Authors
Xin Wang, Cheng-Jun Cao, Yi Zou
Published in
ACS chemical biology. Oct 06, 2025. Epub Oct 06, 2025.
Abstract
Fusacandin A (1) is a glycolipid natural product that targets β-1,3-glucan synthase and exhibits significant antifungal activity. Its most impressive structural feature is a C-arylglycosyl hydroxybenzyl moiety with a varying degree of O-glycosylation. In this study, the biosynthetic gene cluster (sac) of fusacandin A was identified from Fusarium sacchari, and subsequent investigations of the assembly line revealed two key glycosyltransferases (GTs): a C-GT SacA, which catalyzes regioselective C-glucosylation at the C-6 of 3,5-dihydroxybenzyl alcohol (7) to form aryl-glucoside (8); and an O-GT SacH, which catalyzes a rare iterative O-galactosylation step on 9 to generate fusacandin B (2). Further in vitro biochemical assays and molecular docking experiments revealed the broad substrate tolerance and the key catalytic residues for both GTs. Two unusual esterification steps catalyzed by a C-terminal carnitine O-acyltransferase (cAT) domain of highly reducing polyketide synthase (hrPKS) SacB and a transmembrane acyltransferase (mAT) SacG were also identified, respectively. In addition, the relationship of structural moiety to the antifungal activity of fusacandins was investigated. Our work not only uncovers the assembly logic of these complex and synthetically challenging molecules but also provides valuable glycosyltransferase biocatalysts for the future biomimetic or chemo-enzymatic synthesis of more potent fusacandin derivatives.
PMID:
41047882
Bibliographic data and abstract were imported from PubMed on 06 Oct 2025.
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