Tryptophan metabolic fate

The synthesis of NAD from tryptophan involves the non-enzymic cyclization of aminocarboxymuconic semialdehyde to quinolinic acid. The alternative metabolic fate of aminocarboxymuconic semialdehyde is decarboxylation, catalysed by picolinate carboxylase, leading to acetyl CoA and total oxidation. There is thus competition between an enzyme-catalysed reaction, which has hyperbolic, saturable kinetics, and a non-enzymic reaction, which has linear kinetics. At low rates of flux through the pathway, most metabolism will be by way of the enzyme-catalysed pathway, leading to oxidation. As the rate of formation of aminocarboxymuconic semialdehyde increases, and picolinate carboxylase becomes more or less saturated, so an increasing proportion will be available to undergo cyclization to quinolinic acid and onward metabolism to NAD. There is thus not a simple stoichiometric relationship between tryptophan and niacin, and the equivalence of the two coenzyme precursors will vary as the amount of tryptophan to be metabolized and the rate of metabolism vary. 

Several alternative pathways of L-tryptophan metabolism diverge from kynurenine (24). In mammals the quantitatively major fate of the benzene ring of the amino acid appears to be its oxidation to carbon dioxide via 3-hydroxyanthranilic acid (25), Figure 4.5. Kynurenine is first hydroxylated by a typical mixed function oxidase and the side chain is then removed, under the... 

Figure 9-3. Fates of the carbon skeletons upon metabolism of the amino acids. Points of entry at various steps of the tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis are shown for the carbons skeletons of the amino acids. Note the multiple fates of the glucogenic amino acids glycine (Gly), serine (Ser), and threonine (Thr) as well as the combined glucogenic and ketogenic amino acids phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr). Ala, alanine Cys, cysteine lie, isoleucine Leu, leucine Lys, lysine Asn, asparagine Asp, aspartate Arg, arginine His, histidine Glu, glutamate Gin, glutamine Pro, proline Val, valine Met, methionine.

Tryptophan can be converted to indolepyruvic acid either by oxidative deamination or by transamination (e.g., 739, 912) and the indolepyruvic acid can give rise to indoleacetic acid. The fate of indoleacetic acid formed by the bacterial flora of the mammalian gut is discussed below. Bacterial indolelactic acid (e.g., 757) is presumably derived from indolepyruvic acid, but indolelactic acid excreted by mammals (e.g. 17) may be of true mammalian rather than bacterial origin. Indolepropionic acid can also be formed by bacteria (e.g., 412, 633), but further metabolism in mammals of any indolepropionic acid formed in the gut is still obscure (904). Skatole (3-methylindole) has long been known as a product of bacterial decomposition of protein and is formed from tryptophan not only by the bacterial flora of the gut but also in putrefying secretions, e.g., sputum (756). It may well arise by decarboxylation of indoleacetic acid. 

In considering amino acid catabolism, one must distinguish the catabolism of the carbon chain from that of the nitrogen moiety. The breakdown of the carbon chain of the amino acids yields carbon units that can be used in carbohydrate metabolism, acetate metabolism, or the metabolism of single carbon units. The fate of the carbon units of the individual amino acids has been discussed in other sections of this book, and only a synopsis of the results will be presented here. The carbon skeletons of isoleucine, phenylalanine, threonine, tryptophan, valine, histidine, alanine, arginine, aspartic acid, glycine, proline, glutamic acid, and hydroxyproline are ultimately converted to pyruvic acid. 

From the historical point of view, interest in the chemical oxidation of tryptophan and related indole compounds was stimulated by attempts to elucidate the fate of tryptophan in animal metabolism. Biological hydroxylations and oxidative degradations of the indole nucleus represent main steps in the metabolic pathway of tryptophan (see Section II.4). 

---