Mycofactocin (MFT) is a family of small molecules derived from a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

of the type known as

RiPP Ripp may refer to: As a surname * Andrew Ripp, American singer-songwriter * Artie Ripp, American music industry executive * Hans-Jürgen Ripp, American politician * Keith Ripp, German association football player Other * ''Friend Ripp'', a 1923 Ge ...

(ribosomally synthesized and post-translationally modified peptides), naturally occurring in many types of ''

Mycobacterium ''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis (''M. tuberculosis'') and l ...

''. It was discovered in a

bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combin ...

study in 2011. All mycofactocins share a precursor in the form of premycofactocin (PMFT); they differ by the cellulose tail added. Being redox active, both PMFT and MFT have an oxidized

dione Dione may refer to: Astronomy *106 Dione, a large main belt asteroid *Dione (moon), a moon of Saturn *Helene (moon), a moon of Saturn sometimes referred to as "Dione B" Mythology *Dione (Titaness), a Titaness in Greek mythology *Dione (mythology) ...

(mycofactocinone) form and a reduced

diol A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol is also called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. The most common industrial diol is ...

(mycofactocinol) form, respectively termed PMFTH₂ and MFTH₂.

Name

The name "mycofactocin" is derived from three words, the

genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial n ...

name "''

''" (across which it is nearly universal), " 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 Bacteriocins are proteinaceous or peptidic toxins produced by bacteria to inhibit the growth of similar or closely related bacterial strain(s). They are similar to yeast and paramecium killing factors, and are structurally, functionally, and ...

" because a

radical SAM Radical SAM is a designation for a superfamily of enzymes that use a + cluster">Fe-4Ssup>+ cluster to reductively cleave ''S''-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′- deoxyadenosyl radical (5'-dAdo), as a critical int ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

critical to its biosynthesis, MftC, is closely related to the key enzyme for the biosynthesis of subtilosin A, a bacteriocin, from its precursor peptide.

Nomenclature

An MFT with a glucose tail of ''n'' units is termed MFT-''n''; MFT-''n''H₂ in the reduced form. An MFT with a 2-O-methylglucose is termed a ''methylmycofactocin'' (MMFT), with analogous numbering.

Function

Mycofactocin is thought to play a role in

redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...

pathways involving nicotinoproteins, enzymes with non-exchangeable bound

nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ...

(NAD). This notion comes largely from

comparative genomics Comparative genomics is a field of biological research in which the genomic features of different organisms are compared. The genomic features may include the DNA sequence, genes, gene order, regulatory sequences, and other genomic structural ...

work that highlighted the many parallels between mycofactocin and pyrroloquinoline quinone (PQQ). In both cases, maturation of the RiPP requires

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...

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 (SDR) family alone in ''Mycobacterium avium.'' The enzyme LimC (), a nicotinoprotein carveol dehydrogenase (EC 1.1.1.n4), is shown to use both MFT and PMFT ''in vitro''.

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 In biology, a species is the basic unit of Taxonomy (biology), classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of ...

distribution is heavily skewed towards the

Actinomycetota The ''Actinomycetota'' (or ''Actinobacteria'') are a phylum of all gram-positive bacteria. They can be terrestrial or aquatic. They are of great economic importance to humans because agriculture and forests depend on their contributions to soi ...

, including '' Mycobacterium tuberculosis'', which is the causative agent of

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in w ...

and therefore the number one killer among bacterial pathogens of humans. The system is virtually absent from the normal human

microbiome A microbiome () is the community of microorganisms that can usually be found living together in any given habitat. It was defined more precisely in 1988 by Whipps ''et al.'' as "a characteristic microbial community occupying a reasonably we ...

, although common in soil bacteria. # The biosynthesis of mycofactocin from its precursor peptide MftA begins with decarboxylation of the C-terminal

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

residue by the

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* (valine-tyrosine, where * indicates that the tyrosine was previously modified). # Next, MftD converts the VY-derived dipeptide to premycofactocin, which has a biologically active redox center. # And lastly, the glycosyltransferase MftF builds onto premycofactocin a variably sized, beta-1,4 linked oligomeric chain of

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, usi ...

(i.e.

cellulose Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Cellulose is an important structural component of the primary cell wall ...

), sometimes substituting derivatives such as 2-O-methylglucose. Mycofactocin, therefore, is not a single compound, but instead a mixture of closely related electron carriers that differ in the nature of their attached oligosaccharides.

References

External links

TIGR03969 : mycofactocin precursor MftAGO:0140604 : mycofactocin biosynthetic processCHEBI:150862 : premycofactocin
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