人醛氧化酶的催化机理,ACS Catalysis

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人醛氧化酶的催化机理
ACS Catalysis ( IF 11.3 ) Pub Date : 2020-07-22 , DOI: 10.1021/acscatal.0c02627
Pedro Ferreira ₁ , Nuno M. F. Sousa A. Cerqueira ₁ , Pedro Alexandrino Fernandes ₁ , Maria João Romão ₂ , Maria João Ramos ₁

Affiliation

N-杂环酞嗪氧化为酞菁-1（2 H）的机理（1）-及其相关的自由能谱，由人醛氧化酶（hAOX1）催化，使用QM / MM方法对原子进行了详细研究。发现所研究的反应涉及三个连续步骤：（i）Lys893使底物的N2原子质子化；（ii）钼辅因子（Moco）的羟基对底物的亲核攻击；以及（iii）氢化物从底物是Moco的硫原子。计算出的自由能曲线表明，限速步骤对应于氢化物转移。还发现Lys893在反应中起重要作用，不仅对于固定靠近Moco的底物很重要，而且在催化反应中也很重要。还检查了整个催化循环中钼离子氧化态的变化。我们发现，在产物从Moco移开的过程中，电子从催化位点转移到FAD位点是质子耦合的。因此，酶完成其催化循环的最有利，最快的途径是使用Mo^V和Moco的去质子SH配体，其中FAD分子转化为半醌形式FADH ^•。

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Catalytic Mechanism of Human Aldehyde Oxidase

The mechanism of oxidation of N-heterocycle phthalazine to phthalazin-1(2H)-one and its associated free energy profile, catalyzed by human aldehyde oxidase (hAOX1), was studied in atomistic detail using QM/MM methodologies. The studied reaction was found to involve three sequential steps: (i) protonation of the substrate’s N2 atom by Lys893, (ii) nucleophilic attack of the hydroxyl group of the molybdenum cofactor (Moco) to the substrate, and (iii) hydride transfer from the substrate to the sulfur atom of the Moco. The free energy profile that was calculated revealed that the rate-limiting step corresponds to hydride transfer. It was also found that Lys893 plays a relevant role in the reaction, being important not only for the anchorage of the substrate close to the Moco, but also in the catalytic reaction. The variations of the oxidation state of the molybdenum ion throughout the catalytic cycle were examined too. We found out that during the displacement of the products away from the Moco, the transfer of electrons from the catalytic site to the FAD site was proton-coupled. As a consequence, the most favorable and fastest pathway for the enzyme to complete its catalytic cycle was that with Mo^V and a deprotonated SH ligand of the Moco with the FAD molecule converted to its semiquinone form, FADH^•.

更新日期：2020-08-21

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