Cholesterol Synthesis Notes

Cholesterol Synthesis

Steroids

• Definition: Substances derived from the C17 cyclopentanoperhydrophenanthrene ring (steroid nucleus).
• Steroids include: Sterols, bile acids, and steroid hormones.
• Terminology Breakdown:
  • Cyclopentanoperhydrophenanthrene ring:
    • Cyclo Cyclic.
    • Pentano 5-carbon ring (ring D).
    • Phenanthrene ring: 3 hexagonal rings (A, B, & C).
    • Perhydro: Saturated with hydrogen (unless otherwise noted).

Steroid Nucleus Structure

• The steroid nucleus consists of four fused rings:
  • Three six-membered rings (A, B, and C).
  • One five-membered ring (D).
• Carbon atoms are numbered from 1 to 17 in the ring system. Additional methyl groups are attached at positions 10 and 13, designated as carbons 18 and 19.

Types of Steroids and Sterols

• Cholesterol: Animal origin.
• Ergosterol: Plant origin.
• Vitamin D group: D2 and D3.
• Bile acids and salts
• Steroid hormones
  • Male sex hormones.
  • Female sex hormones.
  • Adrenocortical hormones.

Cholesterol

• Main steroid in humans (present in all cells, especially in the nervous system & plasma).
• Precursor to all other steroids.
• Rich sources: Egg yolk, red meat, liver, kidney, butter, and brain.

Cholesterol Characteristics

• Unsaturated double bond between C5 and C6 allows it to accept two hydrogen atoms.
• Esterification: The -OH group at C3 allows cholesterol to form esters with fatty acids.
• Blood Cholesterol:
  • Free form (33%): Contains 27 carbons.
  • Esterified form (67%).
• Normal blood cholesterol level: Less than 200 or 220 mg/dL. Increased levels indicate hypercholesterolemia.
• Oxidation in the liver, intestine, & skin yields 7-dehydrocholesterol, the precursor of vitamin D3 upon exposure to UVR under the skin.

Function of Cholesterol

• Essential component of every body cell, especially in the nervous system + cell membranes.
• Precursor for synthesis of:
  • Steroid hormones.
  • Bile acids and salts.
  • Vitamin D3.

Cholesterol Metabolism

• The liver plays a central role in regulating the body’s cholesterol.
• The liver and intestines are the main sites of synthesis.
• Enzymes involved in synthesis are located in the cytosol & ER.
• The liver is the primary organ responsible for removing cholesterol from the blood.
• All carbons are derived from acetyl CoA + NADPH.
• Balance between input and output is crucial; imbalance leads to cholesterol deposition in tissues, especially the lining of vessels, causing coronary artery disease.

Stages of Cholesterol Synthesis

1. Synthesis of HMG CoA (6C) from acetyl CoA (2C).
2. Conversion of HMG CoA to mevalonate (6C).
3. Conversion of mevalonate to activated isoprene unit (C5).
4. Condensation of 6 activated isoprene units to form squalene (C30).
5. Conversion of squalene to lanosterol.
6. Conversion of lanosterol to cholesterol.

Synthesis of HMG CoA

• HMG CoA is present in both the cytosol and mitochondria of the liver.
• Mitochondrial:
  • Ketogenesis.
• Cytosolic:
  • Cholesterol synthesis.
• Two molecules of Acetyl CoA (2C) combine via Thiolase to form Acetoacetyl CoA (4C).
  $2 \text{ Acetyl CoA (2C)} \xrightarrow{\text{Thiolase}} \text{Acetoacetyl CoA (4C)}$
• Acetoacetyl CoA reacts with another Acetyl CoA molecule, catalyzed by HMG-CoA synthase, to form HMG-CoA (6C).
  $\text{Acetoacetyl CoA (4C)} + \text{Acetyl CoA} \xrightarrow{\text{HMG-CoA synthase}} \text{HMG-CoA (6C)}$

Synthesis of Mevalonic Acid (Mevalonate)

• Enzyme: HMG CoA reductase (rate-limiting & key regulatory step).
• Occurs in the Cytosol.
• The reaction is irreversible.

Ring Closure and Formation of Squalene

• Shift of double bonds occurs during ring closure.
• Formation of active isoprene unit (5C):
  • 3-phosphomevalonate becomes 5-di-P, then isopentenyl di-P (IPP), and finally 3,3-dimethylallyl di-P (DPP).
• Formation of squalene (C30):
  • 1 IPP + 1 DPP ! geranyl di-P (C10)
  • geranyl di-P + IPP ! farnesyl di-P (C15)
  • farnesyl di-P* + farnesyl di-P* ! Squalene (C30). (*they loose the 2 phosphates)
• Formation of lanosterol and cholesterol:
  • A sequence of reactions using molecular oxygen & NADPH converts squalene to lanosterol.
  • Shortening of the carbon chain from 30 to 27.
  • Migration of the double bond from C8 to C5.
  • Reduction of the double bond between C24 & C25.

Summary of Key Steps and Enzymes

• Mevalonic acid phosphorylation:
  • Mevalonic acid is phosphorylated by kinases using ATP to form 5-Pyrophosphomevalonic acid.
• Decarboxylation:
  • 5-Pyrophosphomevalonic acid is decarboxylated to form Isopentenyl pyrophosphate (IPP).
• Isomerization:
  • IPP is isomerized to form 3,3-Dimethylallyl pyrophosphate (DPP).
• Transferase Reactions:
  • IPP and DPP condense to form Geranyl pyrophosphate (GPP).
  • GPP and IPP condense to form Farnesyl pyrophosphate (FPP).
• Squalene Synthase:
  • Two FPP molecules are combined by squalene synthase to form Squalene, using NADPH and releasing pyrophosphate.
• Squalene Monooxygenase:
  • Squalene is converted to Lanosterol by squalene monooxygenase, requiring oxygen and NADPH.
• Conversion to Cholesterol:
  • Lanosterol is converted to Cholesterol through a series of reactions.

Regulation of Cholesterol Synthesis

• HMG CoA reductase is active in its dephosphorylated form; insulin activates it (short term).
• Lovastatin, rosuvastatin & simvastatin are structural analogs of HMG CoA reductase and are used to reduce cholesterol levels in hypercholesterolemia.

Hormonal Regulation

• Insulin and thyroxine increase the upregulation of enzyme expression.
• Glucagon and cortisol have the opposite effect.

Excretion of Cholesterol

• Conversion into bile acids and bile salts, which are excreted in the feces.
• Secretion of cholesterol in bile.
• Transported to the intestine for elimination.
• In the intestine, some cholesterol is converted by bacteria into coprostanol and cholestanol before excretion.

Hypercholesterolemia

• Definition: High concentration of cholesterol in the blood.
• Leads to atherosclerosis.
• Statin drugs are used to decrease plasma cholesterol levels.
  • Statins are structural analogs of HMG CoA reductase.
  • Statins inhibit enzyme activity by competitive inhibition.