2. Academic Validation
  3. Luciferase-based HMG-CoA reductase degradation assay for activity and selectivity profiling of oxy(lano)sterols

Luciferase-based HMG-CoA reductase degradation assay for activity and selectivity profiling of oxy(lano)sterols

  • Bioorg Med Chem. 2020 Feb 1;28(3):115298. doi: 10.1016/j.bmc.2019.115298.
Ikuya Sagimori 1,  Hiromasa Yoshioka 1,  Yuichi Hashimoto 1,  Kenji Ohgane 2
Affiliations

Affiliations

  • 1 Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: ohgane@iam.u-tokyo.ac.jp.
PMID: 31902650 DOI: 10.1016/j.bmc.2019.115298
Abstract

HMG-CoA reductase (HMGCR) is the rate-limiting Enzyme in the Cholesterol biosynthetic pathway, and is the target of cholesterol-lowering drugs, statins. Previous studies have demonstrated that the Enzyme activity is regulated by sterol-induced degradation in addition to transcriptional regulation through sterol-regulatory-element-binding proteins (SREBPs). While 25-hydroxycholesterol induces both HMGCR degradation and SREBP inhibition in a nonselective manner, lanosterol selectively induces HMGCR degradation. Here, to clarify the structural determinants of selectivity for the two activities, we established a luciferase-based assay monitoring HMGCR degradation and used it to profile the structure-activity/selectivity relationships of oxysterols and (oxy)lanosterols. We identified several sterols that selectively induce HMGCR degradation and one sterol, 25-hydroxycholest-4-en-3-one, that selectively inhibits the SREBP pathway. These results should be helpful in designing more potent and selective HMGCR degraders.

Keywords

Degradation; HMG-CoA reductase; Lanosterols; Luciferase; Oxysterols; SREBP.

Figures