From Code to Compound: Hacking Polyketide Synthases for Custom Chemistry
Jay Keasling
Departments of Chemical & Biomolecular Engineering and of Bioengineering, University
of California, Berkeley, CA 94720
Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory,
Berkeley, CA 94720
Abstract: The chemical industry produces over 100,000 molecules worth $2 trillion annually in the
United States alone—nearly all from petroleum. What if we could instead program microorganisms to synthesize these molecules from renewable feedstocks, with exquisite control over structure and stereochemistry, directly from DNA sequence? Polyketide synthases (PKSs) make this vision feasible. These megadalton enzymes function as modular assembly lines: each module selects a building block, extends the carbon backbone by two carbons, and optionally reduces and sets stereocenters. Because PKS architecture is collinear—the order of modules dictates the order of chemical operations—we can rationally redesign these enzymes to produce target molecules by rearranging their modular components. The theoretical chemical space is staggering: a four-module hybrid PKS with available natural building blocks can access over 10 trillion distinct structures.
I will describe our laboratory’s efforts to convert this theoretical potential into practical chemistry. We have engineered hybrid PKSs that produce families of 1,3-diols and amino alcohols, valerolactam monomers for high-performance nylons, adipic acid (a 2.6-million-ton commodity chemical whose conventional synthesis generates copious NOx emissions), monomers for infinitely recyclable polydiketoenamine plastics, and polycyclopropanated fatty acids whose energy density rivals rocket fuels. Underpinning this work are new tools—the ClusterCAD retrobiosynthesis platform, high-throughput protein-folding assays for junction optimization, AI-driven inverse folding with ProteinMPNN, and robotic platforms for combinatorial PKS assembly—that are transforming PKS engineering from bespoke craftsmanship into a systematic, highthroughput design discipline.
Bio: Jay Keasling is the Philomathia Professor of Alternative Energy at the University of California, Berkeley in the Departments of Bioengineering and Chemical and Biomolecular Engineering, senior faculty scientist at Lawrence Berkeley National Laboratory, and Chief Executive Officer of the Joint BioEnergy Institute (JBEI). Dr. Keasling’s research focuses on the metabolic engineering of microorganisms for degradation of environmental contaminants or for environmentally friendly synthesis of drugs, chemicals, and fuels. Keasling received a B.S. in Chemistry and Biology from the University of Nebraska and M.S. and Ph.D. in Chemical Engineering from the University of Michigan, and did post-doctoral research in biochemistry at Stanford University. He is a member of the National Academy of Engineering and the National Academy of Inventors.
10:30am, Remsen Hall 1