BMS 100 Cell Membrane and Cytoskeleton - Cholesterol PDF

Lecture : Cell membrane and cytoskeleton Post-learning 2: Cholesterol Dr. Rhea Hurnik BMS 100 Learning Outcomes Classify cholesterol as belonging to either fatty acid or isoprenoid structural group Name the organs of the body that most significantly contribute to cholesterol synthesis Describe the c...

Lecture : Cell membrane and cytoskeleton Post-learning 2: Cholesterol Dr. Rhea Hurnik BMS 100 Learning Outcomes Classify cholesterol as belonging to either fatty acid or isoprenoid structural group Name the organs of the body that most significantly contribute to cholesterol synthesis Describe the cellular location and basic steps of cholesterol synthesis, including the role of the key regulatory enzyme HMG CoA reductase. Describe the regulation of HMG CoA reductase, including: § Influence of insulin and glucagon § Inhibition by high intracellular levels of cholesterol Lipid introduction Lipids can be broken down structurally into two main classes: § 1) Those based on fatty acid structure § 2) Those based on isoprenoid structure Isoprenoids Isoprenoids contain repeating 5-C structural units called isoprene units § Make up a wide variety of molecules, including cholesterol Cholesterol Steroids are complex molecules made from 6 isoprene units Contain four fused rings with various substituents Steroids with a hydroxy group at C3 may be referred to as sterols (ex cholesterol) Cholesterol In addition to phospholipids, the cell membrane contains large amounts of cholesterol Cholesterol synthesis Cholesterol is acquired through the diet and by synthesis within the body § Most cells can performs cholesterol synthesis, however it occurs most significantly in the liver and kidney § Inside the cell, cholesterol synthesis occurs in the ER Cholesterol synthesis Cholesterol synthesis follows four main steps: § 1. Condensation of 3 acetyl CoA into mevalonate § 2. Formation of isopentenyl pyrophosphate § 3. Creation of squalene Uses 6 isopentenyl pyrophosphates § 4. Cyclization of squalene into cholesterol Cholesterol synthesis - 1 Step 1: Condensation of 3 acetyl CoA into Mevalonate § Rate limiting step is catalyzed by HMG CoA reductase Main regulatory enzyme in cholesterol synthesis pathway All other enzyme names in the pathway FYI Cholesterol synthesis 2 Step 2: Conversion of mevalonate into activated isoprenes § 3 phosphate groups are added to mevalonate to from ATP to form isopentenyl pyrophosphate Note 1 is immediately removed § All intermediates and enzymes are FYI Cholesterol synthesis 3 Step 3: Condensation of 6 activated isoprene units form squalene § All intermediates and enzymes are FYI § How many acetyl CoA are needed to make squalene? Farnesyl pyrophosphate Cholesterol synthesis 4 Step 4: Ring closure § In a complex multi-step process linear squalene is converted into cyclic structure of cholesterol Multi-step Knowledge check How many acetyl CoA are needed to make Mevalonate? § A) 1 acetyl CoA § B) 2 acetyl CoA § C) 3 acetyl CoA § D) 6 acetyl CoA Cholesterol synthesis - regulation Cholesterol is a complex and energy demanding process § Needs to be regulated to complement dietary cholesterol HMG CoA reductase is the main regulatory step of cholesterol synthesis Integral membrane protein in the smooth ER HMG-CoA reductase regulation: genetic HMG-CoA reductase is inhibited by high intracellular levels of cholesterol § High intracellular levels of cholesterol block the transcription of HMG-CoA reductase gene. § The gene for HMG-CoA reductase will only transcribed and translated if intracellular levels of cholesterol are low High intracellular cholesterol levels also promotes esterification of cholesterol for storage in the cell HMG-CoA reductase regulation: covalent modification HMG-CoA reductase can also be regulated via reversible covalent modification § HMG-CoA reductase tends to exist in its inactive, phosphorylated state. § Insulin promotes de-phosphorylation of HMG-CoA reductase, activating the enzyme Promoting cholesterol synthesis § Glucagon promotes phosphorylation of HMG-CoA reductase, inhibiting the enzyme Inhibiting cholesterol synthesis Check your knowledge Fill in the blanks § The highly-regulated enzyme catalyzing the rate-limiting step of cholesterol synthesis is _______? Insulin (activates/inhibits) this enzymes. Glucagon (activates/inhibits) this enzymes. § High intracellular cholesterol levels will (increase/decrease) the transcription of this enzyme. End References Alberts et al. Molecular Biology of the Cell. Garland Science. Betts et al. Anatomy and Physiology (2ed). OpenStax Lehninger Principles of Biochemistry 4th ed. Figure 21-36. Page 818