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Issue 1, 2021
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Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme

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Abstract

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.

Graphical abstract: Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme

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Article information


Submitted
05 Aug 2020
Accepted
26 Dec 2020
First published
15 Jan 2021

This article is Open Access

RSC Chem. Biol., 2021,2, 230-240
Article type
Paper

Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme

C. J. Harding, E. Sutherland, J. G. Hanna, D. R. Houston and C. M. Czekster, RSC Chem. Biol., 2021, 2, 230
DOI: 10.1039/D0CB00142B

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