Which enzyme catalyzes the rate-limiting step of cholesterol synthesis and is the primary target of statin therapy?

Explanation

## Rate-Limiting Enzyme of Cholesterol Synthesis **Key Point:** HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, the committed and rate-limiting step of the cholesterol synthesis pathway. **High-Yield:** This enzyme is the primary therapeutic target of statins (atorvastatin, simvastatin, rosuvastatin), which competitively inhibit HMG-CoA reductase and reduce cholesterol production by 30–50%. ### Regulation of HMG-CoA Reductase The enzyme is regulated by multiple mechanisms: 1. **Allosteric inhibition** — cholesterol and its derivatives directly inhibit enzyme activity 2. **Transcriptional regulation** — high cholesterol suppresses SREBP (sterol regulatory element-binding protein), reducing HMG-CoA reductase gene expression 3. **Post-translational modification** — phosphorylation by AMP-activated protein kinase (AMPK) inactivates the enzyme 4. **Proteolytic degradation** — excess cholesterol triggers ubiquitination and proteasomal degradation of HMG-CoA reductase **Clinical Pearl:** Statins lower LDL cholesterol by 20–55% depending on the agent and dose, and reduce cardiovascular events by ~30% in high-risk patients. ### Cholesterol Synthesis Pathway Overview | Step | Enzyme | Product | Notes | | --- | --- | --- | --- | | 1 | Acetyl-CoA carboxylase | Malonyl-CoA | Initial condensation | | 2 | HMG-CoA synthase | HMG-CoA | Mitochondrial | | **3** | **HMG-CoA reductase** | **Mevalonate** | **Rate-limiting; statin target** | | 4 | Mevalonate kinase | Phosphomevalonate | Cytoplasmic | | 5 | Squalene synthase | Squalene | Farnesyl-PP condensation | | 6 | Lanosterol synthase | Lanosterol | Cyclization | | 7 | Lanosterol 14α-demethylase | Demethylated intermediates | ER-bound | | 8 | Multiple enzymes | Cholesterol | Final product | **Mnemonic:** **AMES** — *Acetyl-CoA → Mevalonate → Enzyme (HMG-CoA reductase is rate-limiting) → Squalene → Sterol (cholesterol)*