Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases.

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).

Inhibition of 3-methylcrotonyl-CoA carboxylase explains the increased excretion of 3-hydroxyisovaleric acid in valproate-treated patients.

Background: Valproic acid (VPA) is a widely used anticonvulsant drug which affects mitochondrial metabolism including the catabolism of fatty acids and branched-chain amino acids.

Aims: To elucidate the effect of valproate on the leucine pathway through a targeted metabolomics approach and the evaluation of the effects of valproate on the activity of biotinidase and 3-methylcrotonyl-CoA carboxylase (3MCC).

Methods: Urine organic acid analysis was performed in patients under VPA therapy and healthy controls using gas-chromatography/mass spectrometry (GC-MS).

Valproic acid utilizes the isoleucine breakdown pathway for its complete β-oxidation.

Unlabelled: Valproic acid (VPA) is a simple branched medium-chain fatty acid with expanding therapeutic applications beyond its prime anticonvulsant properties.

Aims: (1) To resolve the underlying basis for the interference of valproate with the isoleucine degradative pathway and (2) to shed new light on the enzymology of the β-oxidation pathway of valproate.

Methods: Urine organic acids were analyzed by gas chromatography/mass spectrometry.

Role of isovaleryl-CoA dehydrogenase and short branched-chain acyl-CoA dehydrogenase in the metabolism of valproic acid: implications for the branched-chain amino acid oxidation pathway.

Many biological systems including the oxidative catabolic pathway for branched-chain amino acids (BCAAs) are affected in vivo by valproate therapy. In this study, we investigated the potential effect of valproic acid (VPA) and some of its metabolites on the metabolism of BCAAs. In vitro studies were performed using isovaleryl-CoA dehydrogenase (IVD), isobutyryl-CoA dehydrogenase (IBD), and short branched-chain acyl-CoA dehydrogenase (SBCAD), enzymes involved in the degradation pathway of leucine, valine, and isoleucine.

Pyruvate uptake is inhibited by valproic acid and metabolites in mitochondrial membranes.

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), Delta4-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 Delta4-valproyl-CoA, at 1mM). At the same concentration, the specific inhibitor 2-cyano-4-hydroxycinnamate decreased the pyruvate uptake rate by 70%.

Valproic acid metabolites inhibit dihydrolipoyl dehydrogenase activity leading to impaired 2-oxoglutarate-driven oxidative phosphorylation.

The effect of the antiepileptic drug valproic acid (VPA) on mitochondrial oxidative phosphorylation (OXPHOS) was investigated in vitro. Two experimental approaches were used, in the presence of selected respiratory-chain substrates: (1) formation of ATP in digitonin permeabilized rat hepatocytes and (2) measurement of the rate of oxygen consumption by polarography in rat liver mitochondria. VPA (0.

Studies on the extra-mitochondrial CoA -ester formation of valproic and Delta4 -valproic acids.

The hypothesis whether valproic acid (VPA) and its main microsomal metabolite, Delta(4)-valproic acid, can be activated to the respective CoA esters in the cell cytosol was investigated. The valproyl-CoA formation was measured in different subcellular fractions obtained by differential centrifugation of liver homogenates of rats treated with VPA (studies ex vivo) and digitonin fractionation of rat hepatocytes incubated with VPA and cofactors (studies in vitro). The results show that VPA activation may occur in the cytosol and is not restricted to the mitochondrial matrix as believed until now.