MNE- Cholesterol Synthesis & Lipid Transport Exam Solutions Manual

MNE- Cholesterol Synthesis & Lipid Transport Exam Solutions Manual What molecule is the central starting material for cholesterol synthesis? - Answers Acetyl-CoA Describe the structure of cholesterol (6 points) - Answers a) 27 Carbons (all from acetyl-CoA b) Three 6-C rings, one 5-C ring c) An 8-C side chain at C17 d) Composed of isoprene units e) 3' OH group is the only oxygen (*hydrophobic* f) Double bond between C-5 & C-6 (delta-5) What are three classes of compounds that isoprenes are precursors for? - Answers 1) Vitamins 2) Cholesterol 3) Steroid hormones What are the 5 intermediate substrates during cholesterol synthesis? - Answers 1) Acetyl-CoA 2) Mevalonate 3) Isopentenyl Pyrophosphate 4) Squalene 5) Cholesterol What are the 3 steps of cholesterol synthesis up to mevalonate? Why is this important - Answers 1) 2 acetyl-CoA --> acetoacetyl-CoA 2) A third acetyl-CoA added --> *HMG-CoA* 3) HMG-CoA --> mevalonate a) 2 NADPH --> NADP+ b) carboxyl group reduced to OH c) CoA Released HMG-CoA --> mevalonate is a major regulatory step for cholesterol synthesis: *inhibited by statins* How do statins work in the cholesterol biosynthetic pathway? - Answers Resemble mevalonic acid, so they competitively inhibit HMG-CoA Reductase What are the 3 steps of cholesterol synthesis after mevalonate? - Answers 1) activated isoprenes made by 3 sequential phosphorylations & 1 decarboxylation a) yields d3-isopentenyl PPi + dimethylallyl PPi b) 2 Pi added to C-5 c) Pi added at C-3, immediate decarboxylation of C1 d) Removal of C3 phosphate 2) Formation of Squalene a) isoprenes fuse to form geranyl PPi b) another isoprene added to form farnesyl PPi c) 2 farnesyl PPi + NADPH --> Squalene 3) Conversion of Squalene to cholesterol a) squalene - lanosterol - cholesterol (humans) b) squalene - stigmasterol (plants) c) squalene - ergosterol (fungi, yeast) How is cholesterol stored within cells and transported in the blood? - Answers Within cells: fatty acyl-CoA + cholesterol --> *cholesterol ester* via ACAT (Acyl-CoA-cholesterol acyl transferase) In the circulation: cholesterol + Lecithin (PC) --> *cholesterol ester* via LCAT (lecithin-cholesterol acyl transferase), transported via HDLs What are ACAT and LCAT? - Answers Enzymes that convert cholesterol to cholesterol esters. ACAT: Acyl-CoA-cholesterol Acyl Transferase (stores in cells) LCAT: Lecithin-cholesterol acyl transferase (transport in blood) Where do we get most of our cholesterol? How much cholesterol do we product? How much do we get from diet? - Answers De novo synthesis, not diet, predominates. We synthesize 1g cholesterol per day. We consume 0.3g cholesterol per day. What is the plasma concentration of cholesterol? How is it controlled? - Answers Plasma levels are 150-200 mg/dL, controlled by regulation of de novo synthesis. What are the 4 main mechanisms of regulation of cholesterol levels? - Answers 1) HMG-CoA Reductase 2) ACAT regulation 3) LDL/HDL ratios 4) Excretion as bile acids or steroid hormones What are 3 mechanisms of HMG-CoA Reductase regulation? - Answers 1) Negative feedback of cholesterol: *long-term, causes proteolysis* 2) Stimulated by insulin (dephosphorylated) 3) Inhibited by glucagon (phosphorylated) How is cholesterol transported from ingestion into tissues? (4 steps) - Answers 1) Packaged in chylomicrons and enter bloodstream from intestine