Redesign of Polyene Macrolide Glycosylation: Engineered Biosynthesis of 19-(O)-Perosaminyl-Amphoteronolide B

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Title: Redesign of Polyene Macrolide Glycosylation: Engineered Biosynthesis of 19-(O)-Perosaminyl-Amphoteronolide B
Authors: Hutchinson, Eve
Murphy, Barry
Dunne, Terence
Breen, Ciaran
Rawlings, Bernard
Caffrey, Patrick
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Date: 26-Feb-2010
Abstract: Most polyene macrolide antibiotics are glycosylated with mycosamine (3,6-dideoxy-3-aminomannose). In the amphotericin B producer, Streptomyces nodosus, mycosamine biosynthesis begins with AmphDIII-catalysed conversion of GDP-mannose to GDP-4-keto-6-deoxymannose. This is converted to GDP-3-keto-6-deoxymannose, which is transaminated to mycosamine by the AmphDII protein. The glycosyltransferase AmphDI transfers mycosamine to amphotericin aglycones (amphoteronolides). The aromatic heptaene perimycin is unusual among polyenes in that the sugar is perosamine (4,6-dideoxy-4-aminomannose), which is synthesised by direct transamination of GDP-4-keto-6-deoxymannose. Here we use the Streptomyces aminophilus perDII perosamine synthase and perDI perosaminyltransferase genes to engineer biosynthesis of perosaminyl-amphoteronolide B in S. nodosus. Efficient production required a hybrid glycosyltransferase containing an N-terminal region of AmphDI and a C-terminal region of PerDI. This work will assist efforts to generate glycorandomised amphoteronolides for drug discovery.
Funding Details: Higher Education Authority
Science Foundation Ireland
Type of material: Journal Article
Publisher: Elsevier
Journal: Chemistry and Biology
Volume: 17
Issue: 2
Start page: 174
End page: 182
Copyright (published version): 2010 Elsevier
Keywords: CHEMBIO
DOI: 10.1016/j.chembiol.2010.01.007
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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