Nicotinic acid synthesis

Nitrilase-mediated conversion of 3-cyanopyridine into nicotinic acid is an attractive alternative to chemical methods of nicotinic acid synthesis.It has been synthesized using whole cells (containing nitrilase) of some microorganisms and involves the following reaction ... 

An alternative pathway for synthesis of quinoli-nate from aspartate and a triose phosphate exists in bacteria and in plants and provides the major route of nicotinic acid synthesis in nature. In E. coli the reaction is catalyzed by two enzymes, one an FAD-containing L-aspartate oxidase which oxidizes aspartate to a-iminoaspartate.228 The latter condenses with dihydroxyacetone-P to form quinolinate (Eq. 25-13).229 There are at least two other pathways for synthesis of quinolinic acid as well as five or more salvage pathways for resynthesis of degraded pyridine nucleotide coenzymes.224/230/231... 

Nicotinic Add Metabolism. The sequence of reactions leading to the formation of pyridine compounds is of particular interest as a source of nicotinic acid. Nutritional, isotopic, and genetic experiments have all shown that tryptophan and its metabolic derivatives including 3-hydroxy-anthranilic acid are precursors of nicotinic acid in animals and in Neuro-spora. The terminal steps in this sequence are not known. Under certain physiological conditions an increase in picolinic carboxylase appears to reduce nicotinic acid synthesis. This implies a common pathway as far as the oxidation of 3-hydroxyanthranilic acid. Whether quinolinic acid is a precursor of nicotinic acid is still uncertain. The enzyme that forms the amide of nicotinic acid also has not been isolated. Subsequent reactions of nicotinamide include the formation of the riboside with nucleoside phosphorylase and methylation by nicotinamide methyl-kinase. In animals W-methylnicotinamide is oxidized to the corresponding 6-pyridone by a liver flavoprotein. Nicotinic acid also forms glycine and ornithine conjugates. Both aerobic and anaerobic bacteria have been found to oxidize nicotinic acid in the 6-position. ... 

The first enzyme in the kynurenine pathway of tryptophan degradation, liver tryptophan pyrrolase, is inducible by tryptophan and inhibited by reduced nicotinamide adenine dinucleotide. In the case of dietary nicotinic acid deficiency the kynurenine pathway becomes important for nicotinic acid synthesis. Nicotinic acid deficiency causes pellagra. Blocks in the kynurenine pathway because of cofactor deficiencies and/or enzymatic defects result quite often in pellagra-like symptoms. 

There is no evidence at present for the conversion of compound I to nicotinic acid. The formation of the vitamin from hydroxyanthranilic acid, however, has been demonstrated in rat liver slices and homogenates (71,72). The mechanism by which nicotinic acid is formed is not clear at present, although it is possible that the open chain saturated aldehyde shown in reactions (Ila) and (Ilia) in Fig. 2 may be an intermediate. The alpha decarboxylation and ring closure involved in the generation of nicotinic acid from compound I is not a spontaneous reaction and appears to be enzymic. Henderson (28) has pointed out that one of the reasons for the failure to observe nicotinic acid synthesis from compound I might be due to the competitive formation of quinolinic and picolinic acids. 

These studies were confirmed by tracer experiments showing that nitrogen of nicotinic acid (formed by Neurospora) is derived from 3-hydroxyanthranilic acid (478). Experiments with doubly labeled tryptophan demonstrate that tryptophan is probably the only source of quinolinic acid in rat metabolism (645) and that carbon atom 3 of tryptophan, the precursor of the carboxyl carbon of 3-hydroxyanthranilic acid, becomes carboxyl carbon in nicotinic acid (310,340,341,373). In vitro studies of the enzymic oxidation of 3-hydroxyanthranilic acid confirm its relationship to quinolinic acid (498) and show that picolinic acid may also form from it (539,540) but nicotinic acid synthesis under... 

Although there is little doubt that nicotinic acid synthesis takes place in the rat, sheep, cow, and other animals, the simple measurement of nicotinic acid excretion does not seem to be an adequate index. From ail available evidence the only index of nicotinic acid deficiency appears to be the urinary F2 fraction of Najjar and Wood (82-86). This was confirmed by workers using the Fj assay (87, 88) and the so-called trigonelline fraction (89, 90) which is mainly, if not all, F2 (91, 92). The F2 fraction, a derivative of V -methylnicotinamide (80, 91, 93-95) was found to be excreted in substantial quantities in rats and pigs while on a nicotinic-acid-deficient diet, a fact which indicates synthesis of the vitamin. 

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

Craig s synthesis of nicotine (V to VII, p. 42) proceeds via nomicotine. Nicotinic acid nitrile reacts with the Grignard reagent derived from ethyl y-bromopropyl ether to give 3-pyridyl-y-ethoxypropyl ketone (V). This yields an oily oxime (VI) reducible to a-(3-pyridyl)-a-amino-8-ethoxy-w-butane (VII), which with 48 per cent, hydrobromic acid at 130-3° gives womicotine, and this on methylation yields dZ-nicotine. 

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). 

The answer is b. (Hardman, pp 890-891.) Nicotinic acid in large doses stimulates the production of prostaglandins as shown by an increase in blood level. The flush may be prevented by the prior administration of aspirin, which is known to block synthesis of prostaglandins... 

Niacin (nicotinic acid) reduces the hepatic synthesis of VLDL, which in turn leads to a reduction in the synthesis of LDL. Niacin also increases HDL by reducing its catabolism. 

Early investigators assumed that human erythrocytes could convert nicotinic acid, but not the amide, into NAD (H3, H8). There are later reports to the contrary, i.e., that nicotinamide, but not the acid, produced increased synthesis of NAD-active material (L3). To resolve these discrepancies, standards for assaying nicotinic acid activity were prepared by mixing equal weights of the acid and amide, because these... 

H3. Handler, P., and Kohn, H. I., The mechanism of cozymase synthesis in the human erythrocyte a comparison of the role of nicotinic acid and nicotinamide. J. Biol. Chem. 150, 447-452 (1943). 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

Neomycin/nicotinic acid combination therapy lowered Lp(a) markedly in some patients, but nicotinic acid alone was not effective (G35, Ml9). On the other hand, in a subgroup of patients with hypertriglyceridemia, Carlson (C2) and Seed (S27) reported a positive effect of nicotinic acid therapy on Lp(a) levels and ascribed it to an inhibition of synthesis of apo-B. 

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