Collaborative Research: Understanding and exploiting the structure-function link between fatty acid biosynthesis and degradation enzymes for functionalized small molecule synthesis

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Commercially important products are often built up from small molecules. Bacteria and other microbes are proficient at producing such molecules. Many are synthesized from fats and fatty acids. Understanding how the cells make and modify fats will help determine how to make renewable fuels and chemicals in large amounts using microbes. The project will also help educate our society in the challenges and opportunities on the road to a sustainable future. This includes advising and training of undergraduate and high school students from school districts serving predominantly minority populations. Together, these efforts will provide academic and industrial training in areas of strategic national importance.Insight into the evolutionary divergence of fatty acid biosynthesis (FAB) and beta-oxidation (BOX) pathways will be sought by characterizing enzyme/substrate interactions and the unique characteristics of enzymes from various organisms. Using non-decarboxylative condensation and β-reduction reactions, molecules with novel functionalities will be generated. Type II FAB and BOX enzymes will be used interchangeably to capitalize on the advantageous characteristics of each set of enzymes. An integrated approach in which computational protein modeling and design will guide experimentation through molecular modeling of the FAB and BOX enzymes with a wide array of biosynthetically accessible compounds will be undertaken. The specific objectives of the project are: 1) computational protein modeling and design of type II FAB and BOX enzymes; 2) in vitro characterization of type II FAB and BOX enzymes; and 3) in vivo construction and characterization of combinations of type II FAB and BOX enzymes. Medium chain (C5-C8) dicarboxylic and methyl-branched carboxylic acids, specifically dicarboxylates adipic (C6) and suberic (C8) acids and methyl-branched unsaturated tiglic acid (C5) will be produced.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.