Pikromycin was studied by Brokmann and Hekel in 1951 and was the first antibiotic
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. Macrol ...
to be isolated.
Pikromycin is synthesized through a type I
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 ...
system in ''
Streptomyces venezuelae
''Streptomyces venezuelae'' is a species of soil-dwelling Gram-positive bacterium of the genus ''Streptomyces''.
''S. venezuelae'' is filamentous. In its spore-bearing stage, hyphae perfuse both above ground as aerial hyphae and in the soil ...
'', a species of
Gram-positive
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
Gram-positive bacte ...
bacterium in the genus ''
Streptomyces
''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...
''.
Pikromycin is derived from
narbonolide, a 14-membered ring macrolide.
Along with the narbonolide backbone, pikromycin includes a desosamine sugar and a hydroxyl group. Although Pikromycin is not a clinically useful antibiotic, it can be used as a raw material to synthesize antibiotic ketolide compounds such as
ertythromycins and new
epothilone
Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.
, epothilones A t ...
s.
Biosynthesis
The pikromycin polyketide synthase of ''Streptomyces venezuelae'' contains four polypeptides: PikAI, PikAII, PikAIII, and PikAIV. These polypeptides contain a loading module, six extension molecules, and 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 (chemistry), alcohol, in the pres ...
domain that terminated the biosynthetic procedure.
Recently electron cryo-microscopy have been used to determine sub-nanometre-resolution three- dimensional reconstructions of a full-length PKS module from the bacterium Streptomyces venezuelae that revealed an unexpectedly different architecture.
In Figure 1, each circle corresponds to a PKS mutilifuctional protein, where ACP is
acyl carrier protein
The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide biosynthesis machinery. It is one of the most abundant proteins in cells of ''E. coli.'' In both cases, the growing chain is bound to the ACP via a thioester derived fro ...
, KS is keto-ACP synthase, KSQ is a keto-ACP synthase like domain, AT is acyltransferase, KR is keto ACP reductase, KR with cross is inactive KR, DH is hydroxyl-thioester dehydratase, ER is enoyl reductase, TEI is thioesterase domain I, TEII is type II thioesterase.
Des corresponds to the enzymes utilized in desosamine biosynthesis and transfer, which include DesI-DesVIII.
Figure 2 represents the desosamine deoxyamino sugar biosynthetic pathway. DesI-DesVI (des locus of pikromycin PKS) encodes all the enzymes needed to obtain TDP-desoamine from TDP-glucose. DesVII and DesVIII activities transfer desoamine to narbonolide and narbomycin is obtained. PikC cytochrome P450 hydrolase catalyzes the hydroxylation of narbomycin to obtain pikromycin.
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See also
*
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 ...
References
Macrolide antibiotics