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Engineered Biosynthesis of Alkyne-Tagged Polyketides by Type I PKSs

27 Pages Posted: 8 Dec 2019 Sneak Peek Status: Review Complete

See all articles by William Buchanan Porterfield

William Buchanan Porterfield

University of California, Berkeley - Department of Chemical and Biomolecular Engineering

Nannalin Poenateetai

University of California, Berkeley - Department of Chemical and Biomolecular Engineering

Wenjun Zhang

University of California, Berkeley - Department of Chemical and Biomolecular Engineering

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Abstract

Polyketides produced by modular polyketide synthases are important small molecules widely used as drugs, pesticides, herbicides and biological probes. Tagging these polyketides with a clickable functionality enables the visualization, diversification and mode of action study through bio-orthogonal chemistry and is thus actively pursued with multiple tagging strategies reported. We here report the first de novo biosynthesis of alkyne-tagged polyketides by modular type I PKSs through starter unit engineering. Specifically, using JamABC, a carrier protein-dependent terminal alkyne biosynthetic machinery from jamaicamide B biosynthetic pathway, and representative modular PKSs from lipomycin and erythromycin biosynthetic pathways, we show that JamABC works as a trans loading system for engineered Type I PKSs to produce alkyne-tagged polyketides both in vitro and in vivo. 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 which are applicable to additional modular Type I PKSs to produce targeted alkyne-tagged metabolites for chemical and biological applications.

Suggested Citation

Porterfield, William Buchanan and Poenateetai, Nannalin and Zhang, Wenjun, Engineered Biosynthesis of Alkyne-Tagged Polyketides by Type I PKSs (November 4, 2019). Available at SSRN: https://ssrn.com/abstract=3498576 or http://dx.doi.org/10.2139/ssrn.3498576
This is a paper under consideration at Cell Press and has not been peer-reviewed.

William Buchanan Porterfield

University of California, Berkeley - Department of Chemical and Biomolecular Engineering ( email )

Berkeley, CA
United States

Nannalin Poenateetai

University of California, Berkeley - Department of Chemical and Biomolecular Engineering ( email )

Berkeley, CA
United States

Wenjun Zhang (Contact Author)

University of California, Berkeley - Department of Chemical and Biomolecular Engineering ( email )

Berkeley, CA
United States

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