EAST 501 Lecture Notes - Lecture 8: Hmg-Coa Reductase, Acetoacetyl-Coa, Lipid Raft
21 Jun 2018
School
Department
Course
Professor
5- R. Kiss
8- Cholesterols, Steroids and Oxysterols
●What is cholesterol?
○Cholesterol is an alcohol (has an OH group).
■Lipd.
○Hydrophilic and hydrophobic → amphipathic.
○Goes into plasma membranes.
■Planar molecule.
■4 ring structure.
○Need cholesterol to make bile acids.
○Precursor for steroid hormones, signaling molecules.
●How is cholesterol made?
○Rate-limiting step is where most regulation occurs.
■HMG CoA reductase is the main rate limiting step.
○Some steps occur in the mitochondria.
○Excess cholesterol can be esterified and stored in lipid droplets.
○Synthesis: two carbon added to four carbons → make six carbons.
■Acetyl CoA + Acetoacetyl CoA → HMG-CoA
○Converted to mevalonate (know this step**) by HMG-CoA reductase, which is the
rate-limiting enzyme.
■Simvastatin drug: lowers body levels of cholesterol by inhibiting HMG-CoA
reductase. Blocks cholesterol synthesis.
○Mevalonate (6C) → one C is removed→ 5 carbons, added to another 5C → forms
geranyl (10C) to which is added another 5C → formed 15C farnesyl, which is added to
another farnesyl → get 30C squalene.
■Between squalene and cholesterol, loses 3 carbons to become 27C cholesterol.
○Geranylgeranyl and farnesyl: anchor proteins to membranes (lipid anchors*).
■PKC: floats around in the cytoplasm, and is activated by attaching a lipid anchor
to it → goes to right part of the membrane. It is then active.
■Cholesterol itself is also a lipid anchor.
○Lots of things come from this biosynthetic pathway: prenylated proteins, ubiquinone, etc.
●What is cholesterol good for?
○Structural component of membranes: PM, TGN, lipid droplets
○Precursor to signaling molecules
○Precursor to many other products: hormones, bile acids, vitamin D.
●Lipid rafts
○Cholesterol: high affinity for sphingomyelin.
■Tend to clump together.
○Creating lipid rafts → signalling centers.
○Proteins with affinity for those lipids, with lipid tags that have affinity for those lipids
(cholesterol, palmitoyl, GPI-anchor), proteins with TM domains that are longer.
●Hedgehog signalling
○Proteins can be cholesterolated.
1
Document Summary
Cholesterol is an alcohol (has an oh group). Rate-limiting step is where most regulation occurs. Hmg coa reductase is the main rate limiting step. Excess cholesterol can be esterified and stored in lipid droplets. Synthesis: two carbon added to four carbons make six carbons. Acetyl coa + acetoacetyl coa hmg-coa. Converted to mevalonate (know this step**) by hmg-coa reductase , which is the. Simvastatin drug: lowers body levels of cholesterol by inhibiting hmg-coa rate-limiting enzyme . reductase. Mevalonate (6c) one c is removed 5 carbons, added to another 5c forms geranyl (10c) to which is added another 5c formed 15c farnesyl , which is added to another farnesyl get 30c squalene . Between squalene and cholesterol, loses 3 carbons to become 27c cholesterol . Pkc: floats around in the cytoplasm, and is activated by attaching a lipid anchor. Geranylgeranyl and farnesyl : anchor proteins to membranes ( lipid anchors*) . to it goes to right part of the membrane.
