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.
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.
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丙丙酸的构造异构体丙基乙酸（PIA）通过大鼠酰基-COA合成酶4：一种潜在的双相情感障碍药物抑制了丙二酰酸的异构体。
DOI：
10.1016/j.bbalip.2013.01.008
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Rapoport SI
中科院分区：
文献类型：
--
作者：
Modi HR;Basselin M;Taha AY;Li LO;Coleman RA;Bialer M;Rapoport SI
当长期给予大鼠时，用于治疗双相情感障碍（BD）的情绪稳定剂选择性下调脑磷脂中花生四烯酸（AA）的周转（脱酰-再酰化）。体外研究表明，其中之一，丙戊酸（VPA），这是致畸，减少AA周转抑制脑酰基辅酶A合成酶（Acsl）-4介导的AA酰化为AA-CoA。我们测试了非致畸性VPA类似物是否也可以抑制Acsl-4催化的酰化，从而具有潜在的抗BD作用。大鼠Acsl 4-flag蛋白在E.大肠杆菌中，和三种VPA类似物，丙基异丙基乙酸（PIA），丙基异丙基乙酰胺（PID）和N-甲基-2，2，3，3-四甲基环丙烷甲酰胺（MTMCD），和丁酸钠，抑制AA转化为AA-CoA的Acsl 4的能力进行了定量使用Michaelis-Menten动力学。Acsl 4介导的体外AA向AA-CoA的转化被PIA非竞争性抑制，Ki为11.4 mM，而VPA的公开Ki为25 mM，而PID、MTMCD和丁酸钠没有抑制作用。PIA在体外通过Acsl 4抑制AA转化为AA-CoA的能力表明，与VPA一样，PIA可以减少未麻醉大鼠脑磷脂中的AA周转，如果是这样，则可以有效地作为BD患者的非致畸性情绪稳定剂。
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 acyl-CoA synthetase (Acsl)-4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl-4 catalyzed acylation, and thus have potential anti-BD action. Rat Acsl4-flag protein was expressed in E. 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. Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4 mM compared to a published Ki of 25 mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect. 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.
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影响因子：
2.5
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