Stages of Cholesterol Biosynthesis and Detailed First Step
Introduction
Cholesterol biosynthesis is a multi-step anabolic pathway that occurs mainly in the liver. It involves the conversion of acetyl-CoA to cholesterol through several enzymatic reactions. Cholesterol plays a vital role in membrane structure, hormone synthesis, and bile acid formation.
Four Main Stages of Cholesterol Biosynthesis
1. Synthesis of Mevalonate from Acetyl-CoA
This is the rate-limiting and highly regulated step in the pathway. It includes the following reactions:
- Acetoacetyl-CoA formation: Two molecules of acetyl-CoA condense to form acetoacetyl-CoA using thiolase.
- HMG-CoA formation: Acetoacetyl-CoA combines with another acetyl-CoA to form HMG-CoA via HMG-CoA synthase.
- Mevalonate formation: HMG-CoA is reduced to mevalonate by HMG-CoA reductase, using two NADPH. This is the committed step of the pathway and is subject to feedback inhibition by cholesterol.
2. Conversion of Mevalonate to Isoprenoid Units
- Mevalonate is phosphorylated and decarboxylated to form isopentenyl pyrophosphate (IPP), a five-carbon activated isoprene unit.
- IPP is isomerized to dimethylallyl pyrophosphate (DMAPP).
3. Synthesis of Squalene
- Six isoprenoid units are condensed stepwise to form farnesyl pyrophosphate (FPP).
- Two FPP molecules combine to form squalene (30-carbon linear precursor).
4. Conversion of Squalene to Cholesterol
- Squalene is cyclized to form lanosterol by squalene epoxidase and oxidosqualene cyclase.
- Lanosterol undergoes multiple steps including demethylation, reduction, and double bond migration to finally form cholesterol.
Significance of the First Step
- Regulated by HMG-CoA reductase, which is the target of statin drugs used to lower cholesterol levels.
- Controlled through feedback inhibition, gene expression, phosphorylation, and proteolytic degradation.
Conclusion
Cholesterol biosynthesis is a complex yet highly regulated pathway. The first step involving HMG-CoA reductase is crucial in controlling the overall rate of cholesterol production, making it a key point for therapeutic intervention.