squalene synthase activity

Definition

Target type: molecularfunction

Catalysis of the reaction: presqualene diphosphate + NADPH = squalene + NADP+ + diphosphate. [EC:2.5.1.21]

Squalene synthase, also known as farnesyl diphosphate farnesyltransferase, is an enzyme that catalyzes the condensation of two molecules of farnesyl pyrophosphate (FPP) to form squalene, a key intermediate in the biosynthesis of cholesterol and other steroids. This reaction is the committed step in sterol biosynthesis and involves a complex series of steps.

**Mechanism:**

1. **Farnesyl Pyrophosphate Binding:** Two molecules of FPP bind to the active site of squalene synthase.
2. **Prenyl Transfer:** One molecule of FPP acts as a donor, transferring its prenyl group to the other FPP molecule. This generates a transient carbocation intermediate.
3. **Proton Abstraction:** A proton is abstracted from the carbocation intermediate, forming a carbanion.
4. **Squalene Formation:** The carbanion attacks the electrophilic carbon of the second FPP molecule, resulting in the formation of squalene, a 30-carbon linear isoprenoid.

**Importance:**

Squalene synthase plays a crucial role in maintaining cholesterol homeostasis and lipid metabolism. It is essential for the biosynthesis of cholesterol, which is a vital component of cell membranes and a precursor for steroid hormones. Defects in squalene synthase activity can lead to genetic disorders such as Smith-Lemli-Opitz syndrome (SLOS), characterized by severe developmental defects and neurological abnormalities.

**Regulation:**

The activity of squalene synthase is tightly regulated to ensure adequate cholesterol production without excessive accumulation. Regulation occurs at multiple levels, including:

* **Gene Expression:** Transcription of the squalene synthase gene is regulated by various factors, including cholesterol levels, hormones, and dietary lipids.
* **Post-Translational Modifications:** Squalene synthase can be phosphorylated, which can modulate its activity.
* **Feedback Inhibition:** Cholesterol itself can inhibit squalene synthase activity through a negative feedback loop.

**Clinical Relevance:**

Squalene synthase is a target for drug development in the treatment of hypercholesterolemia and other disorders associated with cholesterol metabolism. Inhibitors of squalene synthase can lower cholesterol levels by blocking the production of this key intermediate.'
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Proteins (1)

Compounds (6)