Occurrence, function, and biosynthesis of mycofactocin

Abstract

Mycofactocin is a member of the rapidly growing class of ribosomally synthesized and post translationally modified peptide (RiPP) natural products. Although the mycofactocin biosynthetic pathway is widely distributed among Mycobacterial species, the structure, function, and biosynthesis of the pathway product remains unknown. This mini-review will discuss the current state of knowledge regarding the mycofactocin biosynthetic pathway. In particular, we focus on the architecture and distribution of the mycofactocin biosynthetic cluster, mftABCDEF, among the Actinobacteria phylum. We discuss the potential molecular and physiological role of mycofactocin. We review known biosynthetic steps involving MftA, MftB, MftC, and MftE and relate them to pyrroloquinoline quinone biosynthesis. Lastly, we propose the function of the remaining putative biosynthetic enzymes, MftD and MftF.

Structure elucidation of the redox cofactor mycofactocin reveals oligo-glycosylation by MftF

“… 9 Mycofactocin (MFT) is a putative redox-cofactor whose existence has been postulated on the basis of comparative genomics and bioinformatics. 10 , 11 Its molecular identity and structure, however, have remained elusive to date. The MFT biosynthetic gene cluster is highly conserved and widespread among mycobacteria.…”

Impact of Oxygen Supply and Scale Up on Mycobacterium smegmatis Cultivation and Mycofactocin Formation

“…Therefore, novel redox cofactors present in mycobacteria could open the door to interesting physiological discoveries or even serve as targets for drug development. Mycofactocin (MFT) is a recently identified cofactor, biosynthesized as a ribosomally-produced and post-translationally modified peptide (RiPP) ( Ayikpoe et al, 2019 ; Peña-Ortiz et al, 2020 ). The discovery of MFT started with the observation that its biosynthetic gene cluster was reminiscent of another bacterial redox cofactor, pyrroloquinoline quinone, and was genomically associated with certain subfamilies of oxidoreductases ( Haft, 2011 ).…”

“…The discovery of MFT started with the observation that its biosynthetic gene cluster was reminiscent of another bacterial redox cofactor, pyrroloquinoline quinone, and was genomically associated with certain subfamilies of oxidoreductases ( Haft, 2011 ). The MFT locus was found in all species of the genus Mycobacterium , is widespread in related Actinobacteria like Rhodococcus , but sparsely present in Chloroflexi, Firmicutes, Proteobacteria, and some archaeal species ( Haft, 2011 ; Ayikpoe et al, 2019 ).…”

Genome mining strategies for ribosomally synthesised and post-translationally modified peptides

“…The BGCs were then reannotated to identify a conserved yet previously unannotated mycofactocin PP gene. Subsequent experimental studies have proven this to be a genuine RiPP pathway [74] , [75] . Haft and Mitchell bioinformatically identified Nif11-like and nitrile hydratase-like leader peptides associated with BGCs that had homology to linear-azoline containing peptide BGCs [76] .…”