Cholesterol and Steroids Lecture 36

Cholesterol and Steroids Lecture 36

• King Saud bin Abdulaziz University for Health Sciences, 2005
• Lecture focuses on cholesterol and steroid biosynthesis, regulation, and their derivatives.

Learning Outcomes

• Students should be able to explain the phases of cholesterol biosynthesis
• Understand the regulation of cholesterol synthesis
• Describe the biosynthesis of steroids and bile acids
• Explain the function and activity of Cyt P450
• List the main cholesterol derivatives

Cholesterol Structure & Properties

• 27 carbon atoms
• Four fused rings
• Peripheral side chain
• Only one double bond (C=C)
• Low solubility in water (only 30% in free form)
• Cholesterol is esterified to long chain fatty acids (cholesteryl esters), even less soluble
• Essential for all animal life, precursor to steroid hormones, bile salts, and Vitamin D

Four Stages of Cholesterol Synthesis

• Three acetate condense to form mevalonate
• Mevalonate converts to phosphorylated 5-carbon isoprene
• Six isoprenes polymerize to form 30-carbon linear squalene
• Squalene cyclizes to form four rings, which are modified to produce cholesterol

Step 1: Formation of Mevalonate from Acetyl-CoA

• 2 Acetyl-CoAs → Acetyoacetyl-CoA (catalyzed by acetyl-CoA acyl transferase)
• Acetyl-CoA + Acetoacetyl-CoA → β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) (catalyzed by HMG-CoA synthase)
• HMG-CoA + 2 NADPH → mevalonate (catalyzed by HMG-CoA reductase), rate-limiting step

Step 2: Conversion of Mevalonate to Two Activated Isoprenes

• 3 phosphate groups transferred stepwise from ATP to mevalonate
• Decarboxylation and hydrolysis produce a diphosphorylated 5-C product (isoprene)
• Isomerization to a second isoprene
• Two "activated" isoprene units are Δ3-isopentyl pyrophosphate and dimethylallyl pyrophosphate
• Only reaction using ATP. Three ATPs create each of the six activated isoprenes construct squalene. This costs 18 ATP

Step 3: Six Activated Isoprene Units Condense to Form Squalene

• Two isoprenes join head-to-tail, one set of diphosphates
• Forms geranyl pyrophosphate
• Geranyl joins to another isopentenyl pyrophosphate
• Forms 15-C farnesyl pyrophosphate
• Two farnesyl pyrophosphates join head-to-head to form phosphate-free squalene

Step 4: Conversion of Squalene to Four-Ring Steroid Nucleus

• Squalene monooxygenase adds one oxygen to the end of the squalene chain
• Forms squalene 2,3-epoxide
• Cyclization product in animals is lanosterol, which converts to cholesterol

Fates of Cholesterol After Synthesis

• In vertebrates, most cholesterol synthesized in the liver, then exported as bile acids, biliary cholesterol, or cholesteryl esters
• Some cholesterol used in liver for membrane synthesis
• Other tissues use cholesterol as precursor for steroid hormones and Vitamin D
• Cholesteryl esters are more nonpolar than cholesterol containing a fatty acid esterified to the oxygen.

HMG-CoA Reductase is Most Active When Dephosphorylated

• Covalent modification provides short-term regulation
• AMP-dependent protein kinase (AMP activates AMPK, AMPK phosphorylates and inhibits HMG CoA)
• Glucagon, epinephrine (cascades lead to HMG CoA phosphorylation, reducing activity)
• Insulin (cascades lead to dephosphorylation, increasing activity)

Statin Drugs Inhibit HMG-CoA Reductase to Lower Cholesterol

• Statins resemble mevalonate, competitive inhibitors of HMG-CoA reductase
• Lowers serum cholesterol by tens of percent
• Side effects: muscle weakness, coenzyme Q depletion
• Reported to improve circulation, stabilize plaques, removing cholesterol, reducing inflammation

Regulation of Cholesterol Metabolism

• Oxysterol is a cholesterol metabolite

There Are Several Classes of Cholesterol-Derived Steroids

• Adrenal gland synthesized steroids: mineralocorticoids, glucocorticoids
• Gonad-synthesized steroids (testes and ovaries): progesterone, testosterone, estrogens
• Affects protein and carbohydrate metabolism, suppressing immune response/inflammation/allergic responses.
• Aldosterone regulates Na+, Cl-, and HCO3 reabsorption in the kidney

Steroid Hormones Synthesis

• Steroid hormone synthesis occurs in mitochondria of steroidogenic tissues: placenta, ovaries, testes, adrenal cortex.

How Steroids Are Made From Cholesterol

• Takes place in mitochondria
• Converts cholesterol to pregnenolone
• Two carbons are hydroxylated by mixed-function oxidase (NADPH and cytochrome P450) on side chain at C-17 of D ring
• "Side chain" is cleaved by desmolase
• Hydroxylation makes steroids more water-soluble, easier transport in blood and excretion

Cytochrome P450s

• Found associated with inner mitochondrial and microsomal membranes
• In steroidogenic tissues (placenta, ovaries, testes, adrenal cortex): P450 used to hydroxylate intermediates during cholesterol to steroid hormone conversion
• In liver: P450 used for:
  • Cholesterol to bile acid conversion
  • Hydroxylation of cholecalciferol to 25-hydroxycholecalciferol (vitamin D3)
  • Activation or inactivation of foreign compounds/drugs, changing their toxicity/solubility
  • Hydroxylation of vitamin D3 to active form 1,25-dihydroxyvitamin D3

Activated Isoprenes Have Many Alternative Fates

• Isopentenyl pyrophosphate activated precursor in biosynthesis of many biomolecules (cholesterol, vitamins A, E, K.)
• Prenylation: anchoring proteins to inner membrane by covalent attachment to isoprenoid

This quiz covers the biosynthesis and regulation of cholesterol and steroid hormones, focusing on the processes outlined in Lecture 36 from King Saud bin Abdulaziz University for Health Sciences. Students will learn about the phases of cholesterol synthesis, the role of Cyt P450, and the significance of cholesterol derivatives. Develop a deeper understanding of the structure and properties of cholesterol essential for animal life.