The name "mycofactocin" is derived from three words, the genus name "Mycobacterium", "cofactor" because its presence in a genome predicts the co-occurrence of certain families of enzymes as if it is a cofactor they require, and "bacteriocin" because a radical SAMenzyme critical to its biosynthesis, MftC, is closely related to the key enzyme for the biosynthesis of subtilosin A, a bacteriocin, from its precursor peptide.
Function
Mycofactocin is thought to play a role in redox pathways involving nicotinoproteins, enzymes with non-exchangeable bound nicotinamide adenine dinucleotide. This notion comes largely from comparative genomics work that highlighted the many parallels between mycofactocin and pyrroloquinoline quinone. In both cases, maturation of the RiPP requires post-translational modification of a precursor peptide by a radical SAM enzyme, the system appears in very similar form in large numbers of species, the product appears to be used within the cell rather than exported, and several families of enzymes occur exclusively in bacteria with those systems. The number of putatively mycofactocin-dependent oxidoreductases encoded by a single genome can be quite large: at least 19 for Rhodococcus jostii RHA1, and 26 for the short chain dehydrogenase/reductase family alone in Mycobacterium avium.
Biosynthesis
The mycofactocin biosynthesis pathway is one of the most abundant of any RiPP system in the collection of bacterial genomes sequenced to date. However, its species distribution is heavily skewed towards the Actinobacteria, including Mycobacterium tuberculosis, which is the causative agent of tuberculosis and therefore the number one killer among bacterial pathogens of humans. The system is virtually absent from the normal human microbiome, although common in soil bacteria. The biosynthesis of mycofactocin from its precursor peptide MftA begins with decarboxylation of the C-terminal tyrosine residue by the radical SAM enzyme MftC, with help from the precursor-binding protein MftB.. However, MftC appears next to perform a further modification to the MftA precursor peptide, an easily missed isomerization, by introducing a tyramine-valine cross-link, and consuming another S-adenosylmethionine in the process. The need for two modifications to MftA by MftC might explain the high degree of amino acid conservation in the last eight residues of MftA, as compared to the level of conservation seen for PqqA, precursor of PQQ. Next, the creatininase homolog MftE releases the C-terminal dipeptide, VY*. The biosynthesis may continue with additional modifications to VY* that are not yet characterized; the mature form of mycofactocin is not yet known.
