The sirtuin inhibitor cambinol reduces intracellular glucosylceramide with ceramide accumulation by inhibiting glucosylceramide synthase. Issue 11 (1st November 2020)

• Record Type: Journal Article
• Authors: Ishibashi, Yohei; Ito, Makoto; Hirabayashi, Yoshio
• Is Part Of: Bioscience, biotechnology, and biochemistry. Volume 84:Issue 11(2020)
• Page Start: 2264
• Page End: 2272
• Publication Date: 2020-11-01
• Subjects: Cambinol -- ceramide -- glycosphingolipid -- glucosylceramide synthase -- inhibitor; Biotechnology -- Periodicals; Biochemistry -- Periodicals; 660.6
• DOI: 10.1080/09168451.2020.1794785
• Languages: English
• ISSNs: 0916-8451

Abstract

ABSTRACT: 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. Graphic abstract: uf0001 The sirtuin inhibitor cambinol inhibits the GlcCer synthase (UGCG) activity in an unconventional manner.