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Enzymology of assembly line synthesis by modular polyketide synthases

Nature Chemical Biology volume 19, pages 401–415 (2023)Cite this article

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Abstract

Modular polyketide synthases (PKSs) run catalytic reactions over dozens of steps in a highly orchestrated manner. To accomplish this synthetic feat, they form megadalton multienzyme complexes that are among the most intricate proteins on earth. Polyketide products are of elaborate chemistry with molecular weights of usually several hundred daltons and include clinically important drugs such as erythromycin (antibiotic), rapamycin (immunosuppressant) and epothilone (anticancer drug). The term ‘modular’ refers to a hierarchical structuring of modules and domains within an overall assembly line arrangement, in which PKS organization is colinearly translated into the polyketide structure. New structural information obtained during the past few years provides substantial direct insight into the orchestration of catalytic events within a PKS module and leads to plausible models for synthetic progress along assembly lines. In light of these structural insights, the PKS engineering field is poised to enter a new era of engineering.

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Fig. 1: Modular polyketide biosynthesis.
Fig. 2: Postulated mechanism for modular PKS synthesis, according to PikAIII data obtained by Dutta et al. and Whicher et al.
Fig. 3: The architecture of type I PKS multienzymes.
Fig. 4: Postulated mechanism for modular PKS synthesis, according to DEBS M1 data obtained by Cogan et al.
Fig. 5: Postulated mechanism for modular PKS synthesis, according to Lsd14 data obtained by Bagde et al.
Fig. 6: Kinetic model of vectorial PKS synthesis proposed on the basis of Lsd14 data obtained by Bagde et al.
Fig. 7: ACP stalled at the AT and KS domains.
Fig. 8: Structural and phylogenetic comparison of PKSs.

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Acknowledgements

M.G. thanks E. Helfrich for helpful discussions, A. Nivina for providing sequences of annotated modular PKSs and L. Buyachuihan for carefully reading and discussing the manuscript. Research on PKSs in the laboratory has generously been supported by the LOEWE program (Landes-Offensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz) of the state of Hesse conducted within the framework of the MegaSyn Research Cluster.

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    Martin Grininger

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Grininger, M. Enzymology of assembly line synthesis by modular polyketide synthases. Nat Chem Biol 19, 401–415 (2023). https://doi.org/10.1038/s41589-023-01277-7

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