期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1866, 期 6, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbagen.2022.130118
关键词
Glycobiology; Glycosylation; Glycosyltransferase; Inhibitor; N -acetylglucosaminyltransferase-V (GnT-V); N -glycan
资金
- Leading Initiative for Excellent Young Researchers (LEADER) project [20H03207]
- Japan Society for the Promotion of Science (JSPS)
- AMED [16809274]
- CREST [18070267]
- JST
- Takeda Science Foundation
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the US National Institutes of Health [P20GM130460]
This study aims to design novel inhibitors for GnT-V by chemically synthesizing a series of UDP-GlcNAc analogs and testing their inhibitory effects on GnT-V. The results show that although these analogs have modest inhibition potency, they exhibit a certain selectivity for GnT-V. Additionally, the docking models provide insights into the interactions and inhibitory mechanisms between these analogs and GnT-V.
Background: N-Glycan branching regulates various functions of glycoproteins. N-Acetylglucosaminyltransferase V (GnT-V) is a GlcNAc transferase that acts on N-glycans and the GnT-V-producing branch is highly related to cancer progression. This indicates that specific GnT-V inhibitors may be drug candidates for cancer treatment. To design novel GnT-V inhibitors, we focused on the unique and weak recognition of the donor substrate UDPGlcNAc by GnT-V. On the basis of the catalytic pocket structure, we hypothesized that UDP-GlcNAc analogs with increasing hydrophobicity may be GnT-V inhibitors. Methods: We chemically synthesized 10 UDP-GlcNAc analogs in which one or two phosphate groups were replaced with hydrophobic groups. To test these compounds, we set up an HPLC-based enzyme assay system for all N-glycan-branching GlcNAc transferases in which GnT-I-V activity was measured using purified truncated enzymes. Using this system, we assessed the inhibitory effects of the synthesized compounds on GnT-V and their specificity.Results: Several UDP-GlcNAc analogs inhibited GnT-V activity, although the inhibition potency was modest. Compared with other GnTs, these compounds showed a preference for GnT-V, which suggested that GnT-V was relatively tolerant of hydrophobicity in the donor substrate. Docking models of the inhibitory compounds with GnT-V suggested the mechanisms of how these compounds interacted with GnT-V and inhibited its action.Conclusions: Chemical modification of the donor substrate may be a promising strategy to develop selective inhibitors of GnT-V. General significance: Our findings provide new insights into the design of GnT inhibitors and how GnTs recognize the donor substrate.
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