MOLECULAR BASIS FOR ACYL CARRIER PROTEIN SHUTTLING IN MAMMALIAN FATTY ACID SYNTHASE
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Biochemistry, Biophysics, and Structural Biology
Biology
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Structural Biology
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Abstract
The mammalian fatty acid synthase (FASN) enzyme is an essential metabolic enzyme that synthesizes a 16-carbon saturated fatty acid, palmitate, from the metabolites acetyl-CoA and malonyl-CoA. FASN uses a carrier domain, the acyl carrier protein (ACP), to coordinate shuttle intermediates amongst six catalytic domains for palmitate synthesis. As a promising disease target, increased understanding of FASN and its mechanism may aid in designing small molecule inhibitors for therapeutics or probes for biomedical research. Using single particle analysis cryo-EM, we determined the structure of mammalian FASN with the ACP stalled at three of the six catalytic domains. From our structures, we identified important residues at the ACP interaction interface that are important for proper intermediate shuttling and palmitate synthesis by FASN. Additionally, we determined the structure of FASN complexed with the current leading small molecule inhibitor, Denifanstat, for future work to optimize the compound with structure guided drug design. Altogether, this work provides novel mechanistic insights into the complex mechanism ACP intermediate shuttling in FASN and inhibition by small molecules.