Medium-Chain Acyl-CoA Dehydrogenase- and Enoyl-CoA Hydratase-Dependent Bioactivation of 5,6-Dichloro-4-thia-5-hexenoyl-CoA

Abstract

5,6-Dichloro-4-thia-5-hexenoic acid (DCTH) is a potent hepato- and nephrotoxin that induces mitochondrial dysfunction in rat liver and kidney. Previous studies indicate that DCTH undergoes fatty acid beta-oxidation-dependent bioactivation. The objectives of the present experiments were to elaborate the bioactivation mechanism of DCTH and to examine the interaction of the coenzyme A thioester of DCTH (DCTH-CoA) with the medium-chain acyl-CoA dehydrogenase. In the presence of the terminal electron acceptor ferricenium hexafluorophosphate (FcPF6), DCTH-CoA was oxidized by the medium-chain actyl-CoA dehydrogenase to give 5,6-dichloro-4-thia-trans-2,5-hexadienoyl-CoA. Enoyl-CoA hydratase catalyzed the conversion of 5,6-dichloro-4-thia-trans-2,5-hexadienoyl-CoA to 5,6-dichloro-4-thia-3-hydroxy-5-hexenoyl-CoA, which eliminated 1,2-dichloroethenethiol and gave malonyl-CoA semialdehyde as a product. Chloroacetic acid was detected as a terminal product derived from 1,2-dichloroethenethiol. Incubation of DCTH-CoA with the medium-chain acyl-CoA dehydrogenase in the absence of FcPF6 gave 3-hydroxypropionyl-CoA as the major product and resulted in the irreversible inactivation of the enzyme. Under these conditions, DCTH-CoA apparently undergoes a beta-elimination reaction to give 1,2-dichloroethenethiol and acryloyl-CoA, which is hydrated to give 3-hydroxypropionyl-CoA as the terminal product. The beta-elimination product 1,2-dichloroethenethiol may yield reactive intermediates that inactivate the dehydrogenase. Enzyme inactivation was rapid, DCTH-CoA concentration-dependent, and blocked by octanoyl-CoA, but not by glutathione. The medium-chain acyl-CoA dehydrogenase was not inactivated by acryloyl-CoA, and little inactivation was observed in the presence of FcPF6. These results show that DCTH-CoA is bioactivated by the mitochondrial fatty acid beta-oxidation system to reactive intermediates. This bioactivation mechanism may account for the observed toxicity of DCTH in vivo and in vitro.

Molecular Insight into the Acryloyl-CoA Hydration by AcuH for Acrylate Detoxification in Dimethylsulfoniopropionate-Catabolizing Bacteria

“…Acryloyl-CoA can also be produced in other metabolic pathways in addition to DMSP metabolism pathway. For example, acryloyl-CoA in liver can be produced from 5,6-dichloro-4thia-5-hexenoyl-CoA (DCTH-CoA) by medium-chain acyl-CoA dehydrogenase or be produced from 4-(2-benzothiazole)-4-thiabutanoyl-CoA (BTTB-CoA) by the enoyl-CoA hydratase from R. norvegicus ( Fitzsimmons et al, 1995 ; Baker-Malcolm et al, 2000 ). In addition, AcuH and its homologues are widespread ( Bullock et al, 2017 ; Wang et al, 2017 ).…”

Fourier-Transform Ion Cyclotron Resonance Mass Spectrometric Evidence for the Formation of .alpha.-Chloroenethiolates and Thioketenes from Chloroalkene-Derived, Cytotoxic 4-Thiaalkanoates

“…University of Rochester. 8 Present address: Department of Radiology, 601 Elmwood Ave., @ Abstract published in Aduance ACS Abstracts, September 1, 1995.…”

“…Conversion of thiaalkanoic acid 1 to 5,6-dichloro-4-thia-5-hexenoylCoA (2) and oxidation by the medium chain acyl-CoA dehydrogenase to 5,6-dichloro-4-thia-2,5-hexadienoylCoA (3) is followed by hydration to 5,6-dichloro-4-thia-3-hydroxy-5-hexenoyl-CoA (4) (8). Elimination of 1,2-dichloroethenethiolate (6) from hemithioacetal 4 gives malonyl-CoA semialdehyde (5).…”

“…Recent studies indicate that the formation of 1,2-dichloroethenethiolate, which may give rise to chlorothioketene, is a key step in the bioactivation of 5,6-dichloro-4-thia-5-hexenoic acid (Fitzsimmons et al (1995) Biochemistry 34, 4276-4286). We report here the use of Fouriertransform ion cyclotron resonance mass spectrometry to provide the first direct evidence for the formation of a-chloroenethiolate and thioketene species from a cytotoxic 4-thiaalkanoate.…”

Mitochondrial biotransformation of ω-(phenoxy)alkanoic acids, 3-(phenoxy)acrylic acids, and ω-(1-methyl-1H-imidazol-2-ylthio)alkanoic acids: A prodrug strategy for targeting cytoprotective antioxidants to mitochondria

“…Moreover, the toxicity of several xenobiotic alkanoic acids, including haloalkene-derived 4-thiaalkanoates,12–14 4-bromo-2-butenoic acid,15 valproic acid,16 and hypoglycin,17 is associated with their bioactivation by the mitochondrial β-oxidation pathway.…”