Cholesterol synthesis is regulated at the HMG-CoA reductase step. Which post-translational mechanism rapidly reduces HMG-CoA reductase activity in response to high intracellular sterol levels?
- A Phosphorylation by AMPK causing allosteric inhibition
- B Proteolytic degradation via SCAP/INSIG-mediated ER retention and ubiquitination ✓
- C Glucuronidation and biliary excretion of the enzyme
- D Competitive product inhibition by mevalonate
Explanation
When intracellular cholesterol is sufficient, oxysterols bind INSIG proteins in the ER, which retain SCAP (SREBP cleavage-activating protein) in the ER rather than allowing it to escort SREBP to the Golgi for proteolytic activation. Additionally, high sterols promote INSIG binding to HMG-CoA reductase itself, targeting it for ubiquitin-mediated proteasomal degradation. AMPK can also phosphorylate and inactivate HMG-CoA reductase, but the SCAP/INSIG sterol-sensing mechanism is the primary post-translational sterol-responsive regulatory mechanism. Statins inhibit HMG-CoA reductase competitively and secondarily upregulate LDL receptors.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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