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A Long Residence Time Enoyl-Reductase Inhibitor Explores an Extended Binding Region with Isoenzyme-Dependent Tautomer Adaptation and Differential Substrate-Binding Loop Closure

Eltschkner, Sandra LU ; Kehrein, Josef ; Le, Thien Anh ; Davoodi, Shabnam ; Merget, Benjamin ; Basak, Sneha ; Weinrich, Jonas D. ; Schiebel, Johannes ; Tonge, Peter J. and Engels, Bernd , et al. (2021) In ACS Infectious Diseases 7(4). p.746-758
Abstract

The enoyl-acyl carrier protein (ACP) reductase (ENR) is a key enzyme within the bacterial fatty-acid synthesis pathway. It has been demonstrated that small-molecule inhibitors carrying the diphenylether (DPE) scaffold bear a great potential for the development of highly specific and effective drugs against this enzyme class. Interestingly, different substitution patterns of the DPE scaffold have been shown to lead to varying effects on the kinetic and thermodynamic behavior toward ENRs from different organisms. Here, we investigated the effect of a 4′-pyridone substituent in the context of the slow tight-binding inhibitor SKTS1 on the inhibition of the Staphylococcus aureus enoyl-ACP-reductase saFabI and the closely related isoenzyme... (More)

The enoyl-acyl carrier protein (ACP) reductase (ENR) is a key enzyme within the bacterial fatty-acid synthesis pathway. It has been demonstrated that small-molecule inhibitors carrying the diphenylether (DPE) scaffold bear a great potential for the development of highly specific and effective drugs against this enzyme class. Interestingly, different substitution patterns of the DPE scaffold have been shown to lead to varying effects on the kinetic and thermodynamic behavior toward ENRs from different organisms. Here, we investigated the effect of a 4′-pyridone substituent in the context of the slow tight-binding inhibitor SKTS1 on the inhibition of the Staphylococcus aureus enoyl-ACP-reductase saFabI and the closely related isoenzyme from Mycobacterium tuberculosis, InhA, and explored a new interaction site of DPE inhibitors within the substrate-binding pocket. Using high-resolution crystal structures of both complexes in combination with molecular dynamics (MD) simulations, kinetic measurements, and quantum mechanical (QM) calculations, we provide evidence that the 4′-pyridone substituent adopts different tautomeric forms when bound to the two ENRs. We furthermore elucidate the structural determinants leading to significant differences in the residence time of SKTS1 on both enzymes.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
diphenylether, enoyl-ACP reductase, Mycobacterium tuberculosis, residence time, Staphylococcus aureus, tautomerization
in
ACS Infectious Diseases
volume
7
issue
4
pages
746 - 758
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:33710875
  • scopus:85103498592
ISSN
2373-8227
DOI
10.1021/acsinfecdis.0c00437
language
English
LU publication?
yes
id
773addef-ab32-460b-a9d8-949fe6e86910
date added to LUP
2021-04-15 09:20:00
date last changed
2025-01-13 06:55:04
@article{773addef-ab32-460b-a9d8-949fe6e86910,
  abstract     = {{<p>The enoyl-acyl carrier protein (ACP) reductase (ENR) is a key enzyme within the bacterial fatty-acid synthesis pathway. It has been demonstrated that small-molecule inhibitors carrying the diphenylether (DPE) scaffold bear a great potential for the development of highly specific and effective drugs against this enzyme class. Interestingly, different substitution patterns of the DPE scaffold have been shown to lead to varying effects on the kinetic and thermodynamic behavior toward ENRs from different organisms. Here, we investigated the effect of a 4′-pyridone substituent in the context of the slow tight-binding inhibitor SKTS1 on the inhibition of the Staphylococcus aureus enoyl-ACP-reductase saFabI and the closely related isoenzyme from Mycobacterium tuberculosis, InhA, and explored a new interaction site of DPE inhibitors within the substrate-binding pocket. Using high-resolution crystal structures of both complexes in combination with molecular dynamics (MD) simulations, kinetic measurements, and quantum mechanical (QM) calculations, we provide evidence that the 4′-pyridone substituent adopts different tautomeric forms when bound to the two ENRs. We furthermore elucidate the structural determinants leading to significant differences in the residence time of SKTS1 on both enzymes.</p>}},
  author       = {{Eltschkner, Sandra and Kehrein, Josef and Le, Thien Anh and Davoodi, Shabnam and Merget, Benjamin and Basak, Sneha and Weinrich, Jonas D. and Schiebel, Johannes and Tonge, Peter J. and Engels, Bernd and Sotriffer, Christoph and Kisker, Caroline}},
  issn         = {{2373-8227}},
  keywords     = {{diphenylether; enoyl-ACP reductase; Mycobacterium tuberculosis; residence time; Staphylococcus aureus; tautomerization}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{746--758}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Infectious Diseases}},
  title        = {{A Long Residence Time Enoyl-Reductase Inhibitor Explores an Extended Binding Region with Isoenzyme-Dependent Tautomer Adaptation and Differential Substrate-Binding Loop Closure}},
  url          = {{http://dx.doi.org/10.1021/acsinfecdis.0c00437}},
  doi          = {{10.1021/acsinfecdis.0c00437}},
  volume       = {{7}},
  year         = {{2021}},
}