Question

Cholesterol synthesis is controlled by regulation of

• A. HMG CoA synthase
• B. HMG CoA reductase
• C. Thiolase
• D. Mevalonate kinase

Hint:

Remember that "Statins" (like atorvastatin) target HMG-CoA reductase.
This clinical link makes HMG-CoA reductase one of the most frequently asked rate-limiting enzymes in biochemistry exams.

Answer 1

The Correct Option is B

Step 1: Understanding the Concept:
Cholesterol is an essential structural component of animal cell membranes and serves as the precursor for the synthesis of steroid hormones, bile acids, and vitamin D.
The biosynthesis of cholesterol is a highly complex, multi-step metabolic pathway that occurs primarily in the endoplasmic reticulum of hepatocytes.
To prevent toxic accumulation and conserve cellular energy, the pathway is tightly regulated at its rate-limiting committed step.

Step 2: Detailed Explanation:
The synthesis of cholesterol begins with the condensation of acetyl-CoA molecules.
Thiolase condenses two molecules of acetyl-CoA to form acetoacetyl-CoA.
Next, HMG-CoA synthase catalyzes the condensation of a third acetyl-CoA to produce 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
The next step is the reduction of HMG-CoA to mevalonate, which is catalyzed by the transmembrane glycoprotein HMG-CoA reductase.
This reaction represents the primary rate-limiting and committed step of the entire cholesterogenic pathway.
HMG-CoA reductase is subjected to rigorous feedback control via multiple mechanisms:
Feedback inhibition by cholesterol and its metabolites.
Transcriptional regulation mediated by Sterol Regulatory Element-Binding Proteins (SREBPs).
Proteolytic degradation of the enzyme when sterol levels are high.
Covalent modification (phosphorylation/dephosphorylation) by AMP-activated protein kinase (AMPK).
Mevalonate kinase phosphorylates mevalonate in the subsequent step but is not the primary site of metabolic regulation.
Pharmaceutical agents known as statins act as competitive inhibitors of HMG-CoA reductase to manage hypercholesterolemia.

Step 3: Final Answer:
The key regulatory and rate-limiting enzyme in cholesterol biosynthesis is HMG-CoA reductase.