Amphipathic benzoic acid derivatives: Synthesis and binding in the hydrophobic tunnel of the zinc deacetylase LpxC
Benzoic acid derivatives bearing aliphatic substituents bind to LpxC with micromolar affinity. Surprisingly, the X-ray crystal structure of the complex with 3-(heptyloxy)benzoate reveals a ‘backward’ binding mode. The first committed step in lipid A biosynthesis is catalyzed by uridine diphosphate-(...
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Published in | Bioorganic & medicinal chemistry Vol. 15; no. 7; pp. 2617 - 2623 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Elsevier Ltd
01.04.2007
Elsevier Science |
Subjects | |
Online Access | Get full text |
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Summary: | Benzoic acid derivatives bearing aliphatic substituents bind to LpxC with micromolar affinity. Surprisingly, the X-ray crystal structure of the complex with 3-(heptyloxy)benzoate reveals a ‘backward’ binding mode.
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
Å 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2007.01.044 |