期刊
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
卷 84, 期 11, 页码 2264-2272出版社
OXFORD UNIV PRESS
DOI: 10.1080/09168451.2020.1794785
关键词
Cambinol; ceramide; glycosphingolipid; glucosylceramide synthase; inhibitor
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology
- RIKEN [Special Postdoctoral Researchers Program]
The accumulation of glucosylceramide (GlcCer), which is synthesized by UDP-glucose ceramide glucosyltransferase (UGCG), is associated with several diseases, including Gaucher disease and Parkinson's disease. Since the inhibition of UGCG can be used to treat diseases caused by GlcCer accumulation, several UGCG inhibitors have been developed. In this study, we report on the inhibition of UGCG activity by cambinol, a sirtuin inhibitor. Unlike conventional UGCG inhibitors, cambinol has no structural similarity to GlcCer. LC-ESI MS/MS analysis revealed that the cellular GlcCer levels were reduced by cambinol with an increase in ceramide, the GlcCer precursor. Histidine 193 plays an important role in the inhibition of UGCG via a known UGCG inhibitor, D-PDMP. However, cambinol was found to inhibit UGCG activity in a histidine 193-independent manner. This study provides insights into the mechanism of inhibition of UGCG activity by cambinol, and provides a basis for the development of a cambinol-based novel UGCG inhibitor.
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