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Title: β-Hydroxyacyl-acyl Carrier Protein Dehydratase (FabZ) from Francisella tularensis and Yersinia pestis : Structure Determination, Enzymatic Characterization, and Cross-Inhibition Studies

Abstract

The bacterial system for fatty acid biosynthesis (FAS) contains several enzymes whose sequence and structure are highly conserved across a vast array of pathogens. Coupled with their low homology and difference in organization compared to the equivalent system in humans, this makes the FAS pathway an excellent target for antimicrobial drug development. To this end, we have cloned, expressed, and purified the β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from both Francisella tularensis (FtFabZ) and Yersinia pestis (YpFabZ). We also solved the crystal structures and performed an enzymatic characterization of both enzymes and several mutant forms of YpFabZ. In addition, we have discovered two novel inhibitors of FabZ, mangostin and stictic acid, which show similar potencies against both YpFabZ and FtFabZ. Lastly, we selected several compounds from the literature that have been shown to be active against single homologues of FabZ and tested them against both YpFabZ and FtFabZ. Our results have revealed clues as to which scaffolds are likely to lead to broad-spectrum antimicrobials targeted against FabZ as well as modifications to existing FabZ inhibitors that may improve potency.

Authors:
 [1];  [2];  [3];  [2]
  1. Stony Brook Univ., NY (United States). Biochemistry and Structural Biology Dept. and Medical Scientist Training Program; Brookhaven National Lab. (BNL), Upton, NY (United States). Biology Dept.
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). Biolog Dept.
  3. Brookhaven National Lab. (BNL), Upton, NY (United States). Biolog Dept.; Stony Brook Univ., NY (United States). Physics Dept.
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Workforce Development for Teachers and Scientists (WDTS) (SC-27)
OSTI Identifier:
1335393
Report Number(s):
BNL-111806-2016-JA
Journal ID: ISSN 0006-2960; 456140124
Grant/Contract Number:  
SC00112704
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 55; Journal Issue: 7; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

McGillick, Brian E., Kumaran, Desigan, Vieni, Casey, and Swaminathan, Subramanyam. β-Hydroxyacyl-acyl Carrier Protein Dehydratase (FabZ) from Francisella tularensis and Yersinia pestis : Structure Determination, Enzymatic Characterization, and Cross-Inhibition Studies. United States: N. p., 2016. Web. doi:10.1021/acs.biochem.5b00832.
McGillick, Brian E., Kumaran, Desigan, Vieni, Casey, & Swaminathan, Subramanyam. β-Hydroxyacyl-acyl Carrier Protein Dehydratase (FabZ) from Francisella tularensis and Yersinia pestis : Structure Determination, Enzymatic Characterization, and Cross-Inhibition Studies. United States. doi:10.1021/acs.biochem.5b00832.
McGillick, Brian E., Kumaran, Desigan, Vieni, Casey, and Swaminathan, Subramanyam. Thu . "β-Hydroxyacyl-acyl Carrier Protein Dehydratase (FabZ) from Francisella tularensis and Yersinia pestis : Structure Determination, Enzymatic Characterization, and Cross-Inhibition Studies". United States. doi:10.1021/acs.biochem.5b00832. https://www.osti.gov/servlets/purl/1335393.
@article{osti_1335393,
title = {β-Hydroxyacyl-acyl Carrier Protein Dehydratase (FabZ) from Francisella tularensis and Yersinia pestis : Structure Determination, Enzymatic Characterization, and Cross-Inhibition Studies},
author = {McGillick, Brian E. and Kumaran, Desigan and Vieni, Casey and Swaminathan, Subramanyam},
abstractNote = {The bacterial system for fatty acid biosynthesis (FAS) contains several enzymes whose sequence and structure are highly conserved across a vast array of pathogens. Coupled with their low homology and difference in organization compared to the equivalent system in humans, this makes the FAS pathway an excellent target for antimicrobial drug development. To this end, we have cloned, expressed, and purified the β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from both Francisella tularensis (FtFabZ) and Yersinia pestis (YpFabZ). We also solved the crystal structures and performed an enzymatic characterization of both enzymes and several mutant forms of YpFabZ. In addition, we have discovered two novel inhibitors of FabZ, mangostin and stictic acid, which show similar potencies against both YpFabZ and FtFabZ. Lastly, we selected several compounds from the literature that have been shown to be active against single homologues of FabZ and tested them against both YpFabZ and FtFabZ. Our results have revealed clues as to which scaffolds are likely to lead to broad-spectrum antimicrobials targeted against FabZ as well as modifications to existing FabZ inhibitors that may improve potency.},
doi = {10.1021/acs.biochem.5b00832},
journal = {Biochemistry},
issn = {0006-2960},
number = 7,
volume = 55,
place = {United States},
year = {2016},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
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