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Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder.

AbstractBACKGROUND:
Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic acid (AA) turnover (deacylation-reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic acid (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain long-chain acyl-CoA synthetase (Acsl)4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl4 catalyzed acylation, and thus have a potential anti-BD action.
METHODS:
Rat Acsl4-flag protein was expressed in Escherichia coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis-Menten kinetics.
RESULTS:
Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4mM compared to a published Ki of 25mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect.
CONCLUSIONS:
PIA's ability to inhibit conversion of AA to AA-CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non-teratogenic mood stabilizer in BD patients.
AuthorsHiren R Modi, Mireille Basselin, Ameer Y Taha, Lei O Li, Rosalind A Coleman, Meir Bialer, Stanley I Rapoport
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1831 Issue 4 Pg. 880-6 (Apr 2013) ISSN: 0006-3002 [Print] Netherlands
PMID23354024 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightPublished by Elsevier B.V.
Chemical References
  • Antimanic Agents
  • Arachidonic Acid
  • Valproic Acid
  • Acsl4 protein, rat
  • Coenzyme A Ligases
Topics
  • Acylation (drug effects)
  • Animals
  • Antimanic Agents (chemistry, pharmacology)
  • Arachidonic Acid (metabolism)
  • Bipolar Disorder (metabolism)
  • Coenzyme A Ligases (metabolism)
  • Molecular Structure
  • Rats
  • Valproic Acid (chemistry, pharmacology)

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