Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related

pathogenic In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

Mycobacteria ''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 ...

species that have been assigned a variety of names including, '' M. ulcerans'', '' M. liflandii'' (an unofficial designation), '' M. pseudoshottsii'', and some strains of ''

M. marinum ''Mycobacterium marinum'' is a slow growing mycobacterium (SGM) belonging to the genus ''Mycobacterium'' and the phylum Actinobacteria. The strain marinum was first identified by Aronson in 1926 and it is observed as a pathogenic mycobacterium. F ...

''. These mycobacteria are collectively referred to as mycolactone-producing mycobacteria or MPM. In humans, mycolactone is the toxin responsible for Buruli ulcers, doing so by damaging tissues and inhibiting the immune response.

Variants

Five distinct, naturally occurring mycolactone structural variants have been described so far: * Mycolactone A/B (''M. ulcerans'' from Africa, Malaysia, Japan * Mycolactone C (''M. ulcerans'' from Australia) * Mycolactone D (''M. ulcerans'' from China) * Mycolactone E (''M. liflandii'' from Sub-Saharan Africa) * Mycolactone F (''M. pseudoshottsii'' and ''M. marinum'' from around the world)

Biosynthesis

Mycolactone consists of a 12-membered macrolide core with an ester-linked polyketide chain. Three

plasmid A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...

-encoded polyketide synthase (PKS) enzymes are responsible for its production: MLSA 1 and MLSA 2 which generate the core, and MLSB is responsible for the synthesis of the polyketide chain. As shown in Figure 1, MLSB (1.2 MDa) contains seven consecutive extension modules and MLSA 1 (1.8 MDa) consists of eight. The remaining PKS enzyme, MLSA 2, contains the ninth module of MLSA. The C-terminal domains of both MLSA2 and MLSB includes a thioesterase (TE) that was thought to catalyze the formation of the mycolactone core but appears inactive. Each module consists of either

malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...

or methylmalonyl-CoA

Acyltransferase Acyltransferase is a type of transferase enzyme that acts upon acyl groups. Examples include: * Glyceronephosphate O-acyltransferase * Lecithin-cholesterol acyltransferase *Long-chain-alcohol O-fatty-acyltransferase In enzymology, a long-chain- ...

(AT) that allows for chain extension, a ketosynthase (KS), which catalyzes chain elongation, and an Acyl carrier protein (ACP) where the growing polyketide chain is attached. Modules may also consist of any of the following modifying domains: a dehydratase (DH), an enoyl reductase (ER) and one of two types of ketoreductase (KR) domains. Type A and B KRs refer to the two directions of ketoreduction that are correlated with specific

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

in the

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...

. Four of the DH domains are predicted to be inactive based on a point mutation found in the active site sequence. Figure 1. Domain Organization of Mycolactone.

References

{{reflist, 2 Polyketide antibiotics Macrolides Polyenes