Fatty acids have several functions in cells, including energy storage and building lipids used in cell membranes, making them essential to all organisms. The acyl carrier protein (ACP) plays a key role in endogenous fatty acid synthesis because it holds the growing fatty acid chain as each enzyme acts on it. Various organisms, including some pathogens, are predicted to survive during nutrient-limiting conditions due to the activity of an acyl-acyl carrier protein synthetase (AasS). AasS is believed to recycle fatty acids from the environment and load them directly onto ACP, which allows them to be lengthened and incorporated into lipids. In this project, an AasS inhibitor was designed, synthesized, and tested in vitro. AasS catalyzes two reactions – the formation of an activated fatty acid AMP ester and then the attachment of the fatty acid onto a terminal thiol of ACP. The designed inhibitor mimicked the structure of the aforementioned AMP ester but replaced the phosphate group with a sulfonyl group, stopping the attachment onto ACP. The inhibitor was synthesized in seven steps and each product was analyzed by thin-layer chromatography and characterized by NMR spectroscopy. The inhibitor was tested in vitro on the model system E. coli ACP and successfully inhibited the loading of fatty acids onto ACP by AasS. Future studies will include testing the inhibitor on AasS enzymes from various pathogenic organisms and in vivo trials to determine the inhibitor’s efficacy in live cells.

Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling

2019 Spring National Meeting

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