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 language | English (US) |
|---|---|
| Pages (from-to) | 2465-2473 |
| Number of pages | 9 |
| Journal | ACS Chemical Biology |
| Volume | 12 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 15 2017 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
Cite this
Elucidating Substrate Promiscuity within the FabI Enzyme Family. / Freund, Gabriel S.; O'Brien, Terrence E.; Vinson, Logan; Carlin, Dylan Alexander; Yao, Andrew; Mak, Wai Shun; Tagkopoulos, Ilias; Facciotti, Marc T.; Tantillo, Dean J.; Siegel, Justin.
In: ACS Chemical Biology, Vol. 12, No. 9, 15.09.2017, p. 2465-2473.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Elucidating Substrate Promiscuity within the FabI Enzyme Family
AU - Freund, Gabriel S.
AU - O'Brien, Terrence E.
AU - Vinson, Logan
AU - Carlin, Dylan Alexander
AU - Yao, Andrew
AU - Mak, Wai Shun
AU - Tagkopoulos, Ilias
AU - Facciotti, Marc T.
AU - Tantillo, Dean J.
AU - Siegel, Justin
PY - 2017/9/15
Y1 - 2017/9/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029542425&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029542425&partnerID=8YFLogxK
U2 - 10.1021/acschembio.7b00400
DO - 10.1021/acschembio.7b00400
M3 - Article
C2 - 28820936
AN - SCOPUS:85029542425
VL - 12
SP - 2465
EP - 2473
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 9
ER -