Cysteine S-conjugate p-lyases

This activity has been demonstrated in mammalian liver and kidney, as well as in intestinal bacteria. Glutathione S-transle rases catalyze the formation of glutathione conjugates, which are processed via the mercapturic biosynthetic pathway, to acety-lated cysteine -conjugates. The unacetylated premercapturic acids are substrates for cysteine 5-conjugate P-lyase, whereas the acetylated cysteine -conjugates, the mercapturic acids, do not function as substrates for the enzymes. 

Cysteine-S-conjugates have also been proposed as kidney-selective pro-drugs. Renal metabolism of S-6-(purinyl)-L-cysteine resulted in the formation of 6-mercaptopurine by the action of P-lyase [51]. However, besides formation of the intended parent compound, other S-conjugates may be formed by various radical reactions, which may induce renal toxicity. 

Dekant, W., Berthold, K., Vamavkas, S., Henschler, D. Anders, M.W. (1988) Thioacylating intermediates as metabolites of S-(l, 2-dichlorovinyl)-L-cysteine and 6 -(l,2,2-trichlorovinyl)-L-cysteine formed by cysteine conjugate P-lyase. Chem. Res. Toxicol., 1, 175-178... 

Cysteine. S -con jugate p-lyase is responsible for converting a number of cysteine S-conjugates into pyruvate, ammonia, and thiols. 

Figure 9 Handling of 6-PG in renal proximal tubular cells. Abbreviations BBM, brush border plasma membrane BLM, basolateral plasma membrane 6-MP, 6-mercaptopurine 6-PG, S-(6-purinyl) glutathione 6-PC, S-(6-purinyl)-L-cysteine NAcPC, w-acetyl-S-(6-purinyl)-L-cysteine GGT, y-glutamyltransferase DP, dipeptidase P-lyase, cysteine conjugate P-lyase PLP, pyridoxal phosphate XO, xanthine oxidase 6-ThXan, 6-thioxanthine 6-ThUrate, 6-thiourate AOAA, aminooxyacetic acid and Av /, membrane potential. (Adapted from Ref. 30.)...

Dekant W, Vamvakas S, Berthold K, et al. 1986c. Bacterial P-lyase mediated cleavage and mutagenicity of cysteine conjugates derived from the nephrocarcinogenic alkenes trichloroethylene, tetrachloroethylene, and hexachlorobutadiene. Chem Biol Interact 60 31-45. 

Tetrafluoroethylene is metabolized by hepatic glutathione. S -transferase and the resulting cysteine conjugate is further metabolized by renal P-lyase. This pathway results in the formation of a reactive thiol that causes kidney toxicity in rats. 

---