Cholesterol synthesis

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Cholesterol De Novo Synthesis

Rate-Limiting Enzyme: HMG-CoA Reductase (HMG-CoA → Mevalonate)
Cellular Location: Cytosol & Endoplasmic Reticulum (Mainly liver and intestine)
Primary Reducing Agent: NADPH (Requires 2 molecules per reduction step)
Pharmacological Blockers: Statins (Competitive, reversible inhibitors)
High-Yield Core Realities:

  • Transcriptional Feedback (SREBP-2): When intracellular cholesterol levels fall, the SCAP/SREBP complex moves from the endoplasmic reticulum to the Golgi apparatus. Proteases cleave SREBP-2, releasing a transcription factor that migrates to the nucleus to bind the Sterol Regulatory Element (SRE), upregulating HMG-CoA Reductase and LDL Receptor expression.
  • Covalent & Hormonal Regulators: Insulin promotes cholesterol synthesis by activating a phosphatase that stabilizes HMG-CoA Reductase in its active dephosphorylated state. Glucagon and high intracellular AMP levels activate AMPK, phosphorylating and shutting the enzyme off.
  • The Isoprenoid Multi-Branch Shunt: The condensation sequence forms 5-carbon isoprenoid units (IPPs). Intermediates include Geranyl pyrophosphate (10C) and Farnesyl pyrophosphate (15C). FPP serves as the precursor for Coenzyme Q (ubiquinone) and dolichol, and drives protein prenylation (anchoring proteins like Ras to plasma membranes).
  • Cyclization Mechanics: Two 15-carbon FPP molecules condense to form the first 30-carbon linear intermediate, Squalene. Squalene monooxygenase then introduces oxygen, driving epoxide formation and a massive multi-ring cyclization cascade to yield Lanosterol, which undergoes a 19-step modification process to become cholesterol.
  • Smith-Lemli-Opitz Syndrome (SLOS): Autosomal recessive microdeletion or mutation in 7-Dehydrocholesterol Reductase, the final enzyme in the Kandutsch-Russell pathway of cholesterol generation. Results in systemic cholesterol deficiency and toxic precursor accumulation, presenting with microcephaly, intellectual disability, holoprosencephaly, and characteristic 2-3 toe syndactyly (webbing).