Mark Ellerhorst

Mark Ellerhorst

The biochemistry and physiology of the redox cofactor mycofactocin

Mycofactocin is a recently discovered ribosomally synthesized and post-translationally modified (RiPP) redox cofactor, encoded and synthesized by the gene cluster mftABCDEF [1]. It is present in the genomes of a variety of different bacteria and even archaea [2] but appears to be particularly conserved in mycobacteria [1], hence the name. It was proposed that mycofactocin acts as an electron acceptor for specific alcohol dehydrogenases in vivo [2]. The biosynthesis of mycofactocin was shown to be induced by the presence of ethanol and is necessary for alcohol metabolism in Mycolicibacterium smegmatis [3]. In addition, it was found that the redox-active core molecule can be glycosylated by MftF with up to nine hexoses in β-1,4-glycosidic bonds [4]. Until today, the role of mycofactocin in vivo remains widely unknown. Therefore, this project is aimed at further investigation of the physiology, biochemistry, and biosynthesis of mycofactocin and its derivatives. These investigations will be realized by state-of-the-art “-omics” methods, such as targeted and untargeted metabolomics using high-resolution liquid chromatography coupled to mass spectrometry as well as classical methods in genetics and biochemistry.

References

1 Ayikpoe, R., Govindarajan, V., & Latham, J. A. (2019). Occurrence, function, and biosynthesis of mycofactocin. Applied microbiology and biotechnology, 103(7), 2903–2912. https://doi.org/10.1007/s00253-019-09684-4.

2 Haft, D.H. (2011). Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners. BMC Genomics, 12: 21. https://doi.org/10.1186/1471-2164-12-21.

3 Krishnamoorthy, G., Kaiser, P., Lozza, L., Hahnke, K., Mollenkopf, H. J., and Kaufmann, S. (2019). Mycofactocin Is Associated with Ethanol Metabolism in Mycobacteria. mBio. 10(3): e00190–19. https://doi.org/10.1128/mBio.00190-19.

4 Peña-Ortiz, L., Graça, A.P., Guo, H., Braga, D., Köllner, T.G., Regestein, L., Beemelmanns, C., and Lackner, G. (2020). Structure elucidation of the redox cofactor mycofactocin reveals oligo-glycosylation by MftF. Chem Sci, 11(20): 5182–5190. https://doi.org/10.1039/d0sc01172j.

Supervisor

Gerald Lackner

Co-Supervisors

Dirk Hoffmeister

Start of PhD

November 1, 2020

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