{Reference Type}: Journal Article
{Title}: Control of Unsaturation in De Novo Fatty Acid Biosynthesis by FabA.
{Author}: Bartholow TG;Sztain T;Young MA;Lee DJ;Davis TD;Abagyan R;Burkart MD;
{Journal}: Biochemistry
{Volume}: 61
{Issue}: 7
{Year}: 04 2022 5
{Factor}: 3.321
{DOI}: 10.1021/acs.biochem.2c00094
{Abstract}: Carrier protein-dependent biosynthesis provides a thiotemplated format for the production of natural products. Within these pathways, many reactions display exquisite substrate selectivity, a regulatory framework proposed to be controlled by protein-protein interactions (PPIs). In Escherichia coli, unsaturated fatty acids are generated within the de novo fatty acid synthase by a chain length-specific interaction between the acyl carrier protein AcpP and the isomerizing dehydratase FabA. To evaluate PPI-based control of reactivity, interactions of FabA with AcpP bearing multiple sequestered substrates were analyzed through NMR titration and guided high-resolution docking. Through a combination of quantitative binding constants, residue-specific perturbation analysis, and high-resolution docking, a model for substrate control via PPIs has been developed. The in silico results illuminate the mechanism of FabA substrate selectivity and provide a structural rationale with atomic detail. Helix III positioning in AcpP communicates sequestered chain length identity recognized by FabA, demonstrating a powerful strategy to regulate activity by allosteric control. These studies broadly illuminate carrier protein-dependent pathways and offer an important consideration for future inhibitor design and pathway engineering.