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首页> 外文期刊>Acta crystallographica, Section D. Biological crystallography >New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM
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New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM

机译：原子分辨率X射线衍射和混合QM / MM对人壳三糖苷酶（CHIT1）催化域酶机制的新见解

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摘要

Chitotriosidase (CHIT1) is a human chitinase belonging to the highly conserved glycosyl hydrolase family 18 (GH18). GH18 enzymes hydrolyze chitin, an N-acetylglucosamine polymer synthesized by lower organisms for structural purposes. Recently, CHIT1 has attracted attention owing to its upregulation in immune-system disorders and as a marker of Gaucher disease. The 39 kDa catalytic domain shows a conserved cluster of three acidic residues, Glu140, Asp138 and Asp136, involved in the hydrolysis reaction. Under an excess concentration of substrate, CHIT1 and other homologues perform an additional activity, transglycosylation. To understand the catalytic mechanism of GH18 chitinases and the dual enzymatic activity, the structure and mechanism of CHIT1 were analyzed in detail. The resolution of the crystals of the catalytic domain was improved from 1.65 angstrom (PDB entry 1waw) to 0.95-1.10 angstrom for the apo and pseudo-apo forms and the complex with chitobiose, allowing the determination of the protonation states within the active site. This information was extended by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The results suggest a new mechanism involving changes in the conformation and protonation state of the catalytic triad, as well as a new role for Tyr27, providing new insights into the hydrolysis and transglycosylation activities.
机译：壳三糖苷酶（CHIT1）是一种人几丁质酶，属于高度保守的糖基水解酶家族18（GH18）。 GH18酶水解几丁质，一种由低级生物合成的N-乙酰氨基葡萄糖聚合物，用于结构目的。近来，CHIT1由于其在免疫系统疾病中的上调和作为高雪氏病的标志物而受到关注。 39 kDa的催化域显示了三个酸性残基的保守簇，Glu140，Asp138和Asp136与水解反应有关。在底物浓度过高的情况下，CHIT1和其他同源物执行额外的活性，即转糖基化。为了理解GH18几丁质酶的催化机理和双重酶活性，详细分析了CHIT1的结构和机理。对于载脂蛋白和拟载脂蛋白形式以及壳二糖配合物，催化域晶体的分辨率从1.65埃（PDB进入1waw）提高到0.95-1.10埃，从而可以确定活性位点内的质子化状态。通过混合量子力学/分子力学（QM / MM）计算来扩展此信息。结果表明，涉及催化三联体构象和质子化状态变化的新机制，以及Tyr27的新作用，为水解和转糖基化活性提供了新见解。

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