Elucidating Substrate Promiscuity within the FabI Enzyme Family

Gabriel S. Freund, Terrence E. O'Brien, Logan Vinson, Dylan Alexander Carlin, Andrew Yao, Wai Shun Mak, Ilias Tagkopoulos, Marc T. Facciotti, Dean J. Tantillo, Justin Siegel

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2465-2473
Number of pages9
JournalACS Chemical Biology
Volume12
Issue number9
DOIs
StatePublished - Sep 15 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Freund, G. S., O'Brien, T. E., Vinson, L., Carlin, D. A., Yao, A., Mak, W. S., Tagkopoulos, I., Facciotti, M. T., Tantillo, D. J., & Siegel, J. (2017). Elucidating Substrate Promiscuity within the FabI Enzyme Family. ACS Chemical Biology, 12(9), 2465-2473. https://doi.org/10.1021/acschembio.7b00400