Effects of glycosylation on the bioactivity of rapamycin
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BIOTECHNOLOGICAL PRODUCTS AND PROCESS ENGINEERING
Effects of glycosylation on the bioactivity of rapamycin Peng Zhang 1 & Lijuan Zhang 1 & Xin-jing Yue 1 & Ya-jie Tang 1 & Changsheng Wu 1
&
Yue-zhong Li 1
Received: 30 June 2020 / Revised: 30 August 2020 / Accepted: 5 September 2020 / Published online: 17 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The macrolactone rapamycin (RAP) presents a broad range of bioactivities, but its clinical applications are compromised due to the poor water solubility and low bioavailability, which could probably be overcome by glycosylation. In this study, we tested a set of promiscuous glycosyltransferases (GTs) to modify rapamycin with four different sugar donors. BsGT-1 displayed the best glycosylation activity with a preference for UDP-glucose, and the glycosylation happened at C-28 or C-40 of rapamycin, producing rapamycin-40-O-β-D-glucoside (RG1), and two new compounds rapamycin-28-O-β-D-glucoside (RG2) and rapamycin-28,40O-β-D-diglucoside (RG3). The glycosylation remarkably improved water solubility and almost completely abolished cytotoxicity but simultaneously attenuated the antifungal, antitumor, and immunosuppression bioactivities of rapamycin. We found the glycosylation at C-40 had less effect on the bioactivities than that at C-28. The molecular docking analysis revealed that the glycosylation, especially the glycosylation at C-28, weakened the hydrophobic and hydrogen bonding contacts between the rapamycin glucosides and the binding proteins: the FK506-binding protein (FKBP12) and the FKBP12-rapamycin binding (FRB) domain. This study highlights a succinct approach to expand the chemical diversity of the therapeutically important molecule rapamycin by using promiscuous glycosyltransferases. Moreover, the fact that glycosyl moieties at different positions of rapamycin affect bioactivity to different extents inspires further glycosylation engineering to improve properties of rapamycin. Key points • Rapamycin was glycosylated efficiently by some promiscuous GTs. • Glycosylation improved water solubility, attenuated cytotoxicity, and bioactivities. • Glycosylation affected the interactions between ligand and binding proteins. Keywords Promiscuous glycosyltransferases . Rapamycin glycosylation . Bioactivities of glucosides . Molecular docking analysis
Introduction Rapamycin (RAP, also known as sirolimus) is a 36-membered macrolactone derived from the bacterium Streptomyces rapamycinicus (Vezina et al. 1975). RAP was originally found Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00253-020-10895-3) contains supplementary material, which is available to authorized users. * Changsheng Wu [email protected] * Yue-zhong Li [email protected] 1
State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, People’s Republic of China
to have antifungal activity (Sehgal et al. 1975) and was approved by the FDA in 1999 as an immunosupp
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