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首页> 外文期刊>ACS catalysis >Insights into the Catalytic Mechanism of Domains CD1 and CD2 in Histone Deacetylase 6 from Quantum Calculations
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Insights into the Catalytic Mechanism of Domains CD1 and CD2 in Histone Deacetylase 6 from Quantum Calculations

机译：从量子计算中洞察组蛋白脱乙酰酶6中的域CD1和CD2的催化机制

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摘要

The histone deacetylase 6 enzyme, HDAC6, is a metalloprotein with multiple pathophysiological roles and, as such, is the subject of intense research and drug discovery efforts. Different from the HDAC family, HDAC6 is constituted by a heterodimeric structure with two different catalytic domains, namely CD1 and CD2. Intriguingly, the specific biological relevance of each domain is not fully understood yet. However, a wealth of structural and biochemical data collected on HDAC, and in particular more recently on HDAC6, has revealed that the active sites in both CD1 and CD2 conserve a similar structural architecture. In the present work, we have performed a detailed investigation on the mechanistic aspects of catalysis of HDAC6, comparatively analyzing the enzymatic reaction mechanism in CD1 and CD2. Using density functional theory-based computations, we found that the rate-limiting step of the reaction is the nucleophilic attack of the catalytic water for peptide bond hydrolysis in both domains. Remarkably, the transition state for such a step presents a penta-coordinated metal center. In this regard, we have further validated the crucial contribution to catalysis of Tyr residues (Tyr363 in CD1 and Tyr745 in CD2) for the activation of the substrate, in line with kinetics measures. Importantly, we have quantified the effect on catalysis by the positively charged Lys330 residue in CD1. An analogous contribution is missing in CD2. Our calculations also evidence the contribution of distal residues from the reaction center, such as Gly201/582 and Phe202/583. Taken together, our quantum calculations dissect the catalytic mechanism in HDAC6. These findings may help future experimental studies and drug design efforts for selective HDAC6 targeting.
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