Engineered biosynthesis of hybrid macrolide polyketides containing d-angolosamine and d-mycaminose moieties

Abstract

The glycosylation of natural product scaffolds with highly modified deoxysugars is often essential for their biological activity, being responsible for specific contacts to molecular targets and significantly affecting their pharmacokinetic properties. In order to provide tools for the targeted alteration of natural product glycosylation patterns, significant strides have been made to understand the biosynthesis of activated deoxysugars and their transfer. We report here efforts towards the production of plasmid-borne biosynthetic gene cassettes capable of producing TDP-activated forms of D-mycaminose, D-angolosamine and D-desosamine. We additionally describe the transfer of these deoxysugars to macrolide aglycones using the glycosyl transferases EryCIII, TylMII and AngMII, which display usefully broad substrate tolerance.

Metabolic faecal fingerprinting of trans-resveratrol and quercetin following a high-fat sucrose dietary model using liquid chromatography coupled to high-resolution mass spectrometry

“…37 Accordingly, dTDP-D-mycaminose is a deoxyaminosugar that contains a core aglycone of polyketide origin, with a deoxysugar moiety attached. 38 The union of the deoxysugar moiety has been reported to be essential for the bioactivities of these bacterial products, including antibacterial and anti-inflammatory effects. 39,40 Our group previously demonstrated that quercetin supplementation, but especially the combined administration of trans-resveratrol and quercetin, increased the abundance of the bacterium Clostridium methylpentosum when compared to the HFS diet-fed reference group.…”

Function of Cytochrome P450 Enzymes RosC and RosD in the Biosynthesis of Rosamicin Macrolide Antibiotic Produced by Micromonospora rosaria

“…The primers were designed from two conserved regions of deduced amino acid sequences of P450s implicated in formylation of 16-member macrolides (4)(5)(6)(7)(8). The complete nucleotide sequence of the rosamicin biosynthetic gene cluster in Micromonospora carbonacea subsp.…”

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

“…In principle, 2′-deoxy amphotericin B could be generated by biosynthetic engineering. An activated 2′-deoxymycosamine could be synthesised in vivo using genes for TDP-Dangolosamine formation (Schell et al, 2008). However, current knowledge of polyene GTs indicates that redesigning them to accept alternative dTDP-sugars could prove challenging.…”