Biochemistry - Chemical Reactions in Living Cells Volume 3 - D. Metzler 1980

Metabolism of Nitrogenous Compounds
Tryptophan Metabolism and NAD Synthesis

The Biosynthesis of tryptophan, outlined generally in Fig. 14-15, was discussed in Section 3.3. Its Catabolism in animal Tissues is shown schematically in Fig. 14-26. One series of reactions (beginning at stage a) is carried out by intestinal Bacteria. Indole, produced via ß-elimination, is hydroxylated and converted into indoxyl. The latter partially enters the bloodstream and is excreted in the urine as indoxyl sulfate. In animal Cells, the main catabolic pathway of tryptophan begins (stage b, Fig. 14-26) with the action of tryptophan 2,3-dioxygenase [equation (10-45)]. This enzyme has been the subject of intensive research due to its inducibility in animal tissues, as well as the fact that it is subject to hormonal regulation. Both tryptophan and glucocorticoids serve as inducing agents [17, 142].

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FIG. 14-26. Some pathways of tryptophan catabolism and reactions leading to the synthesis of NAD and NADP.

The hydrolytic removal of formate from the product of the tryptophan dioxygenase reaction leads to The formation of kynurenine, a compound that can act as a substrate for several Enzymes. Kynureninase [equation (8-23)] cleaves it into anthranilate and Alanine, whereas Transamination leads to the formation of cyclic kynurenic acid. As a result of an unusual hydroxyl Cleavage reaction, the latter is converted into quinaldic acid, one of the major products excreted in the urine.

Another major metabolic pathway of kynurenine involves its hydroxylation to form 3-hydroxykynurenine (stage c, Fig. 14-26), which can undergo transamination to yield cyclic xanthurenic acid or be cleaved by kynureninase to produce 3-hydroxyanthranilate. In the latter compound, ring opening occurs under the action of a dioxygenase, followed by degradation to glutaryl-CoA, as indicated in the figure. Animals also utilize another pathway of nutritional importance. The aldehyde formed in the decyclization reaction can re-cyclize (stage d) into the pyridine ring of quinolinic acid. The latter, through a decarboxylation reaction, combines with the phosphoribosyl group of a PRPP molecule to form nicotinic acid mononucleotide. Adenylylation yields deamido-NAD, which is converted into NAD by the amination of a carboxyl group at the expense of glutamine.

As shown in Fig. 14-26, free nicotinic acid can also be utilized for NAD formation. Not surprisingly, as a source of NAD, nicotinic acid—an essential vitamin—is approximately 60 times more effective than tryptophan. Nevertheless, a diet high in tryptophan partially compensates for an inadequate Dietary intake of nicotinic acid. The fact that a diet in which maize serves as the sole protein source causes pellagra (a form of vitamin deficiency disease; Box 8-3) is explained in part by the low tryptophan content of this protein. In plants, there appears to be an alternative pathway for quinolinate synthesis—from aspartate and triose phosphate—which serves as the primary route for the natural synthesis of nicotinic acid.

Tryptophan serves as a precursor to numerous Alkaloids and other metabolites. Some of these are shown in Fig. 14-27. The alkaloid harmine, found in plants of several families, can be formed from tryptophan and acetaldehyde (or Pyruvate) via the same pathway shown in Fig. 14-25 for the formation of papaverine.

Hydroxylation of tryptophan yields 5-hydroxytryptophan, which is converted by decarboxylation into serotonin, an important neurotransmitter. Serotonin is found in both plants and animals. It can undergo Acetylation and methylation to form melatonin, a hormone of the Pineal Gland (Fig. 14-27). Certain characteristic plant metabolites are derived directly from serotonin; in particular, psilocybin, a hallucinogenic compound, is formed in this manner in the mushroom Psilocybe aztecorum. The important plant hormone indol-3-ylacetate (auxin) is presumed to be produced via The oxidative decarboxylation of the a-keto acid corresponding to tryptophan. The corresponding aldehyde may serve as an intermediate. Its reduction product, indol-3-ylethanol, is also present in plants and acts as an active metabolite [142a]. For many years, the barley alkaloid gramine was regarded as a biochemical curiosity because its nitrogen atom is separated from the indole ring by only a single carbon atom. It is now considered a breakdown product of tryptophan resulting from a PLP-dependent reaction similar to the reaction catalyzed by Serine transhydroxymethylase (Chap. 8, Sec. D, 3, c; Fig. 14-27). Other alkaloids are formed via more traditional pathways. The Condensation of an isopentyl group with the indole ring of tryptamine underlies the formation of lysergic acid. The indole ring of tryptophan is clearly discernible in The Structure of reserpine from Rauwolfia; this compound is of great medical interest because it lowers Blood pressure by depleting nerve tissues of excess serotonin, dopamine, and norepinephrine. Reserpine also contains a benzene ring derived from tryptophan via a process involving ring expansion.

FIG. 14-27. Structure and biosynthetic pathways of certain indole-containing alkaloids and Other Tryptophan Metabolites.