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- PublicationPolyene macrollide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studiesThe polyene macrolide group includes important antifungal drugs, to which resistance does not arise readily. Chemical and biological methods have been used in attempts to make polyene antibiotics with fewer toxic side effects. Genome sequencing of producer organisms is contributing to this endeavour, by providing access to new compounds and by enabling yield improvement for polyene analogues obtained by engineered biosynthesis. This recent work is also enhancing bioinformatic methods for deducing the structures of cryptic natural products from their biosynthetic enzymes. The stereostructure of candicidin D has recently been determined by NMR spectroscopy. Genes for the corresponding polyketide synthase have been uncovered in several different genomes. Analysis of this new information strengthens the view that protein sequence motifs can be used to predict double bond geometry in many polyketides. Chemical studies have shown that improved polyenes can be obtained by modifying the mycosamine sugar that is common to most of these compounds. Glycoengineered analogues might be produced by biosynthetic methods, but polyene glycosyltransferases show little tolerance for donors other than GDP-α-D-mycosamine. Genome sequencing has revealed extending glycosyltransferases that add a second sugar to the mycosamine of some polyenes. NppY of Pseudonocardia autotrophica uses UDP-N-acetyl-α-D-glucosamine as donor whereas PegA from Actinoplanes caeruleus uses GDP-α-D-mannose. These two enzymes show 51 % sequence identity and are also closely related to mycosaminyltransferases. These findings will assist attempts to construct glycosyltransferases that transfer alternative UDP- or (d)TDP-linked sugars to polyene macrolactones.
328Scopus© Citations 32
- PublicationNew insights into polyene macrolide biosynthesis in Couchioplanes caeruleusCouchioplanes caeruleus DSM43634 synthesises 67–121C, an aromatic heptaene macrolide that contains a mannosyl-mycosaminyl disaccharide. An improved draft genome sequence was used to obtain the biosynthetic gene cluster for this antifungal. Bioinformatic analysis of the polyketide synthase indicated that extension modules 7 and 8 contain A-type ketoreductase and dehydratase domains. These modules are therefore predicted to form cis double bonds. The deduced stereostructure of the 67–121C macrolactone is identical to that experimentally determined for the partricin subgroup of aromatic heptaenes. Some of these polyenes are N-methylated on the aminoacetophenone moiety. The C. caeruleus AceS protein was shown to methylate 4-aminoacetophenone and esters of 4-aminobenzoate, but not 4-aminobenzoate. This suggests that the substrate specificity of AceS prevents it from interfering with folate biosynthesis. The methyltransferase should be valuable for chemoenzymatic alkylation of compounds that contain aminobenzoyl moieties.
436Scopus© Citations 9