0-Carboxymuconic acid

Degradation of L-tryptophan in most organisms proceeds via L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilic acid and quinolinic acid to acetyl Co A and CO2 (Fig. 244). Anthranilic acid formed as an intermediate may be recycled to L-tryptophan (see above). The ring of 3-hydroxyanthranilic acid is cleaved by a dioxygenase (C 2.5). The x-amino-/3-carboxymuconic acid-e-semialdehyde formed either undergoes a cis trans isomerization of the Zl -double bond and cyclization to quinolinic acid, a compound synthesized in microorganisms and plants from aspartic acid and D-glyceraldehyde-3-phosphate (D 16.2). On the other hand o -amino-/3-carboxymuconic acid-e-aldehyde may be de-carboxylated and is then the immediate precursor of NH3, acetic acid and COg. 

This enzyme catalyzes the aerobic transformation of proto-catechuic acid to p-carboxymuconic acid (equation 26 (501)). The... 

Protocatechuic oxidase was found to be quite specific catechol, hydroxyhydroquinone, 2,3-dihydroxybenzoic acid, 2,4-dihydroxyben-zoic acid, o-, m-, and/ -hydroxybenzoic acids, and several esters of protocatechuic acid were not oxidized, although catechol and the dihydroxy-benzoic acids were found to be competitive inhibitors. Methylene blue failed to replace oxygen in this reaction. A similar enzyme induced in Neurospora by protocatechuic or vanillic acid also requires molecular oxygen and forms j8-carboxymuconic acid (Gross et al., 1956). 

The metabolism of j8-carboxymuconic acid in all species tested results in the formation of -ketoadipic acid, but the route taken seems to vary in each case. The first reaction in all cases is the formation of a lactone by addition of a carboxyl group to a double bond. This reaction has been followed with C -labeled substrate (Gross et al., 1956). In the case of Neurospora, the addition appears to involve carboxyl group 1 and position... 

Vibrio. They have also eliminated ]8, y-dihydroxyadipic acid as an intermediate, in the degradation of protocatechuic acid by Pseudomonas. The monolactone is a precursor of j3-ketoadipic acid in extracts of certain organisms adapted to protocatechuic acid thus, following decarboxylation, the catechol and protocatechuic pathways become identical. The roles of the lactones of j8-carboxymuconic acid are still not certain evidence for a lactone with an absorption spectrum different from known lactones was obtained with Nocardia extracts (Cain and Cartwright, 1960). 

Catabolism of tyrosine and tryptophan begins with oxygen-requiring steps. The tyrosine catabolic pathway, shown at the end of this chapter, results in the formation of fumaric acid and acetoacetic acid. Tryptophan catabolism commences with the reaction catalyzed by tryptophan-2,3-dioxygenase. This enzyme catalyzes conversion of the amino acid to N-formyl-kynurenine. The enzyme requires iron and copper and thus is a metalloenzyme. The final products of the pathway are acetoacetyl-CoA, acetyl-CoA, formic acid, four molecules of carbon dioxide, and two ammonium ions. One of the intermediates of tryptophan catabolism, a-amino-P-carboxymuconic-8-semialdehyde, can be diverted from complete oxidation, and used for the synthesis of NAD (see Niacin in Chapter 9). 

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.

Scheme 12.105. A path from tryptophan (Trp, W) to 2-amino-3-carboxymuconate semialdehyde, which spontaneously cyclizes to quinolinic acid (Begley,T. P. Nat. Prod. Rep., 2006,23,...

Figure 2 NAD metabolism. Tip = tryptophan, 3-HK = 3-hydroxykynurenine, 3-HA = 3-hydroxyanthranilic acid, ACMS = a-amino-P-carboxymuconate- -semialdehyde, AMS = a-aminomuconate- -semialdehyde, NaMN = nicotinic acid mononucleotide, NMN = nicotinamide mononucleotide, NaAD = nicotinic acid adenine dinucleotide. For other abbreviations, see Figure 1. (1) tryptophan oxygenase [EC 1.13.11.11], (2) formy-dase [EC 3.5.1.9], (3) kynurenine 3-hydroxylase [EC 1.14.13.9], (4) kynureninase [EC 3.7.1.3], (5) 3-hydroxyanthranilic acid oxygenase [EC 1.13.11.6], (6) nonenzymatic, (7) aminocarboxymuconate-semialdehyde decarboxylase [EC 4.1.1.45], (8) quinolinate phos-phoribosyltransferase [EC 2.4.2.19], (9) NaMN adenylyltransferase [EC 2.7.2.18], (10) NAD synthetase [EC 6.3.5.1], (11) NAD kinase [EC 2.7.1.23], (12) NAD" glycohydro-lase [EC 3.2.2.5], (13) nicotinamide methyltransferase [EC 2.2.1.1], (14) 2-Py-forming MNA oxidase [EC 1.2.3.1], (15) 4-Py-forming MNA oxidase [EC number not given], (16) nicotinamide phosphoribosyltransferase [EC 2.4.2.12], (17) NMN adenylytransferase [EC 2.7.71], (18) nicotinate phosphoribosyltransferase [EC 2.4.2.11], (19) nicotinate methyltransferase [EC 2.7.1.7], and nicotinamidase [EC 3.5.1.19]. Solid line, biosynthesis dotted line, catabolism.

C. a-Amino-)8-carboxymuconic-6-semialdehyde Quinolinic acid (Bokman and... 

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