Mycolactone is a

polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

-derived

macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...

produced and secreted by a group of very closely related pathogenic Mycobacteria 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''. These mycobacteria are collectively referred to as mycolactone-producing mycobacteria or MPM. In humans, mycolactone is the toxin responsible for

Buruli ulcer Buruli ulcer () is an infectious disease characterized by the development of painless open wounds. The disease is limited to certain areas of the world, most cases occurring in Sub-Saharan Africa and Australia. The first sign of infection is a s ...

s, 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

core with an

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

-linked

chain. Three plasmid-encoded

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

(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 Thioesterases are enzymes which belong to the esterase family. Esterases, in turn, are one type of the several hydrolases known. Thioesterases exhibit esterase activity (splitting of an ester into acid and alcohol, in the presence of water) speci ...

(TE) that was thought to catalyze the formation of the mycolactone core but appears inactive. Each module consists of either malonyl-CoA or

methylmalonyl-CoA Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle (aka the Citric Acid Cyc ...

Acyltransferase (AT) that allows for chain extension, a ketosynthase (KS), which catalyzes chain elongation, and an

Acyl carrier protein The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene ...

(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 in the active site. Four of the DH domains are predicted to be inactive based on a

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...

found in the active site sequence. Figure 1. Domain Organization of Mycolactone.

References

{{reflist, 2 Polyketide antibiotics Macrolides Polyenes