Cysteine conjugate p-lyase

Jones TW, Chen Q, Schaeffer V, et al. 1988. Immunohistochemical localization of glutamine transaminase K, a rat kidney cysteine conjugate p-lyase, and the relationship to the segment specificity of cysteine conjugate nephrotoxicity. Mai Pharm 34 621-627. 

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... 

Kharasch ED, Floffman GM,Thorning D, Flan kins DC, Kilty CG. Role of renal cysteine conjugate P-lyase pathway in inhaled compound A nephrotoxicity in rats. Anesthesiology 1998 88 1624-1633. 

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.)...

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 5-conjugate P-lyase activity has been implicated in the bioactivation of certain halogenated alkenes. This bioactivation results from the generation of reactive thiols. The thiol produced by the P-lyase-dependent metabolism of 5(1,2-dichlorovinyl)-L-cysteine is an unstable electrophile that binds covalently to cellular macromolecules and leads to nephrotoxicity and genotoxicity. Alternatively, certain... 

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. 

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. 

Figure 4.66 Metabolism of a cysteine conjugate by CS lyase (p-lyase). The cysteine conjugate is shown arising from a glutathione conjugate after biliary excretion. The thiol product, which may be toxic (see text) can also be methylated and further oxidized as shown.

Hexachlorobutadiene is a nephrotoxic industrial chemical, damaging the pars recta of the proximal tubule. Initial conjugation with GSH is necessary, followed by biliary secretion and catabolism resulting in a cysteine conjugate. The conjugate is reabsorbed and transported to the kidney where it can be concentrated and becomes a substrate for the enzyme p-lyase. This metabolizes it into a reactive thiol, which may react with proteins and other critical macro molecules with mitochondria as the ultimate target. The kidney is sensitive because the metabolite is concentrated by active uptake processes (e.g., OAT 1), which reabsorb the metabolite into the tubular cells. 

Other halogenated compounds such as trichloroethylene may be metabolized to similar cysteine conjugates, which are also nephrotoxic but may not all require p-lyase activation. 

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. 

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

Several cysteine conjugates are metabolized by p-lyase to produce thiols, ammonia, and pyruvate. Cytosolic p-lyases have been isolated from the kidney, liver, and intestinal microflora. Since it has become clear that p-lyases can play a decisive role in the bioactivation of cysteine conjugates (such as those from hexachloro-1,3-butadiene or other halogenated al-kenes) to nephrotoxic agents, the scientific interest in this enzyme has increased considerably (Elfarra and Anders, 1984 Commandeur et al., 1987). 

As for stereoselectivity, relatively little is known as yet, except that the natural R configuration in the cysteine residue is a prerequisite for a cysteine conjugate to be a substrate of p-lyase. This fact has been used as a tool to ascertain the role of p-lyase in the development of nephrotoxicity by cysteine conjugates. No data are presently available with regard to the substrate-stereoselective effects of the noncysteine part of the thioether substrates of p-lyase (Commandeur and Vermeulen, 1990). Such stereoselective effects may be anticipated, however, since, for example, the regioisomeric 1,2- and 2,2-dichlorovinyl-LrCysteine conjugates have also... 

Glutathione, y-glutamyl derivatives, and (3-lyase substrates have been investigated as renal-specific prodrugs based on the presence of certain transporters such as plasma membrane transport systems for glutathione [28] and cysteine [29] conjugates and/or enzymes such as y-glutamyltrans-ferase (EC 2.3.2.2), dipeptidase, and p-lyase (EC4.4.1.13). 

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