Valproate uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: relevance to valproate's efficacy against bipolar disorder.
Valproate uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: relevance to valproate's efficacy against bipolar disorder.
复制标题
丙戊酸非竞争性抑制大鼠酰基辅酶 A 合成酶 4 的花生四烯酸酰化：与丙戊酸对抗双相情感障碍的功效相关。
DOI：
10.1016/j.bbalip.2010.12.006
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Modi,HirenR
中科院分区：
文献类型：
--
作者：
Shimshoni,JakobA;Basselin,Mireille;Li,LeiO;Coleman,RosalindA;Rapoport,StanleyI;Modi,HirenR
背景：慢性丙戊酸(VPA)能降低非麻醉大鼠脑磷脂中花生四烯酸(AA)的周转，主要归因于其抑制乙酰辅酶A合成酶(ACSL)介导的AA向AA-CoA的活化。方法在大肠杆菌中表达大鼠ACSL3-、Acsl6v1、Acsl6v2-和Acsl4-FLAG蛋白，用Michaelis-Menten动力学方法检测VPA抑制其长链脂肪酸向酰辅酶A转化的能力。结果VPA非竞争性抑制Acsl4介导的AA转化和二十二碳六烯酸(DHA)转化，但不影响ACSL3、Acsl6v1和Acsl6v2介导的AA转化。Acsl4催化的AA转化为AA-CoA具有底物抑制作用，催化效率是DHA转化为DHA-CoA的10倍。丁酸盐、辛酸或锂不抑制Acsl4激活AA的作用。结论VPA抑制AA和DHA对各自酰基-COAs的激活作用，与AA的催化效率高于DHA有关，这可能是VPA选择性减少大鼠脑磷脂中AA翻转的原因之一，也是VPA治疗双相情感障碍的机制之一。
BackgroundThe 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.MethodsRat 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.ResultsVPA 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.ConclusionsVPA'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.