Nicotinic acid from quinoline

Figure 8.2. Synthesis of NAD from nicotinamide, nicotinic acid, and quinolinic acid. Qiiinolinate phosphoribosyltransferase, EC 2.4.2.19 nicotinic acid phosphoribosyl-transferase, EC 2.4.2.11 nicotinamide phosphoribosyltransferase, EC 2.4.2.12 nicotinamide deamidase, EC 3.5.1.19 NAD glycohydrolase, EC 3.2.2.5 NAD pyrophosphatase, EC3.6.1.22 ADP-ribosyltransferases, EC 2.4.2.31 and EC 2.4.2.36 and poly(ADP-ribose) polymerase, EC 2.4.2.30. PRPP, phosphoribosyl pyrophosphate.

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. 

In the first family, the metal is coordinated by one molecule of the pterin cofactor, while in the second, it is coordinated to two pterin molecules (both in the guanine dinucleotide form, with the two dinucleotides extending from the active site in opposite directions). Some enzymes also contain FejSj clusters (one or more), which do not seem to be directly linked to the Mo centers. The molybdenum hydroxylases invariably possess redox-active sites in addition to the molybdenum center and are found with two basic types of polypeptide architecture. The enzymes metabolizing quinoline-related compounds, and derivatives of nicotinic acid form a separate groups, in which each of the redox active centers are found in separate subunits. Those enzymes possessing flavin subunits are organized as a2jS2A2, with a pair of 2Fe-2S centers in the (3 subunit, the flavin in the (3 subunit, and the molybdenum in the y subunit. 

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. 

A purine hydroxylase from fungi,639 bacterial quinoline and isoquinoline oxidoreductases,640/641 and a selenium-containing nicotinic acid hydroxylase from Clostridium barberei6i2 are members of the... 

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 acid and nicotinamide, members of the vitamin B group and used as additives for flour and bread enrichment, and as animal feed additive among other applications, are made to the extent of 24 million pounds (nearly 11 million kilograms) per year throughout the world. Nicotinic acid (pyridine-3-caiboxylic acid), also called niacin, has many uses. See also Niacin. Nicotinic acid is made by the oxidation of 3-picolme or 2-mcthyl-5-cthylpyridine (the isocinchomcnc acid produced is partially deearboxylated). Alternatively, quinoline (the intermediate quinolinic acid) is partially deearboxylated with sulfuric add in the presence of selenium dioxide at about 300° C or with nitric acid, or by electrochemical oxidation. Nicotinic acid also can be made from 3-picoline by catalytic ammoxidation to 3-cyanopyridine, followed by hydrolysis. 

Animals and yeasts can synthesize nicotinamide from tryptophan via hydroxyanthranilic acid (52) and quinolinic acid (53, Fig. 6A) (31), but the biosynthetic capacity of humans is limited. On a diet that is low in tryptophan, the combined contributions of endogenous synthesis and nutritional supply of precursors, such as nicotinic acid, nicotinamide, and nicotinamide riboside, may be insufficient, which results in cutaneous manifestation of niacin deficiency under the clinical picture of pellagra. Exogenous supply of nicotinamide riboside was shown to promote NAD+-dependent Sir2-function and to extend life-span in yeast without calorie restriction (32). 

The results with Neurospora led Bonner and Yanofsky (94) to suggest that the conversion of hydroxyanthranilic acid to nicotinic acid went by way of Intermediates A and B of diagram 21. Quinolinic acid formation was thought to be a shunt or side reaction of intermediate A, slow conversion to nicotinic acid possibly providing an alternative pathway. A similar conclusion was drawn from experiments in the rat (971), and it is now generally agreed that the conversion of quinolinic acid to nicotinic acid is at best of the order of a side reaction (e.g., 685, 754, and in man, 397, 696). 

Quinoline was converted in good yield to nicotinic acid (Sturrock et al., 1960). With indoles, the pyrrole ring opens to give aniline derivatives, as in the formation of 2-aminobenzaldehyde and anthranilic acid from indole (Equation 5.44) (Jurs, 1966). 

Ricinine.—Ricinine (49), the alkaloid of castor bean plants, is derived from nicotinic acid (28) and quinolinic acid (48), and its formation is intimately associated with the pyridine nucleotide cycle cf. ref. 6. Quinolinic acid is built from a C3 fragment that is formed from glycerol via glyceraldehyde and a C4 unit that is related to succinic or aspartic acids. A recent investigation has confirmed this pathway for ricinine (49) and indicated that dihydroxyacetone phosphate lies between glycerol and glyceraldehyde (loss of tritium from C-2 of labelled glycerol). ... 

BiosytMesis In animals tryptophan - kynutenine - 3-hydroxyanthranilic acid - quinolinic acid (pyri-dine-2,3-dicaiboxylic acid) - nicotinic acid - nicotinamide. In bacteria and higher plants from L- aspar-tic acid and a C3-unit, probably D-glyceraldehyde 3-phosphate. Also by cleavage of NAD. 

The pyridine moiety of (-)-nicotine is derived biogenetically from nicotinic acid, which is formed in prokaryotes and plants starting from aspartic acid and glyc-eraldehyde-3-phosphate. [533] In this, the aspartic acid is activated by pyridox-al phosphate. After cycHsation and aromatisation, quinolinic acid is formed first, and then decarboxylation leads to nicotinic acid. 

Quinolinic acid phosphoribosyl transferase (PT) catalyzes the formation of nicotinic acid mononucleotide (NaMN) from quinolinic acid and phosphoribosyl pyrophosphate. The pyridine nucleotide NaMN reacts with ATP (adenosine Hiphos-phate) upon mediation of NaMN adenylyltransferase to form the nicotinic acid adenine dinucleotide (NaAD) (Figure 6.7). The latter is converted to NAD by NAD synthetase. NADP is formed from NAD by the catalysis of NAD kinase. 

Plants produce various pyridine alkaloids derived from nicotinic acid. Trigonelline, the major component in coffee seeds, and ricinine, the toxic alkaloid produced by Ricinus communis, are formed from nicotinic acid originating from the NAD catabolism [20, 25, 26], Quinolinic acid was found to be an efficient precursor in the biosynthesis of nicotine [27]. 

In most bacteria and in higher plants nicotinic acid is formed from aspartic acid and a three carbon unit derived from glycerol, probably D-glyceraldehyde-3-phosphate (D 2). A key intermediate is quinolinic acid, which in animals, however, is derived from l-tryptophan (D 21). Nicotinic acid originates from quinolinic acid via nicotinic acid mononucleotide formed with the participation of 5-phosphoribosyl-l-pyrophosphate. It changes either directly to nicotinic acid or is formed via nicotinamide adenine dinucleotide (NAD+) in the nicotinic acid nucleotide cycle. 

Quinolinate decarboxylation and conversion to nicotinic acid mononucleotide is catalysed by quinolinate phosphoribosyltransferase, a rate-limiting enzyme in the conversion of tryptophan to NAD the reaction requires Mg and is negatively regulated by nicotinamide. Next the transfer of adenylate from ATP by an intermediate of nicotinamide/nicotinate-mononucleotide-adenyl-transferases isoenzymes (NMNAT, see below) yields nicotinic acid adenine... 

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