ACS Chemical Biology
ACS Chemical Biology
5 years ago

Elucidating Substrate Promiscuity within the FabI Enzyme Family

Elucidating Substrate Promiscuity within the FabI Enzyme Family
Andrew Yao, Justin B. Siegel, Dylan Alexander Carlin, Marc T. Facciotti, Wai Shun Mak, Dean J. Tantillo, Terrence E. O’Brien, Ilias Tagkopoulos, Gabriel S. Freund, Logan Vinson
The rapidly growing appreciation of enzymes’ catalytic and substrate promiscuity may lead to their expanded use in the fields of chemical synthesis and industrial biotechnology. Here, we explore the substrate promiscuity of enoyl-acyl carrier protein reductases (commonly known as FabI) and how that promiscuity is a function of inherent reactivity and the geometric demands of the enzyme’s active site. We demonstrate that these enzymes catalyze the reduction of a wide range of substrates, particularly α,β-unsaturated aldehydes. In addition, we demonstrate that a combination of quantum mechanical hydride affinity calculations and molecular docking can be used to rapidly categorize compounds that FabI can use as substrates. The results here provide new insight into the determinants of catalysis for FabI and set the stage for the development of a new assay for drug discovery, organic synthesis, and novel biocatalysts.

Publisher URL: http://dx.doi.org/10.1021/acschembio.7b00400

DOI: 10.1021/acschembio.7b00400

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