Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme
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Cyclodipeptide synthases (CDPSs) produce a variety of cyclic dipeptide products by utilising two aminoacylated tRNA substrates. We sought to investigate the minimal requirements for substrate usage in this class of enzymes as the relationship between CDPSs and their substrates remains elusive. Here, we investigated the Bacillus thermoamylovorans enzyme, BtCDPS, which synthesises cyclo(L-Leu–L-Leu). We systematically tested where specificity arises and, in the process, uncovered small molecules (activated amino esters) that will suffice as substrates, although catalytically poor. We solved the structure of BtCDPS to 1.7 Å and combining crystallography, enzymatic assays and substrate docking experiments propose a model for how the minimal substrates interact with the enzyme. This work is the first report of a CDPS enzyme utilizing a molecule other than aa-tRNA as a substrate; providing insights into substrate requirements and setting the stage for the design of improved simpler substrates.
Harding , C J , Sutherland , E , Hanna , J , Houston , D & Melo Czekster , C 2021 , ' Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme ' , RSC Chemical Biology , vol. Advance article . https://doi.org/10.1039/D0CB00142B
RSC Chemical Biology
Copyright © 2021 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
DescriptionC. J. H. and C. M. C. are funded by the Wellcome trust (210486/Z/18/Z), ES is funded by the Cunningham trust (PhD-CT-18-41).
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