title: Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases.
abstract: BACKGROUND
  Valproic acid (VPA) is an effective antiepileptic drug that may induce progressive microvesicular steatosis. The impairment of mitochondrial function may be an important metabolic effect of VPA treatment with potential adverse consequences.
  
  
  OBJECTIVE
  To investigate the influence of VPA on the activity of GTP- and ATP-specific succinate:CoA ligases (G-SUCL and A-SUCL).
  
  
  METHODS
  The GTP- and ATP-specific SUCL activities were measured in human fibroblasts in the reverse direction, i.e. the formation of succinyl-CoA. These were assessed at different concentrations of succinate in the presence of VPA, valproyl-CoA and zinc chloride, an established inhibitor of the enzymes. Activities were measured using an optimized HPLC procedure.
  
  
  RESULTS
  Valproyl-CoA (1 mM) inhibited the activity of A-SUCL and G-SUCL by 45-55% and 25-50%, respectively. VPA (1 mM) had no influence on the activity of the two enzymes.
  
  
  CONCLUSIONS
  Valproyl-CoA appears to affect the activity of SUCL, especially with the ATP-specific enzyme. Considering the key role of SUCL in the Krebs cycle, interference with its activity might impair the cellular energy status. Moreover, A-SUCL is bound to the nucleoside diphosphate kinase (NDPK), which is responsible for the mitochondrial (deoxy)nucleotide synthesis. An inhibition of A-SUCL 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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences - iMED.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
authors.forename: Paula B M
authors.initials: PB
authors.lastname: Luís
authors.forename: Jos
authors.initials: J
authors.lastname: Ruiter
authors.forename: Lodewijk
authors.initials: L
authors.lastname: IJlst
authors.forename: Isabel Tavares
authors.initials: IT
authors.lastname: de Almeida
authors.forename: Marinus
authors.initials: M
authors.lastname: Duran
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Margarida F B
authors.initials: MF
authors.lastname: Silva
mesh_terms: D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000502:physiology*; D006801:Humans; D017093:Liver Failure / Q000139:chemically induced; D009701:Nucleoside-Diphosphate Kinase / Q000502:physiology; D013389:Succinate-CoA Ligases / Q000037:antagonists & inhibitors*; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000214:Acyl Coenzyme A; D004272:DNA, Mitochondrial; C045335:valproyl-coenzyme A; D014635:Valproic Acid; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D009701:Nucleoside-Diphosphate Kinase; D013389:Succinate-CoA Ligases