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Pyruvate uptake is inhibited by valproic acid and metabolites in mitochondrial membranes
Author(s) -
Aires Cátia C.P.,
Soveral Graça,
Luís Paula B.M.,
ten Brink Herman J.,
de Almeida Isabel Tavares,
Duran Marinus,
Wanders Ronald J.A.,
Silva Margarida F.B.
Publication year - 2008
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2008.08.028
Subject(s) - pyruvate decarboxylation , chemistry , pyruvate dehydrogenase kinase , valproic acid , biochemistry , oxidative phosphorylation , pyruvate carboxylase , pyruvate dehydrogenase complex , metabolite , metabolism , pyruvic acid , mitochondrion , biology , enzyme , neuroscience , epilepsy
The pyruvate uptake rate in inverted submitochondrial vesicles prepared from rat liver was optimized and further characterized; the potential inhibitory effects of the anticonvulsive drug valproic acid or 2‐ n ‐propyl‐pentanoic acid (VPA), Δ 4 ‐valproic acid or 2‐ n ‐propyl‐4‐pentenoic acid and the respective coenzyme A (CoA) conjugates were studied in the presence of a proton gradient. All tested VPA metabolites inhibited the pyruvate uptake, but the CoA esters were stronger inhibitors (40% and 60% inhibition, respectively, for valproyl‐CoA and Δ 4 ‐valproyl‐CoA, at 1 mM). At the same concentration, the specific inhibitor 2‐cyano‐4‐hydroxycinnamate decreased the pyruvate uptake rate by 70%. The reported inhibition of the mitochondrial pyruvate uptake may explain the significant impairment of the pyruvate‐driven oxidative phosphorylation induced by VPA.