Hydroxyanthranilic acid mechanism

Kynureninase catalyzes the hydrolytic cleavage of both kynurenine and 3-hydro-xykynurenine to generate anthranilic acid and 3-hydroxyanthranilic acid, respectively [55]. The majority of inhibitors of kynureninase are substrate based and are designed based on the postulated transition state intermediate where water attacks the benzoyl group carbonyl through a PLP-dependant mechanism. The hydroxy (16 = 0.3 pM) and sulfone (17 IC50 =11 pM) derivatives have... 

The thiol-template mechanism is utilized in other enzymes involved in production of peptide-based antibiotics. Actinomycin synthetase II (ACMSII) and b-L-(a-aminoadipolyl)-L-cysteinyl-D-valine (ACV) synthetase catalyze the stereoinversion of valine residues vithin peptide-based antibiotics, and employ ATP and the PAN cofactor in a mechanism similar to that depicted in Fig. 7.14 [58, 59]. ACMSII catalyzes the stereoinversion of a valine within the tripeptide 4-MHA-L-Thr-D-Val (MHA, 4-methyl-3-hydroxyanthranilic acid), which is a precursor for the antibiotic actinomycin D. ACV synthetase catalyzes the stereoinversion of the valine within ACV, which is a precursor for penicillin and cephalosporin [60-63]. ACV synthetase has been shown to have much broader substrate specificity, also accepting non-natural substrates [64, 65]. 

Moline, S.W., Walker, H.C., Schweigert, B.S. 3-Hydroxyanthranilic acid metabolism. VII. Mechanism of formation of quinolinic acid. J. biol. Chem. 234, 880-883 (1959)... 

Picolinic Carboxylase. An enzyme in liver decarboxylates the original carboxyl group of 3-hydroxyanthranilic acid from the oxidation product. The product of the decarboxylation is picolinic acid. Picolinic carboxylase has no known cofactors. The mechanism of its action is thought to involve a temporary loss of the double bond during decarboxylation. This permits rotation of the amino group into a position favoring condensation to form the pyridine ring (XII). 

There is no evidence at present for the conversion of compound I to nicotinic acid. The formation of the vitamin from hydroxyanthranilic acid, however, has been demonstrated in rat liver slices and homogenates (71,72). The mechanism by which nicotinic acid is formed is not clear at present, although it is possible that the open chain saturated aldehyde shown in reactions (Ila) and (Ilia) in Fig. 2 may be an intermediate. The alpha decarboxylation and ring closure involved in the generation of nicotinic acid from compound I is not a spontaneous reaction and appears to be enzymic. Henderson (28) has pointed out that one of the reasons for the failure to observe nicotinic acid synthesis from compound I might be due to the competitive formation of quinolinic and picolinic acids. 

The primary oxidation product of 3-hydroxyanthranilic acid is the precursor of two pyridine compounds, quinolinic and picolinic acids (Mehler, 1956). The structure of the oxidation product is supported by this information, since a chemically plausible mechanism can be devised to acccount for these reactions. The formation of quinolinic acid is a nonenzymic, first-order reaction. The reaction rate is a function of temperature but not of the composition of the medium except for low pH. At low pH values a rapid, irreversible elimination of ammonia and carbon dioxide competes with quinolinic acid formation. At higher pH values the reaction may be considered as beginning with an isomerization of the double bond, leading to the formation of a compound with cu-carboxyl groups. This structure would ordinarily be the less favorable form. 

---