Evidence map›Paper›PMID 27325754›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2016

Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site.

Monica Kasbekar, Gerhard Fischer, Bryan T Mott, Adam Yasgar, Marko Hyvönen, Helena I M Boshoff, Chris Abell, Clifton E Barry, Craig J Thomas

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
4.4field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed, 42 citations in OpenAlex.

  1. Article
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  5. Design and Synthesis of Novel Antimicrobial Agents.Antibiotics (Basel, Switzerland) · 2023
    Review
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  9. Article
  10. Targeting of Fumarate Hydratase fromJournal of medicinal chemistry · 2019
    Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 2 countries.

Monica KasbekarNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20850; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
Gerhard FischerDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;
Bryan T MottNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20850;
Adam YasgarNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20850;
Marko HyvönenDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;
Helena I M BoshoffNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20850.
Chris AbellDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
Clifton E BarryNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20850.
Craig J ThomasNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20850; craigt@mail.nih.gov.
National Institutes of Health · USUniversity of Cambridge · GBNational Institute of Allergy and Infectious Diseases · US

Funding

Development Of New Chemotherapeutics For TuberculosisZIAAI000693 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI BARRY, CLIFTON · 2009 to 2025
$20.1M
Exploring the metabolism of non-replicating and drug-resistant TBZIAAI000783 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI BARRY, CLIFTON · 2009 to 2017
$8.2M
6 · The paper itself

Abstract

Enzymes in essential metabolic pathways are attractive targets for the treatment of bacterial diseases, but in many cases, the presence of homologous human enzymes makes them impractical candidates for drug development. Fumarate hydratase, an essential enzyme in the tricarboxylic acid (TCA) cycle, has been identified as one such potential therapeutic target in tuberculosis. We report the discovery of the first small molecule inhibitor, to our knowledge, of the Mycobacterium tuberculosis fumarate hydratase. A crystal structure at 2.0-Å resolution of the compound in complex with the protein establishes the existence of a previously unidentified allosteric regulatory site. This allosteric site allows for selective inhibition with respect to the homologous human enzyme. We observe a unique binding mode in which two inhibitor molecules interact within the allosteric site, driving significant conformational changes that preclude simultaneous substrate and inhibitor binding. Our results demonstrate the selective inhibition of a highly conserved metabolic enzyme that contains identical active site residues in both the host and the pathogen.

Indexed as

Allosteric RegulationCrystallography, X-RayFluorescenceFumarate HydrataseMycobacterium tuberculosisFumarate Hydrataseallosteric regulationfumarate hydrataseMycobacterium tuberculosisselective inhibitionTCA cycle

Identifiers

PMID27325754
PMCPMC4941444
OpenAlexW2468255124

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.