Substrate specificity combined with stereopromiscuity in glutathione transferase A4-4-dependent metabolism of 4-hydroxynonenal.
Substrate specificity combined with stereopromiscuity in glutathione transferase A4-4-dependent metabolism of 4-hydroxynonenal.
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DOI：
10.1021/bi902038u
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发表时间：
2010-02-23
期刊：
影响因子：
2.9
通讯作者：
Atkins, William M.
中科院分区：
文献类型：
--
作者：
Balogh, Larissa M.;Le Trong, Isolde;Kripps, Kimberly A.;Shireman, Laura M.;Stenkamp, Ronald E.;Zhang, Wei;Mannervik, Bengt;Atkins, William M.
谷胱甘肽转移酶A4-4（GSTA 4 -4）与谷胱甘肽（GSH）结合是脂质过氧化产物4-羟基壬烯醛（HNE）消除的主要途径，4-羟基壬烯醛是一种导致许多疾病的有毒化合物。HNE的两种对映异构体被认为是有毒的，并且GSTA 4 -4对它们具有可忽略的立体选择性，尽管其对烯醛具有高催化化学特异性。与高度柔性和底物混杂的GSTA 1 -1同种型（其对HNE具有差的催化效率）相反，GSTA 4 -4被假定为是预先组织用于HNE代谢的刚性模板。然而，高底物化学选择性和低底物立体选择性的组合是有趣的。GSTA 4 -4实现这种组合的机制是重要的，因为它必须代谢HNE的两种对映体以有效地解毒生物形成的混合物。GSTA 4 -4和对HNE具有高催化效率的GSTA 1 -1的工程化变体（与GSH-HNE缀合物类似物共结晶）的晶体结构证明GSTA 4 -4不经历对映体特异性诱导的拟合;相反，活性位点残基Arg 15理想地位于与任一HNE对映体的4-羟基相互作用的位置。结果揭示了一种进化策略，用于实现生物学上有用的立体混杂对有毒的rachabitus，伴随着高催化效率和底物特异性对内源性形成的毒素。
Conjugation to glutathione (GSH) by glutathione transferase A4-4 (GSTA4-4) is a major route of elimination for the lipid peroxidation product 4-hydroxynonenal (HNE), a toxic compound that contributes to numerous diseases. Both enantiomers of HNE are presumed to be toxic, and GSTA4-4 has negligible stereoselectivity towards them, despite its high catalytic chemospecificity for alkenals. In contrast to the highly flexible, and substrate promiscuous, GSTA1-1 isoform that has poor catalytic efficiency with HNE, GSTA4-4 has been postulated to be a rigid template that is pre-organized for HNE metabolism. However, the combination of high substrate chemoselectivity and low substrate stereoselectivity is intriguing. The mechanism by which GSTA4-4 achieves this combination is important, because it must metabolize both enantiomers of HNE to efficiently detoxify the biologically formed mixture. The crystal structures of GSTA4-4 and an engineered variant of GSTA1-1 with high catalytic efficiency toward HNE, co-crystallized with a GSH-HNE conjugate analog, demonstrate that GSTA4-4 undergoes no enantiospecific induced fit; instead the active site residue Arg15 is ideally located to interact with the 4-hydroxyl group of either HNE enantiomer. The results reveal an evolutionary strategy for achieving biologically useful stereopromiscuity towards a toxic racemate, concomitant with high catalytic efficiency and substrate specificity towards an endogenously formed toxin.
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DOI：
10.1107/s0907444905039296
发表时间：
2006-02-01
影响因子：
2.2
作者：
Grahn, E;Novotny, M;Kleywegt, GJ
通讯作者：
Kleywegt, GJ
影响因子：
4.1
作者：
Hubatsch, I;Ridderström, M;Mannervik, B
通讯作者：
Mannervik, B
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
5.7
作者：
CAMERON, AD;SINNING, I;JONES, TA
通讯作者：
JONES, TA
影响因子：
4.8
作者：
Balogh, Larissa M.;Roberts, Arthur G.;Atkins, William M.
通讯作者：
Atkins, William M.