title: Valproate uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: relevance to valproate's efficacy against bipolar disorder.
abstract: BACKGROUND
  The ability of chronic valproate (VPA) to reduce arachidonic acid (AA) turnover in brain phospholipids of unanesthetized rats has been ascribed to its inhibition of acyl-CoA synthetase (Acsl)-mediated activation of AA to AA-CoA. Our aim was to identify a rat Acsl isoenzyme that could be inhibited by VPA in vitro.
  
  
  METHODS
  Rat Acsl3-, Acsl6v1- and Acsl6v2-, and Acsl4-flag proteins were expressed in E. coli, and the ability of VPA to inhibit their activation of long-chain fatty acids to acyl-CoA was estimated using Michaelis-Menten kinetics.
  
  
  RESULTS
  VPA uncompetitively inhibited Acsl4-mediated conversion of AA and of docosahexaenoic (DHA) but not of palmitic acid to acyl-CoA, but did not affect AA conversion by Acsl3, Acsl6v1 or Acsl6v2. Acsl4-mediated conversion of AA to AA-CoA showed substrate inhibition and had a 10-times higher catalytic efficiency than did conversion of DHA to DHA-CoA. Butyrate, octanoate, or lithium did not inhibit AA activation by Acsl4.
  
  
  CONCLUSIONS
  VPA's ability to inhibit Acsl4 activation of AA and of DHA to their respective acyl-CoAs, when related to the higher catalytic efficiency of AA than DHA conversion, may account for VPA's selective reduction of AA turnover in rat brain phospholipids, and contribute to VPA's efficacy against bipolar disorder.
authors.affiliation: National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jakob A
authors.initials: JA
authors.lastname: Shimshoni
authors.forename: Mireille
authors.initials: M
authors.lastname: Basselin
authors.forename: Lei O
authors.initials: LO
authors.lastname: Li
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Coleman
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
authors.forename: Hiren R
authors.initials: HR
authors.lastname: Modi
mesh_terms: D000215:Acylation / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism; D001714:Bipolar Disorder / Q000188:drug therapy / Q000201:enzymology*; D001921:Brain / Q000201:enzymology*; D003066:Coenzyme A Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014635:Valproic Acid / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D001095:Arachidonic Acids; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D014635:Valproic Acid; C500958:Acsl4 protein, rat; D003066:Coenzyme A Ligases