BMS100_Ph1-20-W23_Cell membrane post-learning 2_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 • Desc...

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