吡哆醛 5'-磷酸盐依赖性氨基脱氧分支酸裂解酶的催化机制：计算 QM/MM 研究,Journal of Chemical Information and Modeling

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吡哆醛 5'-磷酸盐依赖性氨基脱氧分支酸裂解酶的催化机制：计算 QM/MM 研究
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2023-02-06 , DOI: 10.1021/acs.jcim.2c01593
Lihua Dong ₁ , Yongjun Liu ₂

Affiliation

氨基脱氧分支酸裂解酶 (ADCL) 是一种依赖于吡哆醛 5'-磷酸 (PLP) 的酶，可催化 4-氨基-4-脱氧分支酸 (ADC) 转化为p-氨基苯甲酸 (PABA)，这是叶酸生物合成的关键步骤。为了阐明原子级的反应细节，构建了酶-底物反应物模型，并进行了 QM/MM 计算。我们的计算结果表明，整个催化循环包含 11 个基本步骤，可以用三个阶段来描述，包括 PLP 的转氨基反应、丙酮酸的释放和 ADC 的芳构化，以及初始醛亚胺的回收。反应过程中涉及一系列分子内质子转移，是C-N键形成和断裂以及ADC环芳构化的关键。除了分别在内部醛亚胺和外部醛亚胺中用口袋残基 Lys251 和底物形成席夫碱外，辅酶 PLP 还利用其羟基氧阴离子和磷酸基团在分子内质子转移中发挥关键作用。这些发现可能为进一步了解其他 PLP 依赖性酶的催化机制提供有用的信息。

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Catalytic Mechanism of Pyridoxal 5′-Phosphate-Dependent Aminodeoxychorismate Lyase: A Computational QM/MM Study

Aminodeoxychorismate lyase (ADCL) is a kind of pyridoxal-5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 4-amino-4-deoxychorismate (ADC) to p-aminobenzoate (PABA), which is a key step for the biosynthesis of folate. To illuminate the reaction details at the atomistic level, an enzyme–substrate reactant model has been constructed, and QM/MM calculations have been performed. Our calculation results reveal that the overall catalytic cycle contains 11 elementary steps, which can be described by three stages, including the transamination reaction of PLP, the release of pyruvate and aromatization of ADC, and the recovery to the initial aldimine. During the reaction, a series of intramolecular proton transfer are involved, which are the key for the C–N bond formation and cleavage as well as the aromatization of the ADC ring. In addition to forming the Schiff base with the pocket residue Lys251 and substrate in the internal aldimine and the external aldimine, respectively, the coenzyme PLP also plays a critical role in the intramolecular proton transfer by employing its hydroxyl oxygen anion and phosphate group. These findings may provide useful information for further understanding the catalytic mechanism of other PLP-dependent enzymes.

更新日期：2023-02-06

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