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Cited by 0Carbohydrate Chemistry and SynthesisPhysical Organic Chemistry and Reaction KineticsGlycosylation and Glycoproteins Research

The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.

Mechanistic origin of C - over O -glycosylation in glycosyltransferase GgCGT: a QM/MM study

Open access
Terada, Daisuke, Inagaki, Taichi, Hatanaka, Miho·2026·Bulletin of the Chemical Society of Japan
DOI 10.1093/bulcsj/uoag026

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Abstract

C-glycosylation catalyzed by C-glycosyltransferases affords chemically robust C-glycosides, yet the mechanistic origin of the remarkable selectivity for C- over O-glycosylation remains poorly understood. In this study, we present a comprehensive QM/MM investigation of the GgCGT-catalyzed mono-C-glycosylation of phloretin using UDP-glucose, extending our previous cluster-model analysis to explicitly include the full enzymatic environment. The calculated pathway involves an initial proton transfer from phloretin to UDP-glucose, followed by an SN2-type C-glycoside bond forming step accompanied by dissociation of UDP. The activation barrier of the rate-determining SN2 step is in good agreement with the experimental estimates. Although the alternative O-glycosylation pathway exhibits a lower activation barrier, it is thermodynamically disfavored due to the instability of the O-glycosylated intermediate, which readily undergoes the reverse reaction. In contrast, the C-glycosylated intermediate is strongly stabilized, rendering C-glycosylation effectively irreversible. Structural and natural bond orbital analyses reveal that this stability originates from preservation of a planar His27-Asp122 dyad and a favorable hydrogen-bonding network involving the phosphate group. Furthermore, the C6-OH group of glucose directly stabilizes the key transition state, explaining the reduced reactivity observed experimentally with UDP-xylose. These results establish a dual catalytic strategy in C-glycosyltransferases, combining thermodynamic control for C-selectivity with transition-state stabilization for rate acceleration.

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Cites

Research works printed but not linked: 2

  1. Liang, 2015, Chem. Soc. Rev., 44, 8350, 10.1039/C5CS00600G · DOI · Paper page
  2. Frisch, 2016, Gaussian 16 Revision C.01

Metadata

Authors
Terada, D., Inagaki, T., & Hatanaka, M.
Affiliations
Keio University (JP)
Corresponding author
Hatanaka, Miho
ORCID
Venue
Bulletin of the Chemical Society of Japan
Publisher
Oxford University Press (OUP)
Published
2026-01-31
Volume
99
Issue
2
ISSN
  • 0009-2673 (ISSN-L)
  • 1348-0634
DOI
10.1093/bulcsj/uoag026
OpenAlex
W7128533111
Cited by
0
References
50
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Bulletin of the Chemical Society of Japan (publishedVersion, cc-by-nc)
  • ChemRxiv (acceptedVersion, cc-by-nc-nd)
Funders
Japan Society for the Promotion of Science (23H00288, JP24H01094, 20K05438, JPMJPF2221)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
  • Physical Sciences › Chemistry › Organic Chemistry › Physical Organic Chemistry and Reaction Kinetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
Keywords
C-glycosylation, C-glycosyltransferase, O-glycosylation, phloretin, UDP-glucose, reaction mechanism, SN2 mechanism, activation barrier, transition state stabilization, hydrogen bond network, natural bond orbital analysis, thermodynamic control, glycosylation

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