TY - JOUR
T1 - The sirtuin inhibitor cambinol reduces intracellular glucosylceramide with ceramide accumulation by inhibiting glucosylceramide synthase
AU - Ishibashi, Yohei
AU - Ito, Makoto
AU - Hirabayashi, Yoshio
N1 - Funding Information:
We are grateful to the Support Unit for Bio-material Analysis, RIKEN Center for Brain Science for their assistance in the nucleotide sequencing analyses. This work was supported in part by the RIKEN Special Postdoctoral Researchers Program (to Y. I.), and a Grant-in-Aid for Young Scientists (B) (to Y. I.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Publisher Copyright:
© 2020 Japan Society for Bioscience, Biotechnology, and Agrochemistry.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088497868&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088497868&partnerID=8YFLogxK
U2 - 10.1080/09168451.2020.1794785
DO - 10.1080/09168451.2020.1794785
M3 - Article
C2 - 32705968
AN - SCOPUS:85088497868
SN - 0916-8451
VL - 84
SP - 2264
EP - 2272
JO - Bioscience, Biotechnology and Biochemistry
JF - Bioscience, Biotechnology and Biochemistry
IS - 11
ER -