Abstract
Bioactive natural C-glycosides are rare and chemical C-glycosylation faces challenges while enzymatic C-glycosylation catalyzed by C-glycosyltransferases provides an alternative way. However, only a small number of C-glycosyltransferases have been found, and most of the discovered C-glycosyltransferases prefer to glycosylate phenols with an acyl side chain. Here, a promiscuous C-glycosyltransferase, AbCGT, which is capable of C-glycosylating scaffolds lacking acyl groups, is identified from Aloe barbadensis. Based on the substrate promiscuity of AbCGT, 16 C-glycosides with inhibitory activity against sodium-dependent glucose transporters 2 are chemo-enzymatically synthesized. The C-glycoside 46a shows hypoglycemic activity in diabetic mice and is biosynthesized with a cumulative yield on the 3.95 g L‒1 scale. In addition, the key residues involved in the catalytic selectivity of AbCGT are explored. These findings suggest that AbCGT is a powerful tool in the synthesis of lead compounds for drug discovery and an example for engineering the catalytic selectivity of C-glycosyltransferases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alloxan / toxicity
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Aloe / enzymology*
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Aloe / genetics
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Animals
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Biocatalysis
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Blood Glucose / analysis
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Blood Glucose / drug effects
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Cloning, Molecular
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Diabetes Mellitus, Experimental / blood
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / drug therapy
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Diabetes Mellitus, Type 1 / blood
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Diabetes Mellitus, Type 1 / chemically induced
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Diabetes Mellitus, Type 1 / drug therapy
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Drug Discovery / methods
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Female
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Glycosides / biosynthesis*
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Glycosides / pharmacology
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Glycosides / therapeutic use
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Glycosylation
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Glycosyltransferases / genetics
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Glycosyltransferases / isolation & purification
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Glycosyltransferases / metabolism*
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Humans
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Male
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Mice
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Plant Proteins / genetics
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Plant Proteins / isolation & purification
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Plant Proteins / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Sodium-Glucose Transporter 2 / metabolism
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Sodium-Glucose Transporter 2 Inhibitors / metabolism*
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Sodium-Glucose Transporter 2 Inhibitors / pharmacology
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Sodium-Glucose Transporter 2 Inhibitors / therapeutic use
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Substrate Specificity
Substances
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Blood Glucose
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C-glycoside
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Glycosides
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Plant Proteins
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Recombinant Proteins
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SLC5A2 protein, human
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Slc5a2 protein, mouse
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Sodium-Glucose Transporter 2
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Sodium-Glucose Transporter 2 Inhibitors
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Alloxan
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Glycosyltransferases