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Review
. 2019 Apr;103(7):2903-2912.
doi: 10.1007/s00253-019-09684-4. Epub 2019 Feb 18.

Occurrence, function, and biosynthesis of mycofactocin

Richard Ayikpoe  1 , Vishnu Govindarajan  1 , John A Latham  2
Affiliations
Review

Occurrence, function, and biosynthesis of mycofactocin

Richard Ayikpoe et al. Appl Microbiol Biotechnol. 2019 Apr.

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 remain 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.

Keywords: Biosynthesis; Mycofactocin; Peptide modification; Redox cofactor; RiPP.

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Conflict of interest statement

Conflicts of Interest

The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1.
Figure 1.
The gene organization of the mycofactocin biosynthetic pathway (blue) from various species indicates that the genes mftABCDEF are generally found together and that MftR (black) is the regulator of the pathway. Ancillary genes (red), such as short chain dehydrogenases (SDR) and zinc dependent dehydrogenases (ZnDH) can be found in various combinations but are dependent upon the presence of the mycofactocin biosynthetic cluster. Additional genes, such as the mycofactocin fadH, are also associated with the pathway but for unclear reasons.
Figure 2.
Figure 2.
An iTOL generated taxonomy based phylogenetic tree showing the number of mycofactocin encoding species identified in each genus. The indicated genera are color coordinated by phylum where pink represents Actinobacteria, green represents Chloroflexi, lavender represents Firmicutes, cyan represents Proteobacteria, and purple represents Euryarchaeota.
Figure 3.
Figure 3.
The biosynthesis of pyrroloquinoline quinone begins with the crosslinking of a conserved glutamate and tyrosine by PqqE. The crosslink is then putatively excised from the peptide by PqqF and/or PqqG. PqqB has been proposed to oxidize the tyrosine ring and a subsequent spontaneous oxidation and cyclization results in the formation of 3a-(2-amino-2-carboxyethyl)-4,5-dioxo-4,5,6,7,8,9-hexahydroquinoline-7,9-dicarboxylic acid (AHQQ). The last oxidative and cyclization steps are catalyzed by PqqC which result in the formation of PQQ.
Figure 4.
Figure 4.
Known steps (blue) in mycofactocin biosynthesis begins with the two-step modification of MftA by MftC forming the intermediate MftA*. The peptidase MftE, hydrolyzes MftA* yielding 3-amino-5-[(p-hydroxyphenyl) methyl]-4,4-dimethyl-2-pyrrolidinone (AHDP). The involvement of MftD and MftF in mycofactocin biosynthesis is unknown (red) but could include the hydroxylation of the phenol of AHDP and a sugar attachment to the free amine.
See this image and copyright information in PMC

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