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01-05-2014 | Original Article

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

Authors: Paula B. M. Luís, Jos Ruiter, Lodewijk IJlst, Isabel Tavares de Almeida, Marinus Duran, Ronald J. A. Wanders, Margarida F. B. Silva

Published in: Journal of Inherited Metabolic Disease | Issue 3/2014

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.

Discussion

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.

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Title: Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases
Authors: Paula B. M. Luís
Jos Ruiter
Lodewijk IJlst
Isabel Tavares de Almeida
Marinus Duran
Ronald J. A. Wanders
Margarida F. B. Silva
Publication date: 01-05-2014
Publisher: Springer Netherlands
Published in: Journal of Inherited Metabolic Disease / Issue 3/2014
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-013-9657-4

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