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11 Cards in this Set
- Front
- Back
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Pathophysiologic Significance of Cholesterol
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-Relationship to atherosclerosis and CHD
-Epidemiology -Arterial plaques -Membrane constituent -Precursor to bile acids, steroid hormones and vitamin D -The pathway gives rise to important polyisoprenoid precursors. |
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Cholesterol
THE PATHWAY |
A. Acetyl-CoA ----> HMG-CoA
B. The rate limiting step: HMG-CoA reductase C. mevalonate ----> isopentenyl-PP (the basic 5 carbon unit) D. 5C ----> 10C ----> 15C ----> 30C E. the cyclization (squalene ----> lanosterol) F. lanosterol ----> cholesterol |
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What is the rate limiting step in cholesterol biosynthesis?
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HMG-CoA reductase!
The target for statins. While all of the statins are competitive inhibitors of this enzyme, they differ significantly in potency, pharmacodynamics and metabolism. |
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IMPORTANCE OF THE POLYISOPRENOID PATHWAYS
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A. Post-translational covalent modification of proteins:
B. Biosynthesis of other polyisoprenoid compounds: 1. Dolichol, a hydrophobic polyprenyl compound involved in polysaccharide synthesis and transport. 2. Quinones that serve as electron carriers 3. Plants also utilize the pathway for synthesis of carotenoids, tocopherols, vitamin K, rubber and plant hormones. C. Statins inhibit biosynthesis of polyisoprenoids too by the competitive binding of HMG-CoA reductase |
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How is squalene formed?
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Head to head condensation of two farnesyl pyrophosphate (15 C compounds) molecules forms the hydrocarbon squalene.
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HMG-CoA reductase is the rate-limiting step in cholesterol biosynthesis.
Why is it a good target? For what types of drugs? If inhibited, what else other than cholesterol synthesis will be affected? |
-Highly regulated enzyme
-Major target for pharmacological intervention (statins) -Other isoprenoid products (protein prenylation, quinones-OxPhos) |
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SCAP
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The level of cholesterol or its oxidized metabolite is sensed by a protein known as SREBP Cleavage Activation Protein (SCAP), which controls migration of SREBP to the golgi.
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Mechanisms for Regulation of HMG-CoA Reductase
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1. Covalent Modification
-Inhibition by phosphorylation (cAMP-dependent or AMP-dependent protein kinases). 2. Protein Turnover -Feedback regulation of enzyme degradation (activation of protease by cholesterol and non-sterol intermediate). 3. Transcriptional Regulation -Transcriptional regulation by oxysterol. SREBP and SCAP interaction on the relevant DNA portion. |
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Clinical Application for statins.
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The primary mechanism of action of statins in lowering blood cholesterol is not the one that you might predict; i.e., it does not lower blood cholesterol simply by reducing cholesterol secretion into the blood from the liver and other biosynthetic tissues. Reduced intracellular cholesterol levels resulting from inhibition of cholesterol synthesis induce a compensatory increase in LDL, the lipoprotein receptors primarily responsible for removing cholesterol from the blood.
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Dietary Cholesterol vs. De Novo
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The contribution of dietary cholesterol to total body cholesterol is small, relative to that which is synthesized de novo.
Controlled studies showed that reduced dietary cholesterol has none or small change to serum cholesterol levels. |
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Regulation of Cholesterol Synthesis
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-Phosphorylation inactivates HMG-CoA reductase. (-)
-Cholesterol activates proteolytic cleavage. (-) -SREBPs activate at transcriptional level. (+) -Cholesterol inhibits release of SREBP from endoplasmic reticulum. (-) |
