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  current news   Press   selected story    
     
  12 August 2015  
 
Synthetic Polyketide Enzymology: Platform for Biosynthesis of Antimicrobial Polyketides
 
 




Authors
Maybelle Kho Go†‡, Jantana Wongsantichon§, Vivian Wing Ngar Cheung†‡, Jeng Yeong Chow, Robert C. Robinson*†§, and Wen Shan Yew*†‡

† Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8     Medical Drive, Singapore 117597,
‡ NUS Synthetic Biology for Clinical and Technological Innovation, Life Sciences Institute, National     University of Singapore, 28 Medical Drive, Singapore 117456,
§ Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research),     Biopolis, Singapore 138673

Published online in ACS Catalysis on 27 May 2015.

This article was featured in the virtual special issue of ACS Catalysis,Catalysis in Singapore”, on 29 July 2015 http://pubs.acs.org/page/accacs/vi/singapore

It was also highlighted in an editorial by Keith Carpenter, Andy Hor, and Jackie Ying http://pubs.acs.org/doi/abs/10.1021/acscatal.5b01443

Abstract
Synthetic biology often employs enzymes in the biosynthesis of compounds for purposeful function. Here, we define synthetic enzymology as the application of enzymological principles in synthetic biology and describe its use as an enabling platform in synthetic biology for the purposeful production of compounds of biomedical and commercial importance. In particular, we demonstrated the use of synthetic polyketide enzymology as a means to develop lead polyketide based compounds for antimicrobial therapeutics, as exemplified by the modular coupling of acid:CoA ligases to type III polyketide synthases in the biosynthesis and development of polyketide-based biochemicals. Using wild-type and rationally designed mutants of a type III polyketide synthase isolated from Oryza sativa (OsPKS), we produced a chemically diverse library of novel polyketides and identified two bioactive antimicrobials, 4-hydroxy-6-[(1E)-2-(4-hydroxyphenyl)ethenyl]-2H-pyran-2-one (bisnoryangonin) and 3,6,7-trihydroxy-2-(4-methoxybenzyl)-4H-1-benzopyran-4,5,8-trione (26OH), respectively, from a screen against a collection of Gram-positive and Gram-negative bacteria. The purification, crystallization, and structural resolution of recombinant OsPKS at 1.93 Å resolution are also reported. Using the described route of synthetic polyketide enzymology, a library of OsPKS mutants was generated as an additional means to increase the diversity of the polyketide product library. We expect the utility of synthetic enzymology to be extended to other classes of biomolecules and translated to various purposeful functions as the field of synthetic biology progresses.

Figure:

Figure legend: Crystal structure of dimeric OsPKS, with highlighted active site residues. Catalytic triad residues and residues in OsPKS that were targeted for mutagenesis are highlighted in magenta and green, respectively. CoA from the alfalfa CHS/CoA complex (PDB 1BQ6) was modeled into the active site through superimposition of the proteins and is shown as a ball and stick diagram.


For more information on Robert ROBINSON 's laboratory, please click here.