Towards Precision Engineering of Canonical Polyketide Synthase Domains: Recent Advances and Future Prospects.
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.
Department of Genome Sciences & Technology, The University of British Columbia, Vancouver, BC V5Z 4S6, Canada. c.bayly@alumni.ubc.ca.|Department of Chemical & Biological Engineering, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada. c.bayly@alumni.ubc.ca.
Carmen L
CL
Bayly
Department of Chemical & Biological Engineering, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada. vikramaditya.yadav@ubc.ca.
Vikramaditya G
VG
Yadav
D002384:Catalysis; D008958:Models, Molecular; D048630:Polyketide Synthases / Q000737:chemistry* / Q000378:metabolism*; D000072417:Protein Domains; D015202:Protein Engineering / Q000379:methods; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D048630:Polyketide Synthases
antibiotics; polyketide synthases; protein engineering; structural biology; synthetic biology