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Production of multi-methyl-branched fatty methyl ketones via a chimeric polyketide synthase pathway

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Petroleum and its derivatives revolutionized every aspect of human life, from how we work and travel to what we wear and eat. However, mitigation and prevention of climate change are of utmost ethical and economical importance. Biology is a potential means for reducing greenhouse gas emissions, while maintaining or even diversifying and improving the goods and services the world has grown to depend on. Biofuels, for example, can be made with renewable waste feedstocks and can supplement or replace petroleum-derived fuels but lack optimal molecular properties. We therefore sought a means for customizing biologically-produced carbon backbones. To this end, we engineered enzymes from microbial antibiotic biosynthesis called polyketide synthases. These enzymes form modular “assembly lines” where the activity of each catalytic unit can be predicted with reasonable confidence. We envisioned combining individual enzymes to form a new biosynthetic assembly line which, until this work, did not exist in nature. We first investigated the main biosynthetic chassis, an iterative polyketide synthase, BorM5, from the borrelidin pathway. We discovered that BorM5 is promiscuous for both starting and elongation substrates, producing a variety of mid-length branched and linear saturated fatty acyl intermediates. We next characterized the trans-acting thioesterase, BorB, hoping to use it as an offloading mechanism. We propose that BorB acts to remove dead-end intermediates from the borrelidin pathway, increasing its efficiency. We then engineered on- and off-loading neighbors for BorM5 and observed production of new-to-Nature C11 and C14 methyl branched methyl ketones. Diversification and high-titer production of these compounds, combined with materials testing, may lead to improved biofuels and the environmental, economic, and social benefits that accompany them.

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This item is under embargo until April 28, 2024.