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:
MftG is crucial for ethanol metabolism of mycobacteria by linking mycofactocin oxidation to respiration.
In: eLife. Bd. 13 (2025) . - RP97559.
ISSN 2050-084X
DOI: https://doi.org/10.7554/eLife.97559.4

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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 ∆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.