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PreprintCited by 3Microbial metabolism and enzyme functionTuberculosis Research and EpidemiologyMicrobial Natural Products and Biosynthesis

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MftG is crucial for ethanol metabolism of mycobacteria by linking mycofactocin oxidation to respiration

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Graça, Ana Patrícia, Nikitushkin, Vadim, Ellerhorst, Mark, Vilhena, Cláudia, Klassert, Tilman E., Starick, Andreas, Siemers, Malte, Al-Jammal, Walid K., Vilotijevic, Ivan, Slevogt, Hortense, Papenfort, Kai, Lackner, Gerald·2024·eLife
DOI 10.1101/2024.03.26.586840

Preprint — published as 10.7554/elife.97559.4 · Paper page

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Abstract

Mycofactocin is a redox cofactor essential for the alcohol metabolism of mycobacteria.. While the biosynthesis of mycofactocin is well established, the gene mftG , which encodes an oxidoreductase of the glucose-methanol-choline superfamily, remained functionally uncharacterized. Here, we show that MftG enzymes are almost exclusively found in genomes containing mycofactocin biosynthetic genes and are present in 75% of organisms harboring these genes. Gene deletion experiments in Mycolicibacterium smegmatis demonstrated a growth defect of the Δ mftG mutant on ethanol as a carbon source, accompanied by an arrest of cell division reminiscent of mild starvation. Investigation of carbon and cofactor metabolism implied a defect in mycofactocin reoxidation. Cell-free enzyme assays and respirometry using isolated cell membranes indicated that MftG acts as a mycofactocin dehydrogenase shuttling electrons toward the respiratory chain. Transcriptomics studies also indicated remodeling of redox metabolism to compensate for a shortage of redox equivalents. In conclusion, this work closes an important knowledge gap concerning the mycofactocin system and adds a new pathway to the intricate web of redox reactions governing the metabolism of mycobacteria.

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Metadata

Authors
Graça, A. P., Nikitushkin, V., Ellerhorst, M., Vilhena, C., Klassert, T. E., Starick, A., Siemers, M., Al-Jammal, W. K., Vilotijevic, I., Slevogt, H., Papenfort, K., & Lackner, G.
Affiliations
  • Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
  • Medizinische Hochschule Hannover (DE)
  • Friedrich Schiller University Jena (DE)
Corresponding author
Lackner, Gerald
ORCID
Venue
eLife
Publisher
openRxiv
Published
2024-03-28
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2024.03.26.586840
OpenAlex
W4406929589
Cited by
3
References
2
Citations by year
2025: 3
FWCI
0.91
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Funders
  • Carl-Zeiss-Stiftung
  • Freistaat Thüringen (2019 FGI 0003)
  • Deutscher Akademischer Austauschdienst
  • Deutsche Forschungsgemeinschaft (EXC 2051—, 390713860)
  • Leibniz-Gemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
Keywords
alcohol metabolism, mycobacteria, glucose-methanol-choline oxidoreductase, redox cofactors, Mycolicibacterium smegmatis, redox metabolism, cell division arrest, carbon source utilization

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