Mitochondrial aspartate aminotransferase catalyses cysteine S-conjugate beta-lyase reactions.
Rat liver mitochondrial aspartate aminotransferase (a homodimer) was shown to catalyse a beta-lyase reaction with three nephrotoxic halogenated cysteine S-conjugates [ S -(1,1,2,2-tetrafluoroethyl)-L-cysteine, S -(1,2-dichlorovinyl)-L-cysteine and S -(2-chloro-1,1,2-trifluoroethyl)-L-cysteine], and less effectively so with a non-toxic cysteine S-conjugate [benzothiazolyl-L-cysteine]. Transamination competes with the beta-lyase reaction, but is not favourable. The ratio of beta elimination to transamination in the presence of S -(1,1,2,2-tetrafluoroethyl)-L-cysteine and 2-oxoglutarate is >100. Syncatalytic inactivation by the halogenated cysteine S-conjugates is also observed. The enzyme turns over approx. 2700 molecules of halogenated cysteine S-conjugate on average for every monomer inactivated. Kidney mitochondria are known to be especially sensitive to toxic halogenated cysteine S-conjugates. Evidence is presented that 15-20% of the cysteine S-conjugate beta-lyase activity towards S -(1,1,2,2-tetrafluoroethyl)-L-cysteine in crude kidney mitochondrial homogenates is due to mitochondrial aspartate aminotransferase. The possible involvement of mitochondrial aspartate aminotransferase in the toxicity of halogenated cysteine S-conjugates is also discussed.
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA. acooper@burke.org
Arthur J L
AJ
Cooper
Sam A
SA
Bruschi
Ana
A
Iriarte
Marino
M
Martinez-Carrion
D000818:Animals; D024442:Aspartate Aminotransferase, Mitochondrial / Q000378:metabolism*; D013437:Carbon-Sulfur Lyases / Q000378:metabolism*; D002384:Catalysis; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D013347:Subcellular Fractions; D013379:Substrate Specificity; D013552:Swine; D013885:Thiosulfates / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005466:Fluorocarbons
D024442:Aspartate Aminotransferase, Mitochondrial; D013437:Carbon-Sulfur Lyases; D003545:Cysteine; D006845:Hydrocarbons, Fluorinated; D013885:Thiosulfates; D015091:beta-Alanine; C006977:3-chloroalanine; C064116:S-(1,1,2,2-tetrafluoroethyl)cysteine; D005466:Fluorocarbons; C108902:cysteine-S-conjugate beta-lyase