Engineered Biosynthesis of Alkyne-Tagged Polyketides by Type I PKSs

Porterfield, William B.; Poenateetai, Nannalin; Zhang, Wenjun

doi:10.1016/j.isci.2020.100938

Engineered Biosynthesis of Alkyne-Tagged Polyketides by Type I PKSs

Journal Article · Tue Feb 25 23:00:00 EST 2020 · iScience

DOI:https://doi.org/10.1016/j.isci.2020.100938· OSTI ID:1633263

^[1]; Poenateetai, Nannalin ^[1]; Zhang, Wenjun ^[2]

Univ. of California, Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States); Chan Zuckerberg Biohub, San Francisco, CA (United States)

Polyketides produced by modular polyketide synthases (PKSs) are important small molecules widely used as drugs, pesticides, and biological probes. Tagging these polyketides with a clickable functionality enables the visualization, diversification, and mode of action study through bio-orthogonal chemistry. We report the de novo biosynthesis of alkyne-tagged polyketides by modular type I PKSs through starter unit engineering. Specifically, we use JamABC, a terminal alkyne biosynthetic machinery from the jamaicamide B biosynthetic pathway, in combination with representative modular PKSs. We demonstrate that JamABC works as a trans loading system for engineered type I PKSs to produce alkyne-tagged polyketides. In addition, the production efficiency can be improved by enhancing the interactions between the carrier protein (JamC) and PKSs using docking domains and site-directed mutagenesis of JamC. This work thus provides engineering guidelines and strategies that are applicable to additional modular type I PKSs to produce targeted alkyne-tagged metabolites for chemical and biological applications.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Alfred P. Sloan Foundation; Chan Zuckerberg Biohub

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1633263

Journal Information:: iScience, Journal Name: iScience Journal Issue: 3 Vol. 23; ISSN 2589-0042

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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