolism of the amino acids.
• It acts as a cofactor for glycogen phosphorylase in glycogenolysis. Decreased glucose tolerance may be associated with vitamin B-6 deficiency.
• Pyridoxl phosphate is required for synthesis of neurotransmitters serotonin and norepinephrine.
• It is necessary for the synthesis of sphingolipids necessary for myelin formation. This explains the irritability, nervousness and depression found with mild deficiency and peripheral neuropathy and convulsions observed with severe deficiency.
• Pyridoxal phosphate is required for the synthesis of delta aminolevulinic acid, a precursor of heme. Vitamin B-6 deficiency occasionally cause sideroblastic anemia, which is characteristically a microcytic anemia, observed in the presence of high serum iron.
• Vitamin B-6 is also required for the conversion of homocysteine to cysteine and hyperhomocysteinemia appears to be a risk factor for cardiovascular disease.
• Pyridoxal phosphate is one of the cofactor required for conversion of tryptophan to NAD.

Q15. What is dietary requirement of Vitamin B-6 and what are dietary sources of it?

A15. 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.

Following are the dietary sources of Vitamin B-6:

High: 1000-10,000mcg/100g

Walnut, peanut, wheat germ, brown rice, yeast, liver (Beef), herring, and

Salmon.

Medium: 100-1000mcg/100g

Banana, Avocados, grapes, pears. Cabbage, carrots, peas, potatoes, tomatoes, spinach, soybean, wheat, butter and eggs.

Low: 10-100mcg/100g

Apples, oranges, raisins, watermelon, asparagus, bens, lettuce, onion, cheese and milk

Q16. Describe clinical manifestations of Vitamin B-6 deficiency.

A16. Deficiency of Vitamin B6 can cause convulsions, lethargy, mental changes & retardation, anemia, and skin inflammation.

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 pyridoxal phosphate resulting in a deficiency in this vitamin.

Q17. Write a short note on Pantohenic acid.

A17.

• Pantothenic acid is also known as vitamin B₅.
• Pantothenic acid is formed from b-alanine and pantoic acid.
• Pantothenic acid is required for synthesis of coenzyme A, CoA and is a component of the acyl carrier protein (ACP) domain of fatty acid synthase.
• Pantothenic acid 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.

· Deficiency of pantothenic acid is extremely rare due to its widespread distribution in whole grain cereals, legumes and meat.

• Symptoms of pantothenate deficiency are difficult to assess since they are subtle and resemble those of other B vitamin deficiencies.
• Present in all living tissues almost entirely in the form of a coenzyme A (CoA). This coenzyme has many metabolic roles in the cell and lack of pantothenic acid can lead to depressed metabolism of both carbohydrates and fats.

Q18. Write a short note on Biotin.

A18. Biotin is the prosthetic group for number of caboxylation reactions e.g.

· Pyruvate carboxylase (for synthesis of oxaloacetate for gluconeogensis and replenishment of citric acid cycle.

· Acetyl-CoA carboxylase (fatty acid biosynthesis) and

· Propionyl-CoA carboxlase (methionine, leucine and valine metabolism)

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.

Q19. Describe briefly the structure of Vitamin B-12 and its biochemical role.

A19.

· Vitamin B₁₂ is composed of a complex tetrapyrrol ring structure (corrin ring) and a cobalt ion in the center. It is also known as cobalamin.

• 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.

1. 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.

2. 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 and methylcobalamin during the process of the conversion.

Q20. Describe source, requirement and deficiency manifestations of Vitamin B-12.

A20. Vitamin B12 is not found in plant foods. The main source of B12 in human diet is through animal products like milk, eggs and liver. Vitamin B12 requires the presence of intrinsic factor from the stomach in order to be absorbed in the small intestines. The liver can store up to six years worth of vitamin B-12, hence deficiencies in this vitamin are rare.

B12 is needed for the efficient production of blood cells and for the health of the nervous system.

The inability to absorb Vitamin B12 occurs in pernicious anemia. In pernicious anemia intrinsic factor is missing. The anemia results from impaired DNA synthesis due to a block in purine and thymidine biosynthesis. The block in nucleotide biosynthesis is a consequence of the effect of vitamin B₁₂ on folate metabolism. When vitamin B-12 is deficient essentially all of the folate becomes trapped as the N⁵-methyltetrahydrofolate derivative as a result of the loss of functional methionine synthase. This trapping prevents the synthesis of other tetrahydrofolate derivatives required for the purine and thymidine nucleotide biosynthesis pathways.

Neurological complications also are associated with vitamin B-12 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 B-12 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

Q21. Write short not on Folic acid and its biochemical role.

A21. The active form of folic acid is folacin.

• 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.
• 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 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.

Q22. Describe source, requirement and deficiency manifestations of Folic acid.

A22.

· 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.

· The body needs folic acid and folates (form of folic acid that occurs in food) to make DNA. Rapidly dividing cells in the blood, the lining of the colon and developing neutral tube need folic acid the most.

· Folic acid can prevent at least some children from being born with spina bifida or other birth defects.

· Folic acid might prevent heart disease in adults by lowering levels of an artery damaging substance called homocysteine. Homocysteine is an amino acid that's used to make protein. It could damage arteries. Folic acid along with Vitamin B12 &B6 all are needed to convert homocysteine to other things.

· Folic acid is also used in the treatment of sprue- a chronic form of malabsorption.

• Folate deficiency results in complications nearly identical to those described for vitamin B-12 deficiency.
• The most pronounced effect of folate deficiency on cellular processes is upon DNA synthesis. This is due to impairment in dTMP synthesis, which leads to cell cycle arrest in S-phase of rapidly proliferating cells, in particular hematopoietic cells. The result is megaloblastic anemia as for vitamin B₁₂ deficiency. The inability to synthesize DNA during erythrocyte maturation leads to abnormally large erythrocytes termed macrocytic 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.

Q23. Write a short note on Vitamin C.

A23. Vitamin C is also known as Ascorbic acid.

• Ascorbic acid is derived from glucose via the uronic acid pathway. The enzyme L-gulonolactone oxidase responsible for the conversion of gulonolactone to ascorbic acid is absent in primates, thus making ascorbic acid an essential in the diet.
• 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.

Vitamin C is found in fresh fruits and vegetables including citrus fruits. Vitamin C is necessary for the health of the supporting tissues of the body such as bone, cartilage and connective tissue.

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.