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PreprintCited by 2Enzyme Structure and FunctionTuberculosis Research and EpidemiologyMetalloenzymes and iron-sulfur proteins

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Mycobacterial EtfD contains an unusual linear [3Fe-4S] cluster and enables β-oxidation to drive proton pumping by the electron transport chain

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Courbon, Gautier M., Makarov, Vadim, Cole, Stewart T., Schnapinger, Dirk, Ehrt, Sabine, Rubinstein, John L.·2025·The EMBO Journal
DOI 10.1101/2025.05.14.654035PMC PMC12132442

Preprint — published as 10.1038/s44318-026-00726-y · Paper page

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Abstract

In mycobacteria, the protein EtfD is thought to link β-oxidation of fatty acids with the electron transport chain, two processes that have attracted attention as targets for therapeutics to treat tuberculosis (TB) and other mycobacterial infections. It has been proposed that targeting β- oxidation could shorten treatment duration by killing non-replicating Mycobacterium tuberculosis within granulomas in the lungs. Here we show that Mycobacterium smegmatis , a fast growing and nonpathogenic model for energy metabolism in M. tuberculosis , relies on EtfD for extracting energy from β-oxidation. Electron cryomicroscopy allowed structure determination of M. smegmatis EtfD, revealing an unusual linear [3Fe-4S] cluster that has not been seen in other protein structures, but which resembles the catalytic noncubane [4Fe-4S] clusters in heterodisulfide reductases. The structure suggests how EtfD transfers electrons from β-oxidation to the electron transport chain. We devised an assay that couples EtfD activity to a fluorescent readout of proton pumping by the electron transport chain, which can be used to identify compounds that block mycobacteria from using β-oxidation to power oxidative phosphorylation.

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Metadata

Authors
Courbon, G. M., Makarov, V., Cole, S. T., Schnapinger, D., Ehrt, S., & Rubinstein, J. L.
Affiliations
  • University of Toronto (CA)
  • Russian Academy of Sciences (RU)
  • University of Oxford (GB)
  • Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
  • Weill Cornell Medicine (US)
Corresponding author
  • Courbon, Gautier M.
  • Rubinstein, John L.
ORCID
Venue
The EMBO Journal
Publisher
openRxiv
Published
2025-05-15
Volume
45
Issue
8
Pages
2785-2807
ISSN
0261-4189 (ISSN-L)
DOI
10.1101/2025.05.14.654035
PMC
PMC12132442
OpenAlex
W7138343717
Cited by
2
References
1
Citations by year
2026: 2
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Canadian Institutes of Health Research (PJT191893)
  • Canada Research Chairs
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Metalloenzymes and iron-sulfur proteins
Keywords
Mycobacterium smegmatis, Mycobacterium tuberculosis, fatty acid beta-oxidation, electron transport chain, [3Fe-4S] cluster, electron transfer, oxidative phosphorylation, proton translocation, tuberculosis drug targets, non-replicating mycobacteria

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