Water-soluble vitamins include vitamin B complex and vi- tamin C. Their general properties include:
1. Most of them are converted into coenzymes for vari- ous metabolic reactions.
2. Due to their water solubility, they cannot be stored to any significant extent.
3. Large doses are passed out in urine and they rarely re- sult in toxicity.
Thiamine (Vitamin B1)
Vitamin B1 is also called anti-beriberi factor and antineu- ritic factor (since it can relieve neuritis).
Chemistry
ATP, adenosine triphosphate; AMP, adenosine mono- phosphate; TPP, thiamine pyrophosphate (TPP).
Thiamine contains a pyrimidine ring and a thiazole ring by means of methylene bridge. Alcohol group of thia- mine is esterified with 2 moles of phosphate to form its ac- tive coenzyme thiamine pyrophosphate.
Biochemical Functions
1. Pyruvate dehydrogenase: The coenzyme form is thia- mine pyrophosphate (TPP). It is used in oxidative decarboxylation of alpha-keto acids, e.g. pyruvate de- hydrogenase catalyzes the breakdown of pyruvate to acetyl-CoA and carbon dioxide.
2. Alpha-ketoglutarate dehydrogenase: An analogous biochemical reaction that requires TPP is the oxida- tive decarboxylation of alpha-ketoglutarate to succi- nyl-CoA and CO2.
3. Transketolase: The second group of enzymes that use TPP as coenzyme are the transketolases in the hexose monophosphate shunt pathway of glucose.
Chapter 7: Nutrition 77
4. Alpha-keto acid decarboxylase: Thiamine pyrophos- phate is required for alpha-keto acid decarboxylase to catalyze oxidative decarboxylation of branched-chain amino acids (valine, leucine isoleucine).
5. Tryptophan pyrrolase: Thiamine is required in tryp- tophan metabolism for the activity of tryptophan pyrrolase.
Thiamine antagonists: As follows:
• Pyrithiamine • Oxythiamine.
Recommended Daily Allowance
Recommended daily allowance depends on calorie intake: • Adult: 1–1.5 mg/day (0.5 mg/1,000 calories of energy) • Children: 0.7–1.2 mg/day
• Pregnancy and lactation: 2 mg/day.
Dietary Sources
Aleurone layer of cereals (food grains) is a rich source of thiamine. Therefore whole wheat flour and unpolished hand-pound rice have better nutritive value. Yeast is also a very good source. Thiamine is partially destroyed by heat.
Deficiency Manifestations
Beriberi
Deficiency of thiamine leads to beriberi. It is a Sinhalese word, meaning ‘weakness’. The early symptoms are an- orexia, dyspepsia, heaviness and weakness.
Types of beriberi
1. Wet beriberi: Here cardiovascular manifestations are prominent. Edema of legs, face, trunk and serous cavities are the main features. Death occurs due to heart failure. 2. Dry beriberi: In this condition, CNS manifestations
are the major features. Edema is not commonly seen. Muscles become weak. Peripheral neuritis with sen- sory disturbance leads to complete paralysis.
3. Infantile beriberi: It occurs in infants born to mothers suffering from thiamine deficiency.
4. Wernicke-korsakoff syndrome: It is also called cerebral beriberi. Clinical features are those of encephalopathy: • Ophthalmoplegia
• Nystagmus
• Cerebellar ataxia—loss of muscle coordination caused by disorders of cerebellum with psychosis.
Polyneuritis
Polyenuritis is common in chronic alcoholics. Alcohol inhibits intestinal absorption of thiamine, leading to thia- mine deficiency. Polyneuritis may also be associated with pregnancy and old age. Impairment of conversion of ac- etate to acetyl-CoA.
LDH
Pyruvate Lactate Leading to lactic acidosis
Vitamin B2 (Riboflavin)
Vitamin B2 is also called lactoflavin, ovoflavin, hepatoflavin.
Chemistry
Riboflavin has a dimethyl isoalloxazine ring to which a ri- bitol is attached.
Coenzyme
• Flavin adenine dinucleotide (FAD) • Flavin mononucleotide (FMN).
Biochemical Functions
Carbohydrate metabolism
• Pyruvate to acetyl-CoA by pyruvate dehydrogenase • Alpha-ketoglutarate to succinyl-CoA by alpha-ketoglu-
tarate dehydrogenase
• Succinate to fumarate by succinate dehydrogenase.
Lipid metabolism
• Acyl-CoA to alpha-beta unsaturated acyl-CoA by acyl- CoA dehydrogenase.
Protein metabolism
• Glycine to glyoxylate and ammonia by glycine oxidase • D-amino acid to alpha-keto acid and ammonia by D-
amino acid oxidase.
Purine metabolism
• Xanthine to uric acid by xanthine oxidase.
FMN-dependent enzymes
• L-amino to alpha-keto acid and ammonia by alpha- amino acid oxidase.
• NAD+ FMN CoQ. By NADH dehydrogenase.
Riboflavin antagonists
• Dichloro-riboflavin • Isoriboflavin.
Recommended Daily Allowance
• Adult: 1.5 mg/day
Dietary Sources
Rich sources are liver, dried yeast, egg and whole milk. Good sources are fish, whole cereals, legumes and green leafy vegetables.
Deficiency Manifestations
Causes
Natural deficiency of riboflavin in man is uncommon, be- cause riboflavin is synthesized by the intestinal flora. Ri- boflavin deficiency usually accompanies other deficiency diseases such as beriberi, pellagra and kwashiorkor.
Manifestations
Symptoms are confined to skin and mucous membranes: • Glossitis
• Magenta-colored tongue • Cheilosis
• Angular stomatitis (inflammation at the corners of mouth) • Circumcorneal vascularization
• Proliferation of the bulbar conjunctival capillaries.
Vitamin B3 (Niacin)
Vitamin B3 is also called pellagra-preventing factor of Goldberger and nicotinic acid.
Chemistry
Niacin is pyridine-3-carboxylic acid. In tissues, it occurs principally as amide form.
Coenzyme
• Nicotinamide adenine dinucleotide (NAD+)
• Nicotinamide adenine dinucleotide phosphate (NADP+).
Biochemical Functions
NAD+-dependent enzymes.
Carbohydrate metabolism include:
1. Lactate dehydrogenase (lactate pyruvate). 2. Glyceraldehyde-3-phosphate dehydrogenase (glyceral-
dehyde-3-phosphate 1, 3-bisphosphoglycerate). 3. Pyruvate dehydrogenase (pyruvate acetyl-CoA).
Lipid metabolism
1. Beta hydroxyacyl-CoA dehydrogenase (beta hydroxy- acyl-CoA beta-ketoacyl CoA).
NADP+ dependent enzymes
1. Glucose-6-phosphate dehydrogenase in the hexose monophosphate shunt pathway (glucose-6 phosphate
6-phosphogluconolactone). 2. Malic enzyme (malate to pyruvate).
NADPH-dependent enzymes
1. Ketoacyl-ACP dehydrogenase (beta-ketoacyl-ACP beta-hydroxyacyl-ACP).
2. a,b-unsaturated acyl-ACP acyl-ACP.
3. HMG-CoA reductase (HMG-CoA mevalonate. 4. Folate reductase (folate dihydrofolate
tetrahydrofolate).
5. Phenylalanine hydroxylase (phenylalanine tyrosine).
Recommended Daily Allowance
• Adult: 20 mg/day
• Pregnancy and lactation: 25 mg/day.
Dietary Sources
The richest natural sources of niacin are dried yeast, polished rice, liver, peanut, whole cereals, legumes, meat and fish.
Deficiency Manifestations
Pellagra
Pellagra is characterized by three Ds, which are as follows: 1. Dermatitis: Increased pigmentation around the neck
is known as Casal’s necklace (Fig. 7.5).
2. Dementia: It is frequently seen in chronic cases. De- lirium is common in acute pellagra.
3. Diarrhea: The diarrhea may be mild or severe with blood and mucus.
Vitamin B6 (Pyridoxal Phosphate)
Coenzyme
• Pyridoxine • Pyridoxal • Pyridoxamine.
Active form of pyridoxine is pyridoxal phosphate (PLP).
Fig. 7.5: Pellagra
Chapter 7: Nutrition 79
Biochemical Functions
1. Transamination: These reactions are catalyzed by aminotransferases (transaminases), which employ PLP as coenzyme. For example,
Alanine + Pyruvate+
Alpha-ketoglutarate glutamic acid
Alanine transaminase
2. Decarboxylation: All decarboxylation reactions of amino acids require PLP as coenzymes. For examples,
a. Glutamate GABA.
GABA is an inhibitory neurotransmitter and hence in B6 deficiency, especially in children, convul- sions may occur.
b. Histidine histamine.
3. Sulfur-containing amino acids: Pyridoxal phosphate plays an important role in methionine and cysteine metabolism.
Homocysteine + Serine Cystathionine (by cystathionine synthase).
Cystathionine Homoserine + Cysteine (by cystathionase).
4. Heme synthesis: Aminolevulinic acid synthase is a PLP-dependent enzyme. This is the rate-limiting step in heme biosynthesis so, in B6 deficiency, anemia may be seen.
5. Production of niacin from tryptophan require PLP. 6. Glycogenolysis: Phosphorylase enzyme (glycogen to
glucose-1-phosphate) requires PLP. In fact, more than 70% total PLP content of the body is in muscles, where it is a part of the phosphorylase enzyme.
Recommended Daily Allowance
• Adult: 1–2 mg/day
• Pregnancy and lactation: 2.5 mg/day.
Dietary Sources of Vitamin B6
Rich sources are yeast, polished rice, wheat germs, cereals, legumes (pulses), oil seeds, egg, milk, meat, fish and green leafy vegetables.
Deficiency Manifestations
Neurological manifestations
In vitamin B6 deficiency, PLP-dependent enzymes func- tion poorly. So, serotonin, epinephrine, noradrenalin and GABA are not produced properly. Neurological symptoms are therefore quite common in B6 deficiency. In children, B6 deficiency leads to convulsions due to
decreased formation of GABA. The PLP is involved in the synthesis of sphingolipids; so B6 deficiency leads to demy- elination of nerves and consequent peripheral neuritis.
Dermatological manifestations
Deficiency of B6 will also affect tryptophan metabolism. Since, niacin is produced from tryptophan, B6 deficiency in turn leads to niacin deficiency, which is manifested as pellagra.
Hematological manifestations
In adults, hypochromic microcytic anemia may occur due to the inhibition of heme biosynthesis. The metabolic dis- orders, which respond to vitamin B6 therapy are xanth- urenic aciduria and homocystinuria.
Vitamin B9 (Folic Acid)
Vitamin B9 is also called liver lactobacillus casei factor,
Streptococcus lactis resistance (SLR) factor, pteroylglutam-
ic acid (PGA).
Chemistry
The pteridine group with para-aminobenzoic acid (PABA) is pteroic acid. It is then attached to glutamic acid to form pteroylglutamic acid or folic acid.
Coenzyme
Active form is reduced 5, 6, 7, 8-tetrahydrofolic acid (THFA). The THFA is the carrier of one-carbon groups. One car- bon compound is an organic molecule that contains only a single carbon atom. The following groups are one-carbon compounds: • Formyl (—CH=O) • Formimino (—CH=NH) • Methenyl (—CH=) • Methylene (—CH2–) • Hydroxymethyl (—CH2OH) • Methyl (—CH3). Folate antagonists: • Sulfonamides • Pyrimethamine • Aminopterin.
Recommended Daily Allowance
• Adult: 200 mg/day • Pregnancy: 400 mg/day • Lactation: 300 mg/day.
Dietary Sources
Rich sources of folate are yeast, green vegetables. Moder- ate sources are cereals, oil seeds and egg.
Deficiency Manifestations
Reduced DNA synthesis
In folate deficiency, THFA is reduced and thymidylate synthase enzyme is inhibited. Hence deoxyuridine mo- nophosphate (dUMP) is not converted to deoxythymidine monophosphate (dTMP). So deoxythymidine triphos- phate (dTTP) is not available for DNA synthesis. Thus cell division is arrested.
Macrocytic anemia
1. It is the most characteristic feature of folate deficien- cy. During erythropoiesis, DNA synthesis is delayed, but protein synthesis is continued. Thus hemoglobin accumulates in RBC precursors leading to immature looking nucleus and macrocytic cells.
2. Reticulocytosis is often seen. These abnormal RBCs are rapidly destroyed. Reduced generation and in- creased destruction of RBCs result in anemia.
3. Leukopenia and thrombocytopenia are also manifested.
Homocysteinemia
Folic acid deficiency may cause increased homocysteine levels in blood (above 15 mmol/L) with increased risk of coronary artery diseases. It is treated by adequate doses of pyridoxine, vitamins B12 and B9.
Birth defects
Folic acid deficiency during pregnancy causes homocyste- inemia and neural tube defects in fetus. Folic acid prevents birth defects malformations such as spina bifida.
Cancer
Bronchial carcinoma and cervical carcinoma.
Mnemonic: Folate deficiency causes: ‘A FOLIC DROP’
• Alcoholism
• Folic acid antagonists • Oral contraceptives • Low dietary intake • Infection with Giardia • Celiac sprue
• Dilantin
• Relative folate deficiency • Old
• Pregnant
Vitamin B12 (Cobalamin)
Vitamin B12 is called antipernicious anemia factor and ex- trinsic factor of Castle.
Chemistry
Four pyrrole rings coordinated with a cobalt atom is called a corrin ring. The 5th valence of the cobalt is covalently
linked to a substituted benzimidazole ring. This is then called cobalamin. The 6th valence of the cobalt is satisfied by any of the following groups namely cyanide, hydroxyl, adenosyl or methyl.
When cyanide is added at the (R) position, the mol- ecule is called cyanocobalamin. When cyanide group is substituted by hydroxyl group, it forms hydroxy, co- balamin.
Absorption of Vitamin B12
Absorption of vitamin B12 requires two binding proteins. First is the intrinsic factor (IF) of Castle. The second factor is cobalophilin (Figs 7.6A and B).
Transport and storage
In the blood, methyl B12 form is predominant. Transco- balamin, a glycoprotein is the specific carrier. It is stored in the liver cells, as ado-B12 form, in combination with transcorrin.
Biochemical Functions
In B12 deficiency, methylmalonyl-CoA is excreted in urine (methylmalonic aciduria).
Figs 7.6A and B: Absorption of vitamin B12 (R, cobalophilin; Cbl,
cobalamin; IF, intrinsic factor; TC, trans cobalamin)
Chapter 7: Nutrition 81
1. Homocysteine Methyltransferase (Fig. 7.7). 2. Methyl folate trap and folate deficiency.
The production of methyl THFA is an irreversible step. Therefore, the only way for generation of free THFA is step no. 1 in the Figure 7.7. When B12 is deficient, this reaction cannot take place. This is called the methyl folate trap, this leads to the associated folic acid scar- city in B12 deficiency.
Recommended Daily Allowance
• Adult: 1–2 mg/day
• Pregnancy and lactation: 2 mg/day.
Dietary Sources
Richest source is liver. Curd is a good source.
Causes of B12 Deficiency
Nutritional: Nutritional vitamin B12 deficiency is very com- mon in India.
Decrease in absorption: Absorptive surface is reduced by
gastrectomy, resection of ileum and malabsorption syn- dromes.
Addisonian pernicious anemia: It is manifested usually in
persons over 40 years. It is an autoimmune disease. Anti- bodies are generated against IF. So, the IF becomes defi- cient, leading to defective absorption of B12.
Gastric atrophy: Similar atrophy of gastric epithelium lead-
ing to deficiency of IF and decreased B12 absorption is common in India. In chronic iron deficiency anemia, there is generalized mucosal atrophy.
Fig. 7.7: Action of homocysteine methyltransferase (THFA,
tetrahydrofolic acid; 1, –CH3; 2, homocysteine methyltransferase)
Pregnancy: Increased requirement of vitamin in pregnancy is
another common cause for vitamin B12 deficiency in India.
Fish tapeworm: The fish tapeworm, diphyllobothrium la-
tum has a special affinity to B12 causing reduction in avail- able vitamin.
Deficiency Manifestations
Folate trap: Vitamin B12 deficiency causes simultaneous folate deficiency due to the folate trap. Therefore all the manifestations of folate deficiency are also seen.
Megaloblastic anemia: In the peripheral blood, megalo-
blasts and immature RBCs are observed.
Homocysteinemia: In vitamin B12 deficiency, homocysteine is accumulated, leading to homocystinuria and myocar- dial infarction.
Demyelination: In vitamin B12 deficiency, nonavailability of active methionine leads to inadequate methylation of phosphatidylethanolamine to phosphatidylcholine. This leads to deficient formation of myelin sheaths of nerves, demyelination and neurological lesions.
Subacute combined degeneration: Damage to nervous system
is seen in B12 deficiency. There is demyelination affecting cerebral cortex as well as dorsal column and pyramidal tract of spinal cord. Since sensory and motor tracts are affected, it is named as combined degeneration. Symmetrical pares- thesia of extremities, alterations of tendon, and deep senses and reflexes, loss of position sense, unsteadiness in gait, positive Romberg’s sign (falling when eyes are closed) and positive Babinski’s sign (extensor plantar reflex) are seen.
Achlorhydria: Absence of acid in gastric juice is associated
with vitamin B12 deficiency.
Vitamin C (Ascorbic Acid)
Vitamin C is also called antiscorbutic vitamin.
Chemistry
Vitamin C is easily destroyed by heat, alkali and storage. In the process of cooking, 70% of vitamin C is lost.
The structural formula of ascorbic acid closely resem- bles that of carbohydrates. The strong reducing property of vitamin C depends on the double-bonded (enediol) carbons.
Only L-ascorbic acid and dehydroascorbic acid have antiscorbutic activity. The D-ascorbic acid has no activity.
Biochemical Functions
Reversible oxidation-reduction
The vitamin can change between ascorbic acid and dehy- droascorbic acid. Most of the physiological properties of the vitamin could be explained by this redox system. Oxidation
L-ascorbic acid Dehydroascorbic acid
Reduction
Hydroxylation of proline and lysine
Ascorbic acid is necessary for the post-translational hy- droxylation of proline and lysine residue. Hydroxyproline and hydroxylysine are essential for the formation of cross links in the collagen, which gives the tensile strength to the fibers. This process is necessary for the normal production of osteoid, collagen and intercellular cement substance of capillaries.
Tryptophan metabolism
Ascorbic acid is necessary for the hydroxylation of trypto- phan to 5-hydroxytryptophan. This is required for the for- mation of serotonin.
Tyrosine metabolism
Vitamin C helps in the oxidation of para-hydroxyphenyl pyruvate to homogentisic acid.
Iron metabolism
Ascorbic acid enhances the iron absorption from the in- testine. Ascorbic acid reduces ferric iron to ferrous state, which is preferentially absorbed.
Hemoglobin metabolism
Vitamin C is useful for reconversion of methemoglobin to hemoglobin (Hb) by methemoglobin reductase.
Folic acid metabolism
Ascorbic acid is helping the enzyme folate reductase to re- duce the folic acid to tetrahydrofolic acid. Thus it helps in the maturation of RBC.
Steroid synthesis
Adrenal gland possesses increased level of ascorbic acid, particularly in periods of stress. Vitamin C is necessary for hydroxylation reactions for synthesis of corticosteroids. Vitamin C helps in synthesis of bile acids from cholesterol.
Phagocytosis
Ascorbic acid stimulates phagocytic action of leukocytes and helps in the formation of antibodies.
Antioxidant property
As an antioxidant, it may prevent cancer formation.
Cataract
Vitamin C is concentrated in the lens of eye. Regular intake of ascorbic acid reduces the risk of cataract formation.
Recommended Daily Allowance
• Adult: 75 mg/day
• Pregnancy, lactation and in aged people: 100 mg/day.
Dietary Sources
Rich sources are amla (Indian gooseberry), guava, lime, lemon and green leafy vegetables.
Deficiency Manifestations
Scurvy
Gross deficiency of vitamin C results in scurvy.
Infantile scurvy (Barlow’s disease)
In infants between 6 and 12 months of age, (period in which weaning from breast milk), the diet should be sup- plemented with vitamin C sources. Otherwise, deficiency of vitamin C is seen.
Hemorrhagic tendency
In ascorbic acid deficiency, collagen is abnormal and the intercellular cement substance is brittle. So capillaries are fragile, leading to the tendency to bleed even under minor pressure subcutaneous hemorrhage may be manifested as petechiae (small red or purple spots on skin caused by minor hemorrhage due to broken capillaries) in mild defi- ciency and as ecchymoses (large purple or black and blue spots produced by extravasation of blood into tissues) or even hematoma in severe conditions.
Internal hemorrhage
In severe cases, hemorrhage may occur in the conjunc- tiva and retina resulting in epistaxis, hematuria or melena (black colored stools due to oxidation of iron in Hb).
Oral cavity
In severe cases of scurvy, the gum becomes painful, swol- len and spongy. The pulp is separated from the dentine and finally teeth are lost. Wound healing may be delayed.
Bones
In the bones, the deficiency results in the failure of the osteoblasts to form the intercellular substance, osteoid. Without the normal ground substance, the deposition of bone is arrested. The resulting scorbutic bone is weak and
Chapter 7: Nutrition 83
fractures easily. Painful swelling of joints may prevent lo- comotion of the patient.
Anemia
Microcytic, hypochromic anemia is seen.
MINERALS
Minerals are essential for the normal growth and mainte- nance of the body. If the daily requirement is more than 100 mg, they are called major elements or macromineral. If the requirement is less than 100 mg/day, they are known as minor elements or trace elements.
Calcium
Total calcium in the human body is about 1–1.5 kg. About 99% of which is seen in bone and 1% in extracellular fluid.
Sources of Calcium
Milk is a good source of calcium. Egg, fish and vegetables are medium sources for calcium. Cereals contain only small amount of calcium.
Recommended Daily Allowance
Adult: 500 mg/day. Children: 1,200 mg/day.
Pregnancy and lactation: 1,500 mg/day.
Biological Function
1. Calcification of the growing bones and teeth and maintenance of the mature bones are dependent on adequate dietary intake of calcium and phosphorus. 2. Calcium is an activator for a number of enzymes, e.g.
adenylate cyclase, ATPases, protein kinases, etc. Cal- cium, even in very low concentration, activates phos- phorylase kinase through its binding to calmodulin and thus increases the rate of glycogen breakdown. It activates pyruvate dehydrogenase phosphatase, which in turn activates pyruvate dehydrogenase com- plex to produce acetyl-CoA. Calcium also regulates the enzymes of citric acid cycle at several steps. For example, Ca2+ activates isocitrate dehydrogenase and
alpha-ketoglutarate dehydrogenase. Thus, Ca2+ stimu-
lates the production of ATP. 3. It is essential for clotting of blood.
4. It is required for the contraction of muscles (excita- tion-contraction coupling).
5. It regulates the permeability of the capillary walls and excitability of the nerve fibers.
6. It is also required for secretion of various hormones and acts as a second messenger.
7. Calcium regulates cell growth and differentiation.
Absorption
Mechanism of absorption of calcium is taking place from the first and second part of duodenum. Calcium is ab- sorbed against a concentration gradient and requires energy. Absorption requires a carrier protein, helped by calcium-dependent ATPase.
Factors causing increased absorption
1. Vitamin D: Calcitriol induces the synthesis of the car- rier protein (calbindin) in the intestinal epithelial cells and so facilitates the absorption of calcium.
2. Parathyroid hormone: It increases calcium transport