Nicotinic acid tryptophan transformation

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. 

Figure 2 NAD biosynthesis subsystem diagram. Major functional roles are shown by 4-6 letter abbreviations (explained in Table 1) over the colored background reflecting the key aspects or modules (pathways) that comprise NAD biosynthesis in various species. Catalyzed reactions are shown by solid straight arrows, and corresponding intermediate metabolites are shown as abbreviations within ovals Asp, L-aspartate lA, Iminoaspartate Qa, quinolinic acid Nm, nicotinamide Na, nicotinic acid NaMN, nicotinic acid mononucleotide NMN, nicotinamide mononucleotide RNm, N-ribosyInicotinamide NaAD, nicotinate adenine dinucleotide NAD, nicotinamide adenine dinucleotide NADP, NAD-phosphate Trp, tryptophan FKyn, N-formylkynurenine Kyn, kynurenine HKyn, 3-hydroxykynurenine HAnt, 3-hydroxyanthranilate and ACMS, a-amino-/3-carboxymuconic semialdehyde. Unspecified reactions (including spontaneous transformation and transport) are shown by dashed arrows.

The conversion of tryptophan into nicotinic acid involves a series of molecular transformations. The original tryptophan molecule not only loses its alanine side chain and its imidazole ring, but it also includes nitrogen in its benzoic ring to form a pyridine ring [69-71]. 

Niacin, also known as vitamin B3, nicotinic acid or vitamin PP, is a water-soluble B-complex vitamin (Table 7.1). This vitamin is the generic descriptor for two vitamers niacin and niacinamide. In the research literature the terms nicotinic acid/nicotinamide are most commonly used, while in medical practice niacin/niadnamide are preferred. The vitamin is obtained from the diet in the form of nicotinic acid, nicotinamide and tryptophan, which are transformed to nicotinamide adenine dinucleotides, NAD and NADP. These compounds participate in cellular oxidation-reduction reactions that are critical for energy production. NAD and NADP also participate in a wide variety of... 

The mechanism of the transformation of the indole ring of tryptophan to the pyridine ring of nicotinic acid is of singular interest to both the organic chemist and the biochemist. 

Quinolinic acid was identified as a metabolite of tryptophan in the rat by Henderson and Hirsch in 1949 (65). Quinolinic acid has been known to be a key intermediate of the tryptophan-NAD and aspartate + dihydroxyacetone phosphate-NAD pathways since the clear demonstration in vitro by Nishizuka and Hayaishi in 1963 (50). It has been proven that quinolinic acid is transformed into nicotinic acid mononucleotide in the presence of 5-phosphoribosyl-l-pyrophosphate by quinolinate phosphoribosyltransferase (50). In 1978 Lapin (52) first reported that quinolinic acid induced seizures when injected directly into the brains of mice. Later, quinolinic acid was shown to increase neuronal activity when ionophoreti-cally applied to neurons in rats cerebral cortex, striatum, and hippocampus (53,66,67). Now, quinolinic acid is known as a potent neurotoxin and as a precursor of NAD in the liver. 

NAD(P)+ from the diet is first hydrolysed to a mixture of nicotinic acid and nicotinamide. Nicotinic acid can then be transformed into nicotinamide and then to NAD(P)+ in the body. These dinucleotides are de novo synthesised by bacteria and some plants from aspartic acid and 1,3-dihydroxyacetone phosphate (glycerone phosphate). Quinolinic acid is an intermediate. It arises from tryptophan in some microorganisms and in animals. 

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