Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism

Abstract

Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)- l-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)- l-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate β-lyases to pyruvate, ammonia, and an α-chloroenethiolate (with DCVC) or an α-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with ϵ-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5′-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate β-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT m). Most of the cysteine S-conjugate β-lyases are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the α-ketoglutarate- and branched-chain α-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT m may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction.