A-Ketoadipic acid

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. 

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. 

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. 

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). 

Biological. A proposed microbial degradation mechanism is as follows 4-hydroxy-3-methylbenzyl alcohol to 4-hydroxy-3-methylbenzaldehyde to 3-methyl-4-hydroxybenzoic acid to 4-hydroxyisophthalic acid to protocatechuic acid to p ketoadipic acid (Chapman, 1972). In anaerobic sludge, diethyl phthalate degraded as follows monoethyl phthalate to phthalic acid to protocatechuic acid followed by ring cleavage and mineralization (Shelton et al, 1984). 

The catabolism of lysine merges with that of tryptophan at the level of (3-ketoadipic acid. Both metabolic pathways are identical from this point on and lead to the formation of acetoacetyl-CoA (Figure 20.21). Lysine is thus ketogenic. It does not transaminate in the classic way. Lysine is a precursor of carnitine the initial reaction involves the methylation of e-amino groups of protein-bound lysine with SAM. The N-methylated lysine is then released proteolytically and the reaction sequence to carnitine completed. See Equation (19.6) for the structure of carnitine. 

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... 

In prokaryotic mechanisms the essential steps allowing an aromatic or substituted aromatic to enter the 3-ketoadipic acid pathway are often but not always encoded by plasmid DNA. In some cases both a chromosomal and plasmid pathway are available. Extrachromosomal DNA can be obtained through a variety of mechanisms and can be very infectious. The rapid transmission of extrachromosomal DNA has the potential to enhance genetic recombination and results in rapid evolutionary change. In addition the availability of pathways on relatively easy-to-manipulate genetic material enhances our ability to sequence and artificially modify the code and, perhaps, to enhance the degradative capability of microorganisms. 

ALAS is the initial enzyme of the pathway and catalyzes the formation of ALA from succinyl-CoA and glycine. The enzyme is mitochondrial and requires pyridoxal phosphate as a cofactor, which forms a Schiff base with the amino group of glycine at the enzyme surface. The carbanion of the Schiff base displaces Co enzyme A from succinyl-CoA with the formation of a-amino-P-ketoadipic acid, which is then... 

The reaction mechanism consists of formation of a Schiff base by pyridoxal phosphate with a reactive amino group of the enzyme entry of glycine and formation of an enzyme-pyridoxal phosphate-glycine-Schiff base complex loss of a proton from the a carbon of glycine with the generation of a carbanion condensation of the carbanion with succinyl-CoA to yield an enzyme-bound intermediate (a-amino-yS-ketoadipic acid) decarboxylation of this intermediate to ALA and liberation of the bound ALA by hydrolysis. ALA synthesis does not occur in mature erythrocytes. 

The mechanism for the hydroxylation of aromatic substrates by flavoprotein monooxygenases has been the subject of signiflcant research interest and controversy over the past decade. These enzymes (p-hydroxybenzoate hydroxylase, phenol hydroxylase, and melilotate hydroxylase) catalyze the initial step in the )8-ketoadipic acid pathway, the hydroxylation of substituted phenols into catechols (Scheme 55). Oxygen is required as cosubstrate, which is activated by the reduced FAD cofactor. The complex mechanism for the oxidative half-reaction is thought to consist of at least four steps and three intermediates 239-242) and to involve a controversial 4a,5-ring-opened flavin 242, 249, 250) (Scheme 56). The flavin C4a-hydroperoxy intermediate 64 and flavin C4a-hydroxy intermediate 65 have been assigned the structures shown in Scheme 56 based on the UV absorbance spectra of various model compounds compared with that of the modified enzyme cofactor alkylated at N(5) 243). However, evidence for the intermediacy of various ring-opened flavin species has been tentative at best, as model compounds and model reactions do not support such an intermediate 242). 

Differently, a Moraxdla strain degraded PNP by replacing the nitrogroup with a hydroxyl group and accumulating traces of hydroquinone in the medium. Hydroquinone was then converted into P-ketoadipic acid via Y hydroxymuconic semialdehyde [65]. 

The outlines of the biosynthetic pathway of the complicated porphyrin structure have been established through elegant use of isotopic methods and biochemical genetics and several of the intermediates have been established, but the details of the enzymatic reactions are only now being investigated. The atoms of porphyrins are all derived from active succinate and glycine.These condense to form a-amino-j8-ketoadipic acid. The decarboxylation of this /3-keto acid results in the formation of... 

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