Daily requirement of niacin is 20 mg
Daily requirement of niacin is 20 mg
Niacin is pyridine-3-carboxylic acid. Niacinamide is the acid amide. In NAD+ or NADP+ , the reactive site is the carbon atom 4 and the nitrogen atom of the nicotinamide ring. The co-enzyme is bound to the apo-enzyme.
Co-enzyme Forms of Niacin
Niacin is converted to its co-enzyme forms, viz, Nicotinamide adenine dinucleotide (NAD+ ) and Nicotinamide adenine dinucleotide phosphate (NADP+ ). The niacin is attached to a ribose phosphate to form a mononucleo[1]tide. It is then attached to AMP, to form the dinucleotide. The nitrogen atom of niacinamide contains one positive charge. The structure is abbreviated as NAD+ . (The +ve sign is always shown). In the case of NADP+, one more phosphoric acid is attached to the ribose of the AMP.
One Hydrogen Atom and One Electron
In the oxidized form, nitrogen of the nicotinamide residue has a positive charge. Hence the oxidized form of co-enzyme is usually written as NAD+. In the process of reduction, NAD+ accepts one hydrogen atom fully. The other hydrogen is ionized. Only the electron is accepted. See the positive sign in the molecule is removed.
2H --------------->H + H+ + e-.
Thus NAD+ accepts one H atom and one e- (electron), to form NADH. The hydrogen ion (H+ ) is released
into the surrounding medium. During the oxidation of NADH, the reaction is reversed.
NAD+ Dependent Enzymes
They are so many, that an exhaustive listing is not attempted. One NADH molecule is oxidized in the respiratory chain to generate 2 ½ ATPs. But NADPH is used almost exclusively for reductive biosynthetic reactions.
- Lactate dehydrogenase (lactate → pyruvate)
- Glyceraldehyde-3-phosphate dehydrogenase (glyceraldehyde-3-phosphate → 1,3-bisphosphoglycerate)
- Pyruvate dehydrogenase (pyruvate → acetyl CoA)
- Alpha ketoglutarate dehydrogenase (alpha ketoglutarate → succinyl CoA)
- Beta hydroxyacyl CoA dehydrogenase (beta hydroxyacyl CoA → beta ketoacyl CoA
- Glutamate dehydrogenase (Glutamate → alpha ketoglutarate
NADPH Dependent Reactions
The NADPH generating reactions are shown in Box 37.4. A few examples of NADPH utilizing enzymes are
- Glucose-6-phosphate dehydrogenase in the hexose monophosphate shunt pathway (Glucose-6-phosphate → 6-phospho-glucono lactone)
- 6-phospho gluconate dehydrogenase in the shunt pathway (6-phospho gluconate → 3-keto-6-phospho gluconate).
- Cytoplasmic isocitrate dehydrogenase
- Malic enzyme (malate to pyruvate).
Some enzymes can use either NAD+ or NADP+ as co-enzyme, e.g. glutamate dehydrogenase. In addition to this co-enzyme role, NAD+ is the source of ADP-ribose for the ADP-ribosylation of proteins and poly-ADP-ribosylation of nucleoproteins.
Niacin deficiency
Pellagra
Deficiency of niacin leads to the clinical condition called pellagra. Pellagra is an Italian word, meaning “rough skin”. Pellagra is caused by the deficiency of Tryptophan as well as Niacin. Pellagra is seen more in women; this may be because tryptophan metabolism is inhibited by estrogen metabolites. The symptoms of pellagra are:
- Dermatitis: In early stages, bright red erythema occurs, especially in the feet, ankles and face. Increased pigmentation around the neck is known as Casal’s necklace. The dermatitis is precipitated by exposure to sunlight.
- Diarrhea: The diarrhea may be mild or severe with blood and mucus. This may lead to weight loss. Nausea and vomiting may also be present.
- Dementia: It is frequently seen in chronic cases. Delerium is common in acute pellagra. Irritability, inability to concentrate and poor memory are more common in mild cases. Ataxia, and spasticity are also seen.
Niacin is Synthesized from Tryptophan
Quinolinate phosphoribosyl transferase is the rate limiting enzyme in the conversion of niacin to NAD+ . About 60 mg of tryptophan is equivalent to 1 mg of niacin.
Causes for Niacin Deficiency
- Dietary deficiency of tryptophan: Pellagra is seen among people whose staple diet is maize (South and Central America). In maize, niacin is present; but it is in a bound form, and is unavailable. Pellagra is also seen when staple diet is sorghum (jowar or guinea corn) as in Central and Western India. Sorghum, contains leucine in high quantities. Leucine inhibits the QPRT enzyme, and so niacin cannot be converted to NAD+ (Leucine pellagra).
- Deficient synthesis: Kynureninase, an important enzyme in the pathway of tryptophan, is pyridoxal phosphate dependent. So conversion of tryptophan to niacin is not possible in pyridoxal deficiency.
- Isoniazid (INH): It is an antituberculous drug, which inhibits pyridoxal phosphate formation. Hence, there is block in conversion of tryptophan to NAD+.
- Hartnup disease: Tryptophan absorption from intestine is defective in this congenital disease. Moreover, tryptophan is excreted in urine in large quantities. This leads to lack of tryptophan and consequently deficiency of nicotinamide.
- Carcinoid syndrome: The tumor utilizes major portion of available tryptophan for synthesis of serotonin; so tryptophan is unavailable.
Dietary Sources of Niacin
The richest natural sources of niacin are dried yeast, rice polishing, liver, peanut, whole cereals, legumes, meat and fish. About half of the requirement is met by the conversion of tryptophan to niacin. About 60 mg of tryptophan will yield 1 mg of niacin.
Recommended Daily Allowance (RDA)
Normal requirement is 20 mg/day. During lactation, additional 5 mg is required.
Therapeutic Use of Niacin
Nicotinic acid inhibits the flux of free fatty acids from adipose tissue; so acetyl CoA pool is reduced; and hence serum cholesterol is lowered. In high doses niacin is useful to reduce Lp(a) levels.
Toxicity of Niacin
Nicotinic acid when given orally or parenterally produces a transient vasodilatation of the cutaneous vessels and histamine release. The reaction is accompanied by itching, burning and tingling. Intake of nicotinic acid in excess of 50 mg/day may lead to liver damage.
DM Vasudevan textbook of biochemistry for medical students 7th edition