Wang Zhen-Yu, Ma Xin-Yuan, Wu Ying, Liu Yang, Lin Guang-Xin, Liu Xiao-Qi, Zhang Chun, Chen Peng, Zheng Yongxiang, Jia Zhi-Jun
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Biopharmaceutics, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
Key Laboratory of Birth Defects and Related Disease of Women and Children, Children's Medicine Key Laboratory of Sichuan Province, Department of Pharmacy/Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
Angew Chem Int Ed Engl. 2025 Aug 18;64(34):e202509359. doi: 10.1002/anie.202509359. Epub 2025 Jun 29.
Unspecific peroxygenases (UPOs) are promising biocatalysts for selective oxyfunctionalization. Compared to cytochrome P450 enzymes (P450s), the catalytic potential of UPOs has been less investigated, largely due to their limited natural diversity and the challenges associated with their optimization through enzyme engineering. In this study, we engineered an UPO from Aspergillus niger (AniUPO) to catalyze the enantioselective α-hydroxylation of β-ketoesters, a valuable transformation yet to be realized in biocatalysis. Through enzyme engineering, two AniUPO variants, AniUPO-M3 and AniUPO-M6, were developed to produce a wide range of enantioenriched α-hydroxy-β-ketoesters, achieving up to 97% yield, 4140 total turnover number (TTN), and >99:1 enantiomeric ratio (er). The biocatalytic process operates under mild conditions and is scalable for preparative applications. This study broadens the catalytic repertoire of UPOs and enhances their potential for industrial applications.
非特异性过氧酶（UPOs）是用于选择性氧官能化的有前景的生物催化剂。与细胞色素P450酶（P450s）相比，UPOs的催化潜力研究较少，这主要是由于它们有限的天然多样性以及通过酶工程对其进行优化所面临的挑战。在本研究中，我们对黑曲霉的一种UPO（AniUPO）进行了工程改造，以催化β-酮酯的对映选择性α-羟基化反应，这是生物催化中尚未实现的有价值的转化反应。通过酶工程，开发了两种AniUPO变体，AniUPO-M3和AniUPO-M6，以生产多种对映体富集的α-羟基-β-酮酯，产率高达97%，总周转数（TTN）达4140，对映体比例（er）>99:1。该生物催化过程在温和条件下运行，可扩展用于制备应用。本研究拓宽了UPOs的催化范围，增强了它们在工业应用中的潜力。
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