Tryptophan Kynurenine formamidase

The experiments discussed above on the biosynthesis of a pseudan have also shown that kynurenic acid is not the precursor of the 2-alkylquinolin-4(lH)-ones. Based on the putative function of the genes of the qbs operons (176), a pathway was proposed for the biosynthesis of kynurenic acid (I), xanthurenic acid [10(8)], and quinolobactin [IO(8) j in Pseudomonas fluorescens ATCC 17400 (Scheme 5). The first step, the oxidation of tryptophan to N-formylkynurenine, is likely to be catalyzed by the enzyme tryptophan 2,3-dioxygenase (TDO) (QbsF), which is a heme-dependent enzyme. The second step, the deformylation of N-formyl-kynurenine to L-kynurenine is catalyzed by kynurenine formamidase (KFA). The product of qbsH, a metal-dependent hydrolase found also in other bacterial genomes, is the likely candidate. 

Figure 8.4. Pathways of tryptophan metaholism. Tryptophan dioxygenase, EC 1.13.11.11 formylkynurenine formamidase, EC 3.5.1.9 kynurenine hydroxylase, EC 1.14.13.9 kynureninase, EC 3.7.1.3 3-hydroxyanthranilate oxidase, EC 1.10.3.5 picolinate carboxylase, EC 4.1.1.45 kynurenine oxoglutarate aminotransferase, EC 2.6.1.7 kynurenine glyoxylate aminotransferase, 2.6.1.63 tryptophan hydroxylase, EC 1.14.16.4 and 5-hydroxytryptophan decarboxylase, EC 4.1.1.26. Relative molecular masses (Mr) tryptophan, 204.2 serotonin, 176.2 kynurenine, 208.2 3-hydroxykynurenine, 223.2 kynurenic acid, 189.2 xanthurenic acid, 205.2 and quinolinic acid 167.1. CoA, coenzyme A.

IDO is a key enzyme in the degradation of tryptophan in extra-hepatic tissues [37], through the generation of AAformyl kynurenine which is further degraded to kynurenine (l-KYN) by formamidase. In addition to its potential role in neurodegeneration, inhibition of IDO has been implicated as an important new therapeutic target for the treatment of cancer through tumor immunosuppression [3, 38]. 

Samples of (3R)- and (3S)-[3- Hi]tryptophans 331 have been converted to the corresponding kynurenines 336 using the enzymes tryptophan dioxygenase (EC 1.13.11.11) and formylkynurenine formamidase (EC 3.5.1.9). These have been used to investigate the fission of kynurenine 336 to anthranilic acid 300 and alanine 337 in H20 (337) (Scheme 85). Conversion of the alanine to acetate and assessment of sense of chirality indicated that... 

Fig. 244. Degradation of L-tryptophan via kynurenine and 3-hydroxyanthranilic acid 1 Tryptophan 2,3-dioxygenase (tryptophan pyrrolase, C 2.5) 2 formamidase 3 kynurenine 3-monooxygenase 4 kynureninase 5 3-hydroxyanthranilate 3,4-dioxygenase 6 aminocarhoxy-muconate semialdehyde decarboxylase 7 aminomuconate semialdehyde dehydrogenase 8 0x0-glutarate dehydrogenase system 9 spontaneous cyclization...

The tryptophan-oxidizing activity can be assayed by various determinations of the substrate, but more rapid and convenient assays have been used based on the appearance of the product. The initial product of tryptophan oxidation is A -formylkynurenine, but this is rapidly hydrolyzed by an enzyme, kynurenine formylase (Mehler and Knox, 1951) or formamidase, that is much more active than tryptophan pyrrolase. The kynurenine that is produced in the second reaction accumulates... 

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