All of the following enzymes/proteins are involved in cholesterol synthesis or its regulation EXCEPT:

Explanation

## Enzymes in Cholesterol Synthesis Pathway ### The Cholesterol Synthesis Cascade **Key Point:** Cholesterol synthesis is a multi-step process requiring approximately 19 enzymatic reactions, beginning with acetyl-CoA and culminating in the 27-carbon sterol. ### Major Enzymatic Steps ```mermaid flowchart LR A["Acetyl-CoA"] -->|HMG-CoA synthase| B["HMG-CoA"] B -->|HMG-CoA reductase| C["Mevalonate"] C -->|Kinases & decarboxylase| D["Isopentenyl-PP"] D -->|Squalene synthase| E["Squalene"] E -->|Squalene monooxygenase| F["Lanosterol"] F -->|14α-demethylase| G["Cholesterol"] G -->|ACAT| H["Cholesterol esters"] style A fill:#e1f5ff style H fill:#c8e6c9 ``` ### Squalene Monooxygenase **High-Yield:** Also called **squalene 2,3-epoxide cyclase** or **oxidosqualene cyclase**: - Catalyzes the **cyclization** of squalene (a 30-carbon linear precursor) to form **lanosterol** (a 30-carbon tetracyclic structure) - This is a critical branch point: squalene → lanosterol → cholesterol - Requires molecular oxygen (O₂) and NADPH - Located in the ER membrane ### Lanosterol 14α-Demethylase (CYP51A1) **Mnemonic:** **CYP51 = Cytochrome P450 family 51** - Removes the **C-14 methyl group** from lanosterol - A cytochrome P450 enzyme requiring O₂ and NADPH - One of the early demethylation steps (lanosterol has three methyl groups that must be removed) - Produces 4,4-dimethyl-cholesta-8,14,24-trien-3β-ol as an intermediate ### ACAT (Acyl-CoA:Cholesterol Acyltransferase) **Clinical Pearl:** ACAT is essential for cholesterol **storage**: - Esterifies free cholesterol with long-chain fatty acids (from acyl-CoA) - Forms cholesterol esters, which are stored in lipid droplets - Two isoforms: ACAT1 (ubiquitous) and ACAT2 (liver, intestine) - Prevents toxicity from excess free cholesterol by sequestering it - Inhibitors of ACAT are being investigated as anti-atherosclerotic agents ### Phosphofructokinase-1 (PFK-1) — The Outlier **Warning:** PFK-1 is **NOT** involved in cholesterol synthesis. It is: - The rate-limiting enzyme of **glycolysis** (not lipogenesis) - Catalyzes: Fructose-6-phosphate + ATP → Fructose-1,6-bisphosphate + ADP - Regulated by energy status (inhibited by ATP, citrate; activated by AMP, ADP, F-2,6-BP) - A key control point in carbohydrate metabolism, not sterol synthesis ### Summary: Cholesterol Synthesis Enzymes | Enzyme | Reaction | Cofactors | Location | |--------|----------|-----------|----------| | HMG-CoA reductase | HMG-CoA → Mevalonate | NADPH | ER membrane | | Squalene monooxygenase | Squalene → Lanosterol | O₂, NADPH | ER membrane | | CYP51A1 (14α-demethylase) | Lanosterol → demethylated product | O₂, NADPH | ER membrane | | ACAT | Free cholesterol → Cholesterol esters | Acyl-CoA | ER/lipid droplets | | **PFK-1** | **Glycolysis (F-6-P → F-1,6-BP)** | **ATP** | **Cytoplasm** | [cite:Lehninger Principles of Biochemistry 7e Ch 21; Berg, Tymoczko, Stryer Biochemistry 9e Ch 26]