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

DOI: 10.1039/D0CB00142B DOI Help

Authors: Christopher Harding (University of St Andrews) , Emmajay Sutherland (University of St Andrews) , Jane G. Hanna (Arab Academy for Science, Technology, and Maritime Transport (AASTMT)) , Douglas R. Houston (University of Edinburgh) , Clarissa M. Czekster (University of St Andrews)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Rsc Chemical Biology , VOL 9

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 19844

Open Access Open Access

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.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 25/01/2021 15:24


Discipline Tags:

Catalysis Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)