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Title: Amphipathic Benzoic Acid Derivativies: Synthesis and Binding in the Hydrophobic Tunnel of the Zinc Deacetylase LpxC

Abstract

The first committed step in lipid A biosynthesis is catalyzed by uridine diphosphate-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC), a zinc-dependent deacetylase, and inhibitors of LpxC may be useful in the development of antibacterial agents targeting a broad spectrum of Gram-negative bacteria. Here, we report the design of amphipathic benzoic acid derivatives that bind in the hydrophobic tunnel in the active site of LpxC. The hydrophobic tunnel accounts for the specificity of LpxC toward substrates and substrate analogues bearing a 3-O-myristoyl substituent. Simple benzoic acid derivatives bearing an aliphatic 'tail' bind in the hydrophobic tunnel with micromolar affinity despite the lack of a glucosamine ring like that of the substrate. However, although these benzoic acid derivatives each contain a negatively charged carboxylate 'warhead' intended to coordinate to the active site zinc ion, the 2.25 {angstrom} resolution X-ray crystal structure of LpxC complexed with 3-(heptyloxy)benzoate reveals 'backward' binding in the hydrophobic tunnel, such that the benzoate moiety does not coordinate to zinc. Instead, it binds at the outer end of the hydrophobic tunnel. Interestingly, these ligands bind with affinities comparable to those measured for more complicated substrate analogue inhibitors containing glucosamine ring analogues and hydroxamate 'warheads' that coordinate to the active site zinc ion. Wemore » conclude that the intermolecular interactions in the hydrophobic tunnel dominate enzyme affinity in this series of benzoic acid derivatives.« less

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930389
Report Number(s):
BNL-81111-2008-JA
Journal ID: ISSN 0960-894X; TRN: US200904%%671
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: BioOrganic and Medicinal Chemistry Letters; Journal Volume: 15; Journal Issue: 7
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; AFFINITY; BACTERIA; BENZOIC ACID; BIOSYNTHESIS; CRYSTAL STRUCTURE; ENZYMES; GLUCOSAMINE; LIPIDS; RESOLUTION; SPECIFICITY; SUBSTRATES; SYNTHESIS; URIDINE; ZINC; ZINC IONS; national synchrotron light source

Citation Formats

Shin,H., Gennadios, H., Whittington, D., and Christianson, D. Amphipathic Benzoic Acid Derivativies: Synthesis and Binding in the Hydrophobic Tunnel of the Zinc Deacetylase LpxC. United States: N. p., 2007. Web.
Shin,H., Gennadios, H., Whittington, D., & Christianson, D. Amphipathic Benzoic Acid Derivativies: Synthesis and Binding in the Hydrophobic Tunnel of the Zinc Deacetylase LpxC. United States.
Shin,H., Gennadios, H., Whittington, D., and Christianson, D. Mon . "Amphipathic Benzoic Acid Derivativies: Synthesis and Binding in the Hydrophobic Tunnel of the Zinc Deacetylase LpxC". United States. doi:.
@article{osti_930389,
title = {Amphipathic Benzoic Acid Derivativies: Synthesis and Binding in the Hydrophobic Tunnel of the Zinc Deacetylase LpxC},
author = {Shin,H. and Gennadios, H. and Whittington, D. and Christianson, D.},
abstractNote = {The first committed step in lipid A biosynthesis is catalyzed by uridine diphosphate-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC), a zinc-dependent deacetylase, and inhibitors of LpxC may be useful in the development of antibacterial agents targeting a broad spectrum of Gram-negative bacteria. Here, we report the design of amphipathic benzoic acid derivatives that bind in the hydrophobic tunnel in the active site of LpxC. The hydrophobic tunnel accounts for the specificity of LpxC toward substrates and substrate analogues bearing a 3-O-myristoyl substituent. Simple benzoic acid derivatives bearing an aliphatic 'tail' bind in the hydrophobic tunnel with micromolar affinity despite the lack of a glucosamine ring like that of the substrate. However, although these benzoic acid derivatives each contain a negatively charged carboxylate 'warhead' intended to coordinate to the active site zinc ion, the 2.25 {angstrom} resolution X-ray crystal structure of LpxC complexed with 3-(heptyloxy)benzoate reveals 'backward' binding in the hydrophobic tunnel, such that the benzoate moiety does not coordinate to zinc. Instead, it binds at the outer end of the hydrophobic tunnel. Interestingly, these ligands bind with affinities comparable to those measured for more complicated substrate analogue inhibitors containing glucosamine ring analogues and hydroxamate 'warheads' that coordinate to the active site zinc ion. We conclude that the intermolecular interactions in the hydrophobic tunnel dominate enzyme affinity in this series of benzoic acid derivatives.},
doi = {},
journal = {BioOrganic and Medicinal Chemistry Letters},
number = 7,
volume = 15,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}