Analysis of the Ambruticin and Jerangolid Gene Clusters of Sorangium cellulosum Reveals Unusual Mechanisms of Polyketide Biosynthesis

Abstract

Ambruticins and jerangolids are structurally related antifungal polyketides produced by Sorangium cellulosum strains. Comparative analysis of the gene clusters and characterization of compounds produced by gene knockout strains suggested hypothetical schemes for biosynthesis of these compounds. Polyketide synthase (PKS) architecture suggests that the pyran ring structure common to ambruticins and jerangolids forms by an intramolecular reaction on a PKS-bound intermediate. Disrupting ambM, encoding a discrete enzyme homologous to PKS C-methyltransferase domains, gave 15-desmethylambruticins. Thus, AmbM is required for C-methylation, but not pyran ring formation. Several steps in the post-PKS modification of ambruticin involve new enzymology. Remarkably, the methylcyclopropane ring and putative carbon atom excision during ambruticin biosynthesis apparently occur on the PKS assembly line. The mechanism probably involves a Favorskii rearrangement, but further work is required to elucidate these complex events.

Mutational Analysis Reveals That All Tailoring Region Genes Are Required for Production of Polyketide Antibiotic Mupirocin by Pseudomonas fluorescens

“…Directed inactivation of aviG4 and aviH of the avilamycin pathway also generated two new antibiotics confirming roles as methyltransferase and halogenase, respectively (41). Disruption of inter alia ambM, encoding a discrete C-methyl-transferase in the ambruticin gene cluster in Sorangium cellulosum, results in the production of 15-demethylambruticins (42).…”

A Polyketide Synthase Component for Oxygen Insertion into Polyketide Backbones

“…In this analysis, PedG forms a distinct clade with 29 oxygenases, including those from trans ‐AT PKSs for the pederin‐like compound diaphorin ( 3 ) from a psyllid symbiont,10 for oocydin A ( 4 ) from S. plymuthica 4Rx13,11 and for the methylobacterial toblerol A ( 5 ) 12. Another member of the clade is the myxobacterial AmbI from the cis‐AT PKS ambruticin ( 6 ) pathway, an enzyme suggested to be involved in a decarboxylative hydroxylation 13. In addition, the clade contains at least five homologues from as‐yet uncharacterized and unrelated trans ‐AT PKS pathways from diverse bacteria (Figure 2).…”

The Group III Two-Component Histidine Kinase of Filamentous Fungi Is Involved in the Fungicidal Activity of the Bacterial Polyketide Ambruticin

“…However, while they were shown to be active against Aspergillus species that have a high incidence in chronic respiratory infections in humans, their development as commercial drugs has been hampered by their narrow activity spectrum on animals and human fungal pathogens (17) and by the high cost of total chemical synthesis. The recent characterization of the gene cluster involved in their synthesis in S. cellulosum (16) may pave the way toward future development of a less expensive biological production process for these metabolites. Moreover, they have also been tested successfully in vitro against at least one important crop pathogen, i.e., Botrytis cinerea (17).…”