Nicotinic acid from tryptophan

Vitamins must be derived from the diet because either they cannot be synthesized de novo in human beings or their rate of synthesis, e.g. the production of nicotinic acid from tryptophan, is inadequate for the maintenance of health. Only vitamin D can be manufactured by the body at a sufficient rate. 

A8. Auricchio, S., Rigillo, N., and Di Toro, R., Researcbes on the biosynthesis of nicotinic acid from tryptophan during pregnancy, the foetal and the neonatal periods. I. Tryptophan pyrrolase and 3-hydrorgrantfaranilic oxidase activity of the rat liver. Minerva Pediat. 12, 1463-1470 (I960). 

Therefore, there is substantial evidence that 3-hydroxyanthranilic acid is an intermediate on the direct pathway of the synthesis of nicotinic acid from tryptophan. 

Pellagra is now recognized as a multifactorial disease and the vitamin status of nicotinic acid is questionable. The body is able to synthesize nicotinic acid from tryptophan so that nicotinic acid only becomes a dietary essential when the tryptophan content of the diet is low. The fact that maize proteins are relatively poor in tryptophan, and that the nicotinic acid it contains is in a form which is not readily available, would seem to explain the association of pellagra and the use of maize as a staple foodstuff. For nutritional purposes 60 mg tryptophan are believed to be equivalent to 1 mg of nicotinic acid and the recommended intake for an adult male is given as 18 mg of nicotinic acid or its equivalent. Primary nicotinic acid deficiency is unlikely to occur in this country where appreciable amounts of animal products are consumed and where flour must, by law, contain 1-6 mg nicotinamide per 100g. 

Tryptophan conversion to niacin (nicotinic acid). It assists in forming niacin (nicotinic acid) from tryptophan, thereby playing a role in the niacin supply. 

It has been reported that germ-free Drosophila (SO), TriboUum con-fusium (SI), or Tenebrio molitor (SI) can synthesize nicotinic acid from tryptophan. 

There are numerous sources of niacin that are essential and these include poultry, fish (tuna, salmon), meat (beef), yeast, legumes, milk and fortified eereals. In addition, niacin is naturally occurring in tiny amounts and the human body can make nicotinic acid from the metabolism of dietary tryptophan (Vosper 2009). The body requires tryptophan for two main reasons (i) for the synthesis of niacin and (ii) to raise serotonin levels, which is essential for the regulation of sleep, appetite and mood. The vast majority of proteins contain about 1 % of tryptophan and it is suggested that approximately 100 g of protein intake a day will be sufficient to ensure optimum levels of niacin in the body. The recommended dose of niacin is higher when there is an increase in physiological states such as pregnancy and lactation. Importantly, the Committee of Medical Aspects of Food Policy (COMA) in the UK stated that the Reference Nutrient Intake (RNI) for niacin was 17 mg/day and 13 mg/day. 

This dietary deficiency disease is due to lack of the vitamin niacin or of the amino acid tryptophan (which is converted in the E)ody to nicotinic acid). It usually afflicts people whose dietary protein comes mainly from maize (corn) (which is deficient in both nicotinic acid and tryptophan). Also, it occurs in areas of India where the diet consists mainly of a millet called Jowar (Sorghum vulgare) without any animal foods. Some alcoholics and persons with disorders of abrsorp-tion have also been found to have the disease. 

Most foods of animal origin contain nicotinamide in the coenzyme form (high bioavialability). Liver and meat are particularly rich in highly bioavailable niacin. Most of the niacin in plants, however, occurs as nicotinic acid in overall lower concentrations and with a lower bioavailability. The major portion of niacin in cereals is found in the outer layer and its bioavailability is as low as 30% because it is bound to protein (niacytin). If the diet contains a surplus of L-tryptophan (Ttp), e.g., more than is necessary for protein synthesis, the liver can synthesize NAD from Trp. Niacin requirements are therefore declared as niacin equivalents (1 NE = 1 mg niacin = 60 mg Trp). 

Niacin was discovered as a nutrient during studies of pellagra. It is not strictly a vitamin since it can be synthesized in the body from the essential amino acid tryptophan. Two compounds, nicotinic acid and nicotinamide, have the biologic activity of niacin its metabolic function is as the nicotinamide ring of the coenzymes NAD and NADP in oxidation-reduction reactions (Figure 45-11). About 60 mg of tryptophan is equivalent to 1 mg of dietary niacin. The niacin content of foods is expressed as mg niacin equivalents = mg preformed niacin + 1/60 X mg tryptophan. Because most of the niacin in cereals is biologically unavailable, this is discounted. 

Nicotinic acid derivatives occur in biologic materials as the free acid, as nicotinamide, and in two coenzymatic forms nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes act in series with flavoprotein enzymes and, like them, are hydrogen acceptors or, when reduced, donors. Several plants and bacteria use a metabolic pathway for the formation of nicotinic acid that is different from the tryptophan pathway used by animals and man (B39). 

Epileptiform fits associated with degenerative changes in the myelin sheath of peripheral nerves and spinal cord occur in B6-deficient animals. Lesions in the arteries, resembling those of human atherosclerosis, have been observed in Be-deficient monkeys. Recently, a state of Be deficiency in human infants, characterized by loss of ability to convert tryptophan to nicotinic acid, by impaired growth, convulsions, and hypochromic anemia, has been described, following omission of vitamin B6 from the diet. 

An intriguing feature of nicotinic acid formation in animals is that it is a metabolite produced from the amino acid tryptophan. This means the pyridine ring is actually formed by biochemical modification of the indole fused-ring system (see Section 11.8.2), and, as you might imagine, it involves a substantial sequence of transformations. 

Alkaloids derived from nicotinic acid contain a pyridine nucleus. Nicotinic acid itself is synthesized from L-tryptophan via A-formylkynurenine, L-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid. 

Niacin is also known as vitamin PP or vitamin Bj. The term niacin describes two related compounds, nicotinic acid and nicotinamide (Figure 19.18), both with biological activity. Niacin is formed from the metabolism of tryptophan, and therefore it is not strictly a vitamin. It is a precursor of two cofactors nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are essential for the functioning of a wide range of enzymes involved in redox reactions. 

Drug-induced niacin deficiency has resulted from the use of isonicotinic acid hydrazide, which interferes with the conversion of niacin from tryptophan. Administration of ethanol or the antimetabolites 6-mercaptop-urine and 5-fluorouracil also may lead to niacin deficiency. The uricosuric effects of sulfinpyrazone and probenecid may be inhibited by nicotinic acid. 

Niacin is a generic term which refers to two related chemical compounds, nicotinic acid (6.22) and its amide, nicotinamide (6.23) both are derivatives of pyridine. Nicotinic acid is synthesized chemically and can be easily converted to the amide in which form it is found in the body. Niacin is obtained from food or can be synthesized from tryptophan (60 mg of dietary tryptophan has the same metabolic effect as 1 mg niacin). Niacin forms part of two important co-enzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are co-factors for many enzymes that participate in various metabolic pathways and function in electron transport. 

FIGURE 13-17 Structures of niacin (nicotinic acid) and its derivative nicotinamide. The biosynthetic precursor of these compounds is tryptophan. In the laboratory, nicotinic acid was first produced by oxidation of the natural product nicotine—thus the name. Both nicotinic acid and nicotinamide cure pellagra, but nicotine (from cigarettes or elsewhere) has no curative activity. 

Niacin is found in unrefined and enriched grains and cereal, milk, aid lean meats, especially liver. Limited quantities of niacin can also be obtained from the metabolism of tryptophan. [Note The pathway is inefficient in that only about 1 mg of nicotinic acid is formed from 60 mg of tryptophan. Further, tryptophan is metabolized to niacin orty when there is a relative abundance of the amino acid—that is, alter the needs for protein synthesis and energy production have been met]... 

There are exceptions to the above. Most or all vitamins can be synthesized chemically. Vitamin D can be synthesized in the skin of animals by exposure to ultraviolet irradiation, and nicotinic acid (niacin) can be synthesized in the body from the AA tryptophan. 

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