State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
Faculty of Life Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
Nat Commun. 2017 Nov 14;8(1):1485. doi: 10.1038/s41467-017-01508-1.
GyrI-like proteins are widely distributed in prokaryotes and eukaryotes, and recognized as small-molecule binding proteins. Here, we identify a subfamily of these proteins as cyclopropanoid cyclopropyl hydrolases (CCHs) that can catalyze the hydrolysis of the potent DNA-alkylating agents yatakemycin (YTM) and CC-1065. Co-crystallography and molecular dynamics simulation analyses reveal that these CCHs share a conserved aromatic cage for the hydrolytic activity. Subsequent cytotoxic assays confirm that CCHs are able to protect cells against YTM. Therefore, our findings suggest that the evolutionarily conserved GyrI-like proteins confer cellular protection against diverse xenobiotics via not only binding, but also catalysis.
GyrI 样蛋白广泛分布于原核生物和真核生物中，被认为是小分子结合蛋白。在这里，我们将这些蛋白的一个亚家族鉴定为环丙烷环丙烷水解酶（CCHs），它们可以催化强 DNA-烷化剂 yatakemycin（YTM）和 CC-1065 的水解。共结晶和分子动力学模拟分析表明，这些 CCHs 共享一个保守的芳香族笼用于水解活性。随后的细胞毒性测定证实，CCHs 能够保护细胞免受 YTM 的侵害。因此，我们的研究结果表明，进化上保守的 GyrI 样蛋白不仅通过结合，而且还通过催化，赋予细胞对多种异源物的保护作用。
