A-Ketoadipate

This enzyme [EC 1.1.1.155] catalyzes the reaction of (-)-l-hydroxy-1,2,4-butane tricarboxylate with NAD+ to produce a-ketoadipate (or, 2-oxoadipate), carbon dioxide, and NADH. 

Example of Gene Duplication Mandelate and a-Ketoadipate Pathways... 

In fungi, lysine is synthesized via an a-aminoadipate pathway [33], The conversion of homoisocitric acid to a-ketoadipic acid occurs due to enzyme homoisocitrate dehydrogenase (EC 1.1.1.87, NAD-HDH) ... 

Catabolism of tryptophan can be divided into the serotonin and 3-hy-droxyanthranilic acid pathways, the latter being by far the more prevalent. It may lead to the formation of NAD+ or to a-ketoadipic acid. Only about 3% of 3-... 

A different approach was adopted in the synthesis by Justoni and Pessina (111). The Japp-Klingemann reaction of p-benzyloxyphenyl-hydrazine with cyclopentanone carboxylic ester gave the p-benzyloxy-phenylhydrazone of a-ketoadipic acid (XIV) Fischer cyclization of the corresponding dimethyl ester then yielded 5-benzyloxyindole-2-car-boxylic-3-jS-propionic acid (XV). Decarboxylation of XV followed by Curtius degradation and debenzylation eventually afforded 5-hydroxy-tryptamine. 

Classical biosynthetic studies with C-labeled compounds and later with stable isotopes established that nonactic acid is derived from two acetates (or malonates), succinate and propionate (Fig. 3d) (21). Feeding studies with 36 (Fig. 3e) has shown that the first committed step of macrotetrolide biosynthesis is the coupling of the succinate unit with an acetate (or malonate) to give a-ketoadipate 40 (22). The late steps of non-actate biosynthesis (Fig. 3 g) were shown to involve the cycliza-tion of 42a into (-)-nonactate and 42b into (-l-)-nonactate, which... 

Lysine. Lysine is converted to a-ketoadipate in a series of reactions that include two oxidations, removal of the side chain amino group, and a transamination. Acetoacetyl-CoA is produced in a further series of reactions that involve several oxidations, a decarboxylation, and a hydration. Acetoacetyl-CoA can be converted to acetyl-CoA in a reaction that is the reverse of a step in ketone body formation. 

Tryptophan. Tryptophan is converted to a-ketoadipate in a long, complex series of eight reactions, which also yield formate and alanine. Acetyl-CoA is synthesized from a-ketoadipate as described for lysine. The alanine produced in this pathway is converted to acetyl-CoA via pyruvate. 

Glutaric acid a-Ketoadipic acid a-Aminoadipic acid... 

The alanine produced at this step can be converted to pyruvate and then acetyl-CoA. The 3-hydroxyanthranilate is further metabolized by a series of eight reactions to acetoacetyl-CoA via a-ketoadipic acid. 

Compound Imidazole acetol phosphate a-Ketoglutarate of-Keto-5- a-Ketoadipate guanidovalerate ... 

Borsook and co-workers arrived at the scheme of catabolism shown in Fig. 11 by isolating C -labeled a-ketoadipic acid and glutaric acid from guinea pig liver homogenates incubated with isotopic a-aminoadipic acid. These authors observed that the deamination of a-aminoadipic acid is much slower than its formation from L-lysine and that the decarboxylation of a-ketoadipic acid is faster than the deamination of the above acid. 

This scheme is that acetate may condense with a-ketoglutarate to yield a homolog of citric acid, which, by undergoing a series of reactions analogous to the citric acid cycle, should yield homoisocitrate, oxalo-glutarate, a-ketoadipate, and ultimately, a-aminoadipic acid. 

The formation of glutaric acid in the pathway of lysine catabolism was demonstrated by Borsook ef al. (157, 158) and by Rothstein and Miller (162). Borsook el oH. incubated L-a-aminoadipic-6-O acid with guinea pig liver homogenates and isolated from the deproteinized filtrates, after addition of carriers, radioactive a-ketoadipic acid as the ph ylhydrazone and glutaric acid, first as the barium salt and subsequently as the ciystalline free acid. The radioactive purity of both products were verified by the maintenance of constant specific activity on repeated recrystallizations. 

Borsook el al. concluded from their results that the a-aminoadipic acid is oxidatively deaminated to a-ketoadipic acid at a slower rate than the formation of the former from lysine, while the decarixnqrlation of the a-ketoadipic acid is a faster reaction than the deamination of a-aminoadipic acid. The normal pathway for the deamination of a-aminoadipic acid might be, however, by transamination and not by dehydrogenation. 

After weighing the different posibilities to counter the lack of equal labeling in carbons 3 and 6 of lysine, Strassman and Weinhouse 180) propose as the more likely synthetic mechanism, a condensation of an acetyl methyl carbon with the carbonyl carbon of a-ketoglutarate, similar to the condensation of acetyl CoA and oxalacetate to yield citrate. This reaction would form homocitric acid. Upon oxidation and decarboxylation of the latter there would be obtained a-ketoadipic acid. Transamination of a-ketoadipic acid produces a-aminoadipic acid, which can be converted to lysine by reduction to the corresponding semialdehyde, followed by transamination. 

Strassman, M., L. N. Ceci, and B. E. Silverman Enzymatic conversion of homoisocitric acid into a-ketoadipic acid. Biochem. Biophys. Research Commun. 14, 268 (1964). 

Bremer, H. J., Wadman, S.K., Przyrembel, H., Wendel, U. and Lombeck, I. (1976), a-Ketoadipic aciduria - a new inborn defect of lysine degradation. Proceedings of the 12th Meeting of the Society for the Study of Inborn Errors of Metabolism, Heidelberg, 1974. In Inborn Errors of Calcium and Bone Metabolism (eds. H. Bickel and J. Stern), Medical and Technical Publishing Co., Lancaster, pp. 271-285. 

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