Bacterial cysteine conjugate beta-lyase and the metabolism of cysteine S-conjugates: structural requirements for the cleavage of S-conjugates and the formation of reactive intermediates.
The cysteine conjugate beta-lyase mediated metabolism and the mutagenicity of the synthetic cysteine conjugates S-(2-chloroethyl)-L-cysteine (CEC), S-(2-chlorovinyl)-L-cysteine (CVC), S-(1,2,3,3,3-pentachloroprop-1-enyl)-L-cysteine (PCPC), S-(pentachlorophenyl)-L-cysteine (PCPhC), S-(chloro-1,2,2-trifluoroethyl)-L-cysteine (CTFEC), S-benzyl-L-cysteine (SBC) and S-methyl-L-cysteine (SMC) were investigated in Salmonella typhimurium strains TA100, TA2638, TA102 and TA98 to establish structure/activity relationships. Bacterial 100,000 X g supernatants cleaved CTFEC, PCPC, CVC, PCPhC and SBC to pyruvate; pyruvate formation was inhibited by the beta-lyase inhibitor aminooxyacetic acid (AOAA) in all cases. Of the compounds tested, CEC, PCPC and CVC were mutagenic in the Ames-test. CTFEC, PCPhC and SBC failed to increase the number of revertants above control levels. The mutagenicity of PCPC and CVC could be inhibited by AOAA. CEC exerted a potent mutagenic effect in the Ames-test which was not affected by AOAA; CEC was not transformed to pyruvate by bacterial beta-lyase. Neither pyruvate formation nor mutagenicity were observed with SMC. These results indicate that the structure of the substituent on the sulfur atom is an important determinant for the biological activity of cysteine S-conjugates. Electronegative and/or unsaturated substituents are required for beta-lyase catalysed beta-elimination reactions. The formation of chemically unstable thiols, which may be converted to thioacylating intermediates, seems to be a prerequisite for beta-lyase dependent mutagenicity of S-conjugates.
Vamvakas
S
S
Institut für Toxikologie, Universität Würzburg, F.R.G.
Berthold
K
K
Dekant
W
W
Henschler
D
D
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D001711:Biotransformation; D013437:Carbon-Sulfur Lyases; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D008190:Lyases / Q000378:metabolism*; D008297:Male; D009152:Mutagenicity Tests; D011773:Pyruvates / Q000096:biosynthesis; D019289:Pyruvic Acid; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions; D013379:Substrate Specificity
D001426:Bacterial Proteins; D011773:Pyruvates; D000625:Aminooxyacetic Acid; D019289:Pyruvic Acid; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D003545:Cysteine