Towards Precision Engineering of Canonical Polyketide Synthase Domains: Recent Advances and Future Prospects.

Carmen Bayly,Vikramaditya Yadav

doi:10.3390/molecules22020235

Carmen Bayly, Vikramaditya Yadav

Open Access

https://doi.org/10.3390/molecules22020235

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Abstract

Modular polyketide synthases (mPKSs) build functionalized polymeric chains, some of which have become blockbuster therapeutics. Organized into repeating clusters (modules) of independently-folding domains, these assembly-line-like megasynthases can be engineered by introducing non-native components. However, poor introduction points and incompatible domain combinations can cause both unintended products and dramatically reduced activity. This limits the engineering and combinatorial potential of mPKSs, precluding access to further potential therapeutics. Different regions on a given mPKS domain determine how it interacts both with its substrate and with other domains. Within the assembly line, these interactions are crucial to the proper ordering of reactions and efficient polyketide construction. Achieving control over these domain functions, through precision engineering at key regions, would greatly expand our catalogue of accessible polyketide products. Canonical mPKS domains, given that they are among the most well-characterized, are excellent candidates for such fine-tuning. The current minireview summarizes recent advances in the mechanistic understanding and subsequent precision engineering of canonical mPKS domains, focusing largely on developments in the past year.

Highlights

Antibiotic resistance is on the rise, and it is essential to maintain a steady pipeline of antimicrobial candidates [1]
The ability to alter polyketide products is impactful in the context of therapeutics development: hits yielded by high-throughput screening often require modification and optimization before they can become drug candidates [6]
The KS plays a key role by interfacing with the translocating ACP to receive its acyl substrate

Summary

Introduction

Antibiotic resistance is on the rise, and it is essential to maintain a steady pipeline of antimicrobial candidates [1]. Polyketide biosynthetic pathways are promising, and have contributed numerous antibiotics currently on the market (Figure 1) [4]. While detailed and focused enzymatic studies are patently beneficial, the goal of efficiently engineering these megasynthases has benefitted from keeping in-step with other developments in the field of PKS research—gaining from it new parts and Molecules 2017, 22, 235; doi:10.3390/molecules22020235 www.mdpi.com/journal/molecules better tools. This minireview gives a brief orientation to the overall field before diving into the most from it new parts and better tools. This minireview gives a brief orientation to the overall field before recent advances fine-tuning controlinover canonical mPKS modules

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Conclusion