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.

摘要

由UDP-葡萄糖神经酰胺葡糖基转移酶（UGCG）合成的葡萄糖神经酰胺（GlcCer）积累与多种疾病有关，包括高雪氏病和帕金森氏病。由于UGCG的抑制作用可用于治疗由GlcCer蓄积引起的疾病，因此已经开发了几种UGCG抑制剂。在这项研究中，我们报道了sirtuin抑制剂cambinol对UGCG活性的抑制作用。与常规的UGCG抑制剂不同，坎宾醇与GlcCer没有结构相似性。LC-ESI MS / MS分析显示，山cam酚可降低细胞的GlcCer水平，同时增加GlcCer前体神经酰胺的含量。组氨酸193通过已知的UGCG抑制剂D-PDMP在UGCG的抑制中起重要作用。然而，发现卡宾醇以组氨酸193非依赖性的方式抑制UGCG活性。