Biosynthesis of the unnatural extender units with polyketides and their structural modifications for applications in medicines
The natural products polyketides include over 10 000 molecules with a wide range of bioactivities and are among the most prominent classes of approved clinical agents.Usually,active lead compounds require structural modifications to improve their assimilation,distribution,metabolism,and excretion as well as to facilitate the drug development process.However,due to the large number of stereocenters and inert carbon atoms,it is challenging for chemical synthesis to accurately and efficiently derive polyketide scaffolds,making their biological synthesis for structural optimization of the polyketides a hot topic.In nature,the majority of polyketides are assembled from simple the building blocks acetate and propionate catalyzed by polyketide synthases,but a few polyketides with special building blocks provide inspiration for researchers to introduce unnatural building blocks selectively into the scaffolds of polyketides for their structure modifications.Polyketides can be built with predictable biosynthetic logic,each module of a modular polyketide synthase elongates the product backbone with two carbons by synergetic actions of its three essential domains:ketosynthase,acyltransferase and acyl carrier protein.The acyltransferase domain selects for and loads a carboxyacyl-Coenzyme A extender unit for the phosphopantetheinyl modification of the acyl carrier protein domain,whereas the ketosynthase domain then uses the extender unit to elongate the growing polyketide intermediate,before passing it to the following module.Given the hierarchical domain and module organization of the type Ⅰmodular PKSs that make these molecules,gene sequences and product structures are directly connected such that changes can be introduced site-selectively into the molecule by targeting building blocks and promiscuous acyltransferase domain with the corresponding domain.Besides,the biosynthesis of polyketide scaffolds depends on the assembly of a starter unit and variable extender units,therefore,introducing anticipated structures into the polyketides through incorporating the artificial extender units is considered as a powerful breakthrough for precise and effective modifications of the polyketides.This review summarizes three important enzymatic synthesis methods for unnatural polyketides extender units reported within the past decade.As results,a large number of unnatural extender units have been obtained through mining novel extender unit synthetase and exploring their substrates,or using enzyme engineering methods to modify the substrate spectrum.Also,this review comments on the cases of modifying polyketide structures using unnatural extender units to achieve the desired derivatives either through the natural synthetic pathway of polyketides or by utilizing modified synthetic pathways.Finally,we discuss some challenges existing in this research field and potential solutions for better applications of polyketides,including the compatibility issue of polyketides synthase with unnatural extender units,precursor supply for unnatural extender units,and etc.In recent years,interest and enthusiasm for the modifications of polyketides using unnatural extender moieties have increased dramatically,and our review draws a concise and clear map for the research of polyketide structure modifications by artificial extender units,with an expectation of laying a solid foundation for accelerating the development of polyketides drugs.
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