揭示单个活性水分子在2,4'-二羟基苯乙酮双加氧酶催化的2,4'-二羟基苯乙酮的脂族CC键的氧化裂解中的关键作用：量子力学/分子力学研究,ACS Catalysis

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揭示单个活性水分子在2,4'-二羟基苯乙酮双加氧酶催化的2,4'-二羟基苯乙酮的脂族CC键的氧化裂解中的关键作用：量子力学/分子力学研究
ACS Catalysis ( IF 11.3 ) Pub Date : 2018-09-25 00:00:00 , DOI: 10.1021/acscatal.8b03201
Rabindra Nath Manna ₁ , Tanmay Malakar ₂ , Biman Jana ₁ , Ankan Paul ₂

Affiliation

2,4'-二羟基苯乙酮双加氧酶（DAD）是一种非血红素双加氧酶，在存在分子氧（O ₂）的情况下，在脂肪族CC键裂解2,4'-二羟基苯乙酮（DHAP）方面显示出极好的选择性）。分子动力学模拟揭示了在酶的活性位点上存在单个水分子。从我们的混合量子力学/分子力学（QM / MM）研究发现，这种孤独的水分子对于促进DAD酶催化的2,4'-DHAP的脂肪族碳-碳键的氧化裂解至关重要。首先，在活性位点水分子的帮助下，通过中继质子转移机制使2,4'-DHAP质子化。该水分子还积极参与O–O和C–C键的裂解步骤。活化的水分子起着催化酸碱物质的作用。O–O裂解步骤被认为是决定速率的步骤，在五重体自旋表面上，在理论上的uB3LYP-D3 / def2-TZVP / OPLS水平计算出的相关势垒为20.3 kcal / mol。细菌DAD酶的多序列比对显示了在中继质子转移过程中Tyr93和Glu108残基的进化重要性，其中Tyr93充当质子载体，Glu108充当储库。我们的研究证明了水在DAD酶催化循环中的积极作用，另外还揭示了两个氨基酸（Tyr93和Glu108）在酶促循环中的重要间接作用。

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Unraveling the Crucial Role of Single Active Water Molecule in the Oxidative Cleavage of Aliphatic C–C Bond of 2,4′-Dihydroxyacetophenone Catalyzed by 2,4′-Dihydroxyacetophenone Dioxygenase Enzyme: A Quantum Mechanics/Molecular Mechanics Investigation

2,4′-Dihydroxyacetophenone dioxygenase (DAD), a nonheme dioxygenase enzyme, shows exquisite selectivity in the aliphatic C–C bond cleavage of 2,4′-dihydroxyacetophenone (DHAP) in the presence of molecular oxygen (O₂). Molecular dynamics simulations revealed the presence of a single water molecule at the active site of the enzyme. This lone water molecule is pivotal for facilitating the oxidative cleavage of the aliphatic C–C bond of 2,4′-DHAP catalyzed by DAD enzyme, as evident from the findings of our hybrid quantum mechanics/molecular mechanics (QM/MM) studies. 2,4′-DHAP is initially deprotonated through a relay proton transfer mechanism with the aid of the active site water molecule. This water molecule also actively participates in the O–O and C–C bond cleavage steps. The activated water molecule acts as catalytic acid–base species. The O–O cleavage step has been predicted to be the rate-determining step with an associated barrier of 20.3 kcal/mol calculated at the uB3LYP-D3/def2-TZVP/OPLS level of theory on the quintet spin surface. Multiple sequence alignment of the bacterial DAD enzyme has shown the evolutionary importance of the Tyr93 and Glu108 residues, in which Tyr93 acts as proton carrier and Glu108 acts as reservoir, during the relay proton transfer. Our study demonstrates the active role of water in the catalytic cycle of DAD enzyme and additionally unearthed important indirect roles of the two amino acids (Tyr93 and Glu108) in the enzymatic cycle.

更新日期：2018-09-25

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