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Research ArticleArticle

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

Paula B. M. Luís, Jos P. N. Ruiter, Lodewijk IJlst, Isabel Tavares de Almeida, Marinus Duran, Al-Walid Mohsen, Jerry Vockley, Ronald J. A. Wanders and Margarida F. B. Silva
Drug Metabolism and Disposition July 2011, 39 (7) 1155-1160; DOI: https://doi.org/10.1124/dmd.110.037606
Paula B. M. Luís
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Jos P. N. Ruiter
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Lodewijk IJlst
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Isabel Tavares de Almeida
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Marinus Duran
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Al-Walid Mohsen
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Jerry Vockley
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Ronald J. A. Wanders
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Margarida F. B. Silva
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Abstract

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. The enzymatic activities of the three purified human enzymes were measured using optimized high-performance liquid chromatography procedures, and the respective kinetic parameters were determined in the absence and presence of VPA and the corresponding CoA and dephosphoCoA conjugates. Valproyl-CoA and valproyl-dephosphoCoA inhibited IVD activity significantly by a purely competitive mechanism with Ki values of 74 ± 4 and 170 ± 12 μM, respectively. IBD activity was not affected by any of the tested VPA esters. However, valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism with a Ki of 249 ± 29 μM. In addition, valproyl-dephosphoCoA inhibited SBCAD activity via a distinct mechanism (Ki = 511 ± 96 μM) that appeared to be of the mixed type. Furthermore, we show that both SBCAD and IVD are active, using valproyl-CoA as a substrate. The catalytic efficiency of SBCAD turned out to be much higher than that of IVD, demonstrating that SBCAD is the most probable candidate for the first dehydrogenation step of VPA β-oxidation. Our data explain some of the effects of valproate on the branched-chain amino acid metabolism and shed new light on the biotransformation pathway of valproate.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK54936] (to J.V.); and Fundação para a Ciência e a Tecnologia, Lisboa, Portugal [Grant SFRH/BD/25913/2005].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.037606.

  • ABBREVIATIONS:

    VPA
    2-n-propylpentanoic acid or valproic acid
    Δ2(E)-VPA
    2-n-propyl-2-pentenoic acid
    DephCoA
    dephosphoCoA
    BCAA
    branched-chain amino acid
    VP-CoA
    valproyl-CoA
    VP-DephCoA
    valproyl-dephosphoCoA
    IVD
    isovaleryl-CoA dehydrogenase
    BSA
    bovine serum albumin
    IBD
    isobutyryl-CoA dehydrogenase
    SBCAD
    short branched-chain acyl-CoA dehydrogenase
    HPLC
    high-performance liquid chromatography
    ESI
    electrospray ionization
    BCAD
    branched-chain acyl-CoA dehydrogenase
    ACD
    acyl-CoA dehydrogenase.

  • Received December 7, 2010.
  • Accepted March 14, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (7)
Drug Metabolism and Disposition
Vol. 39, Issue 7
1 Jul 2011
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Research ArticleArticle

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

Paula B. M. Luís, Jos P. N. Ruiter, Lodewijk IJlst, Isabel Tavares de Almeida, Marinus Duran, Al-Walid Mohsen, Jerry Vockley, Ronald J. A. Wanders and Margarida F. B. Silva
Drug Metabolism and Disposition July 1, 2011, 39 (7) 1155-1160; DOI: https://doi.org/10.1124/dmd.110.037606

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Research ArticleArticle

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

Paula B. M. Luís, Jos P. N. Ruiter, Lodewijk IJlst, Isabel Tavares de Almeida, Marinus Duran, Al-Walid Mohsen, Jerry Vockley, Ronald J. A. Wanders and Margarida F. B. Silva
Drug Metabolism and Disposition July 1, 2011, 39 (7) 1155-1160; DOI: https://doi.org/10.1124/dmd.110.037606
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