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A QM/MM study of the catalytic mechanism of succinic semialdehyde dehydrogenase from Synechococcus sp PCC 7002 and Salmonella typhimurium

机译：QM / MM研究SyneChocccus SPCC 7002和沙门氏菌的琥珀型半醛脱氢酶催化机理及沙门氏菌血硫醇

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摘要

Succinic semialdehyde dehydrogenase (SSADH) belongs to the aldehyde dehydrogenase (ALDH) superfamily, which oxidizes succinic semialdehyde (SSA) to succinate (SA) in the final step of the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In this article, the catalytic mechanism of SSADH has been studied using a combined quantum mechanics and molecular mechanics (QM/MM) approach on the basis of the crystal structures of SSADH from Synechococcus sp. PCC 7002 (SySSADH) and Salmonella typhimurium (StSSADH). Our calculations reveal that, for SySSADH, the acylation process of substrate SSA is relatively difficult owing to the fact that the catalytic cysteine residue has already formed an adduct with the cofactor (NADP(+)), which corresponds to an overall energy barrier of 18.2 kcal mol(-1). However for StSSADH, the cysteine residue exists as the thiolate ion and the acylation process is easily occurs, corresponding to an overall energy barrier of 9.6 kcal mol(-1). In the subsequent deacylation process, using SySSADH to construct the computational model, the activation of the hydrolytic water molecule is concerted with the formation of a thioester intermediate, which is the rate-limiting step for the deacylation process, corresponding to an energy barrier of 18.2 kcal mol(-1). Thus, for SySSADH, both the acylation and deacylation are possible rate-limiting steps. The pocket residues such as S261, C262 and S419/S425 play an important role in stabilizing the substrate and involved intermediates. Our calculation results may provide useful information for further understanding the catalytic mechanism of SSADH.
机译：琥珀酸半醛脱氢酶（SSADH）属于醛脱氢酶（ALDH）超家族，其在氧化抑制性神经递质γ-氨基丁酸（GABA）的降解的最终步骤琥珀酸半醛（SSA）到琥珀酸（SA）。在本文中，SSADH的催化机制已经使用组合的量子力学和分子力学从聚球藻SSADH的晶体结构的基础上（QM / MM）的方法的研究。 7002（SySSADH）和鼠伤寒沙门氏菌（StSSADH）。我们的计算表明，对于SySSADH，基板SSA的酰化方法是相对困难的，由于这一事实的催化性半胱氨酸残基已经形成了与辅因子的加合物（NADP（+）），这对应于18.2的总能量势垒千卡摩尔（-1）。然而，对于StSSADH，半胱氨酸残基存在作为硫醇盐离子，并且易于发生酰化方法中，对应于9.6千卡摩尔（-1）的总能量势垒。在随后的脱酰过程中，采用SySSADH构建的计算模型，水解水分子的激活一致，其中形成硫酯中间体的，其是用于脱酰过程中的限速步骤，相应于18.2的能量势垒千卡摩尔（-1）。因此，对于SySSADH，无论是酰化和脱酰化是可能的限速步骤。口袋的残基如S261，C262和S419 / S425起到稳定衬底和涉及的中间体重要的作用。我们的计算结果可进一步理解SSADH的催化机制提供有用的信息。

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  • 来源
    《RSC Advances》 |2015年第123期|共11页
  • 作者

    Zhang Jing; Liu Yongjun;

  • 作者单位

    Shandong Univ Sch Chem &

    Chem Engn Minist Educ Key Lab Colloid &

    Interface Chem Jinan 250100 Shandong Peoples R China;

    Shandong Univ Sch Chem &

    Chem Engn Minist Educ Key Lab Colloid &

    Interface Chem Jinan 250100 Shandong Peoples R China;

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  • 正文语种 eng
  • 中图分类 化学;
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