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The impairment of mitochondrial function may be an important metabolic effect of VPA treatment with potential adverse consequences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the influence of VPA on the activity of GTP\u2010 and ATP\u2010specific succinate:CoA ligases (G\u2010SUCL and A\u2010SUCL).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The GTP\u2010 and ATP\u2010specific SUCL activities were measured in human fibroblasts in the reverse direction, i.e. the formation of succinyl\u2010CoA. These were assessed at different concentrations of succinate in the presence of VPA, valproyl\u2010CoA and zinc chloride, an established inhibitor of the enzymes. Activities were measured using an optimized HPLC procedure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Valproyl\u2010CoA (1 mM) inhibited the activity of A\u2010SUCL and G\u2010SUCL by 45\u201055 % and 25\u201050 %, respectively. VPA (1 mM) had no influence on the activity of the two enzymes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Valproyl\u2010CoA appears to affect the activity of SUCL, especially with the ATP\u2010specific enzyme. Considering the key role of SUCL in the Krebs cycle, interference with its activity might impair the cellular energy status. Moreover, A\u2010SUCL is bound to the nucleoside diphosphate kinase (NDPK), which is responsible for the mitochondrial (deoxy)nucleotide synthesis. An inhibition of A\u2010SUCL might influence the activity of NDPK inducing an imbalance of nucleotides in the mitochondria and eventually mitochondrial DNA depletion. This may account for the potential liver failure associated with valproate therapy, reported in patients with deficiencies within the mitochondrial DNA replicase system such as polymerase gamma 1.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10545-013-9657-4","type":"journal-article","created":{"date-parts":[[2013,10,23]],"date-time":"2013-10-23T11:52:12Z","timestamp":1382529132000},"page":"353-357","source":"Crossref","is-referenced-by-count":9,"title":["Valproyl\u2010CoA inhibits the activity of ATP\u2010 and GTP\u2010dependent succinate:CoA ligases"],"prefix":"10.1002","volume":"37","author":[{"given":"Paula B. M.","family":"Lu\u00eds","sequence":"first","affiliation":[{"name":"Research Institute for Medicines and Pharmaceutical Sciences \u2013 iMED.UL Faculty of Pharmacy, University of Lisbon Av. Prof. Gama Pinto Lisboa 1649\u2010003 Portugal"},{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Jos","family":"Ruiter","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Lodewijk","family":"IJlst","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Isabel Tavares","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines and Pharmaceutical Sciences \u2013 iMED.UL Faculty of Pharmacy, University of Lisbon Av. Prof. Gama Pinto Lisboa 1649\u2010003 Portugal"},{"name":"Department of Biochemistry and Human Biology, Faculty of Pharmacy University of Lisbon Av. Prof. Gama Pinto Lisboa 1649\u2010003 Portugal"}]},{"given":"Marinus","family":"Duran","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Ronald J. A.","family":"Wanders","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Margarida F. B.","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines and Pharmaceutical Sciences \u2013 iMED.UL Faculty of Pharmacy, University of Lisbon Av. Prof. Gama Pinto Lisboa 1649\u2010003 Portugal"},{"name":"Department of Biochemistry and Human Biology, Faculty of Pharmacy University of Lisbon Av. 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