PMID- 21184843
OWN - NLM
STAT- MEDLINE
DCOM- 20110329
LR  - 20211020
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1811
IP  - 3
DP  - 2011 Mar
TI  - Valproate uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA 
      synthetase 4: relevance to valproate's efficacy against bipolar disorder.
PG  - 163-9
LID - 10.1016/j.bbalip.2010.12.006 [doi]
AB  - 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.
CI  - Copyright (c) 2010 Elsevier B.V. All rights reserved.
FAU - Shimshoni, Jakob A
AU  - Shimshoni JA
AD  - National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
FAU - Basselin, Mireille
AU  - Basselin M
FAU - Li, Lei O
AU  - Li LO
FAU - Coleman, Rosalind A
AU  - Coleman RA
FAU - Rapoport, Stanley I
AU  - Rapoport SI
FAU - Modi, Hiren R
AU  - Modi HR
LA  - eng
GR  - P30 ES010126/ES/NIEHS NIH HHS/United States
GR  - R01 DK059935/DK/NIDDK NIH HHS/United States
GR  - ZIA AG000145-09/ImNIH/Intramural NIH HHS/United States
GR  - DK59935/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101222
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Anticonvulsants)
RN  - 0 (Arachidonic Acids)
RN  - 0 (Isoenzymes)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 25167-62-8 (Docosahexaenoic Acids)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - EC 6.2.1.- (Acsl4 protein, rat)
RN  - EC 6.2.1.- (Coenzyme A Ligases)
SB  - IM
MH  - Acylation/drug effects
MH  - Animals
MH  - Anticonvulsants/*chemistry/pharmacology
MH  - Arachidonic Acid/chemistry/metabolism
MH  - Arachidonic Acids/chemistry/metabolism
MH  - Bipolar Disorder/drug therapy/*enzymology
MH  - Brain/*enzymology
MH  - Coenzyme A Ligases/*chemistry/genetics/metabolism
MH  - Docosahexaenoic Acids/chemistry/metabolism
MH  - Enzyme Activation/drug effects
MH  - Escherichia coli
MH  - Humans
MH  - Isoenzymes/chemistry/metabolism
MH  - Nerve Tissue Proteins/*chemistry/metabolism
MH  - Rats
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Valproic Acid/*chemistry/pharmacology
PMC - PMC3037030
MID - NIHMS266619
COIS- Disclosure/Conflict of interest. No author has a financial or other conflict of 
      interest related to this work.
EDAT- 2010/12/28 06:00
MHDA- 2011/03/30 06:00
PMCR- 2012/03/01
CRDT- 2010/12/28 06:00
PHST- 2010/08/19 00:00 [received]
PHST- 2010/12/10 00:00 [revised]
PHST- 2010/12/15 00:00 [accepted]
PHST- 2010/12/28 06:00 [entrez]
PHST- 2010/12/28 06:00 [pubmed]
PHST- 2011/03/30 06:00 [medline]
PHST- 2012/03/01 00:00 [pmc-release]
AID - S1388-1981(10)00254-4 [pii]
AID - 10.1016/j.bbalip.2010.12.006 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2011 Mar;1811(3):163-9. doi: 10.1016/j.bbalip.2010.12.006. 
      Epub 2010 Dec 22.