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.
BACKGROUND
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.
Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, MD, USA. modihr@mail.nih.gov
Hiren R
HR
Modi
Mireille
M
Basselin
Ameer Y
AY
Taha
Lei O
LO
Li
Rosalind A
RA
Coleman
Meir
M
Bialer
Stanley I
SI
Rapoport
D000215:Acylation / Q000187:drug effects*; D000818:Animals; D018692:Antimanic Agents / Q000737:chemistry / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D001714:Bipolar Disorder / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D014635:Valproic Acid / Q000737:chemistry* / Q000494:pharmacology*
D018692:Antimanic Agents; D016718:Arachidonic Acid; D014635:Valproic Acid; C500958:Acsl4 protein, rat; D003066:Coenzyme A Ligases