Fatty acids have several functions in cells, including energy storage and serving as building blocks for lipids 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 tailoring 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. This enzyme may help organisms survive, even when fatty acid synthesis is targeted with known inhibitors. 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. Here, we designed inhibitors to mimic the fatty acid AMP ester, and succesffully synthesized and characterized them. The inhibitors were tested in vitro on AasS enzymes from a model organism and pathogens, as well as in vivo. These inhibitors provide a tool to further study fatty acid recyling in a variety of organisms, as well as present a candidate for drug design.

Synthesis of small molecule inhibitors to study fatty acid recycling

2019 Fall National Meeting

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