Biochemical and Structural Basis for Controlling Chemical Modularity in Fungal Polyketide Biosynthesis

Winter, Jaclyn M.; Cascio, Duilio; Dietrich, David; Sato, Michio; Watanabe, Kenji; Sawaya, Michael R.; Vederas, John C.; Tang, Yi

doi:10.1021/jacs.5b04520

Title: Biochemical and Structural Basis for Controlling Chemical Modularity in Fungal Polyketide Biosynthesis

Journal Article · Tue Jul 14 00:00:00 EDT 2015 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.5b04520· OSTI ID:1212209

Winter, Jaclyn M. ^[1]; Cascio, Duilio ^[2]; Dietrich, David ^[3]; Sato, Michio ^[4]; Watanabe, Kenji ^[4]; Sawaya, Michael R. ^[2]; Vederas, John C. ^[3]; Tang, Yi ^[5]

Univ. of California, Los Angeles, CA (United States). Dept. of Chemical and Biomolecular Engineering
Univ. of California, Los Angeles, CA (United States). DOE Inst. for Genomics and Proteomics
Univ. of Alberta, Edmonton, AB (Canada). Dept. of Chemistry
Univ. of Shizuoka (Japan). Dept. of Pharmaceutical Sciences
Univ. of California, Los Angeles, CA (United States). Dept. of Chemical and Biomolecular Engineering; Univ. of California, Los Angeles, CA (United States). Dept. of Chemistry and Biochemistry

Modular collaboration between iterative fungal polyketide synthases (IPKSs) is an important mechanism for generating structural diversity of polyketide natural products. Inter-PKS communication and substrate channeling are controlled in large by the starter unit acyl carrier protein transacylase (SAT) domain found in the accepting IPKS module. Here in this study, we reconstituted the modular biosynthesis of the benzaldehyde core of the chaetoviridin and chaetomugilin azaphilone natural products using the IPKSs CazF and CazM. Our studies revealed a critical role of CazM’s SAT domain in selectively transferring a highly reduced triketide product from CazF. In contrast, a more oxidized triketide that is also produced by CazF and required in later stages of biosynthesis of the final product is not recognized by the SAT domain. The structural basis for the acyl unit selectivity was uncovered by the first X-ray structure of a fungal SAT domain, highlighted by a covalent hexanoyl thioester intermediate in the SAT active site. Finally, the crystal structure of SAT domain will enable protein engineering efforts aimed at mixing and matching different IPKS modules for the biosynthesis of new compounds.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: FC02-02ER63421; AC02-06CH11357; CHE-1048804; 5P41RR015301-10

OSTI ID:: 1212209

Journal Information:: Journal of the American Chemical Society, Vol. 137, Issue 31; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 37 works

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