Engineered biosynthesis and characterisation of disaccharide-modified 8-deoxyamphoteronolides

Title: Engineered biosynthesis and characterisation of disaccharide-modified 8-deoxyamphoteronolides
Authors: Walmsley, Simon
De Poire, Eimear
Rawlings, Bernard
Caffrey, Patrick
Permanent link: http://hdl.handle.net/10197/8286
Date: Mar-2017
Abstract: Several polyene macrolides are potent antifungal agents that have severe side effects. Increased glycosylation of these compounds can improve water solubility and reduce toxicity. Three extending glycosyltransferases are known to add hexoses to the mycosaminyl sugar residues of polyenes. The Actinoplanes caeruleus PegA enzyme catalyses attachment of a D-mannosyl residue in a β-1,4 linkage to the mycosamine of the aromatic heptaene 67-121A to form 67-121C. NppY from Pseudonocardia autotrophica adds an N-acetyl-D-glucosamine to the mycosamine of 10-deoxynystatin. NypY from Pseudonocardia sp. P1 adds an extra hexose to a nystatin, but the identity of the sugar is unknown. Here, we express the nypY gene in Streptomyces nodosus amphL and show that NypY modifies 8-deoxyamphotericins more efficiently than C-8 hydroxylated forms. The modified heptaene was purified and shown to be mannosyl-8-deoxyamphotericin B. This had the same antifungal activity as amphotericin B but was slightly less haemolytic. Chemical modification of this new disaccharide polyene could give better antifungal antibiotics.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Springer
Copyright (published version): 2016 Springer
Keywords: Streptomyces nodosus;Glycosyltransferases;Amphotericin disaccharides
DOI: 10.1007/s00253-016-7986-6
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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