3/16/151Biochemistry401Lecture 29 CholesterolFunctionSynthesisRegulationCholesterol DerivativesFunction SynthesisCholesterol Structure & Function Structure: Steroid - 4 rings, Hydrophobic Tail • Planar • Hydrophobic Function: • Membrane Lipid - Modulates Membrane fluidity - Found in Lipid Rafts • Precursor for Synthesis of: - Steroid Hormones - Bile Salts - Vitamin D Cholesterol Structure & Function • For transport in lipoproteins and for storage in the cell, polar OH can be esterified to a fatty acid to increase hydrophobicity • In membranes, the polar hydroxyl group is oriented towards the aqueous environment and interacts with polar head groups of membrane lipids.Site of fatty acid additionFlexible tail3/16/152 Dietary Cholesterol Ingested Packaged in Intestines Chylomicrons Endogenous Cholesterol Synthesized de novo, Packaged in liver Very low density lipoprotein particles (VLDL) Two Sources of Cholesterol Cholesterol Synthesis Counting by 5s5 Important Steps in Cholesterol Synthesis:!Step 1 Condensation of 3 activated acetyl units to form 6C HMG CoA Step 2 Reduction of HMG CoA to mevalonate Step 3 Decarboxylation to 5C activated isoprene: isopentenyl pyrophosphate Step 4 Condensations of 6 activated isoprenes isopentenyl pyrophosphate, dimethylallyl pyrophosphate, to form 30-carbon squalene • formation of geranyl pyrophosphate (5 + 5 = 10 carbons) • formation of farnesyl pyrophosphate (10 + 5 = 15 carbons) • formation of squalene from 2 farnesyl-PP groups (15+15 = 30) Step 5 Cyclization to lanosterol Modification, in several steps, to form cholesterol Enzyme:HMG-CoA SynthaseCondensation reaction HMG-Co A is also an intermediate in ketone body synthesis.3/16/153Synthesis of MevalonateEnzyme:HMG Co A ReductaseIntegral membrane protein Catalyzes the rate-limiting step The next step uses 3 molecules of ATP Activity is highly regulated Reduction reactions: 1. NADPH - Aldehyde 2. NADPH - Alcohol Cytosol!ER Membrane!ER!One monomer of the tetrameric enzymeEva S. Istvan,Washington University School of Medicine!NADPH binding!HMG CoA binding!Catalytic site!3/16/1543 Molecules of ATP are used to make an activated 5C unit loss of CO2,Pi Decarboxylation Loss of Pi 6C 5C Activated Isoprene Unit Activated Isoprene units used for: • Cholesterol synthesis • Steroid synthesis • Lipid additions for membrane insertion 1 2 3 Next 3 reactions require ATP Activated Isoprene derivatives Lipid anchors Cholesterol Steroid Hormones Bile Acids, Salts Vitamin D Vitamin A Vitamin E Vitamin K Quinone Electron Carriers Dolichols In Plants Abcsisic Acid Gibberellic Acid Rubber Phytol Chain of Chlorophyll Carotenoids Activated Isoprene 3-isopentyl pyrophosphate Isomerization Reaction Isomerization forms a second activated isoprene Both are used in next reaction.3/16/155A Series of Condensation Reactions Driven forward by PPi hydrolysis Class: Prenyl transferase 5 + 5 =10 Geranyl Pyrophosphate 5 + 10 = 15 Farnesyl Pyrophosphate 15 +15 = 30 Squalene Squalene synthase catalyzes the first committed step of cholesterol synthesis Oxidosqualene Cyclase Cyclization of Squalene to Lanosterol3/16/156difference in saturation loss of 3C 30C 27C Sterol Sensor?!HMG CoA-reductase Monomer!Sterol Sensor?!Sterol Sensor?!3/16/157What is Bile? Bile is a watery substance, secreted by the liver, that contains organic and inorganic molecules. Organic compounds: phosphatidylcholine & bile salts. Bile is: • secreted by the liver • stored in the gall bladder • released into the small intestines Bile Function: • emulsifies dietary lipids • is way to lose excess cholesterol excreted by the liver Bile Salt Synthesis Goals: 1.Make Cholesterol more soluble 2.Make Cholesterol a good Detergent 1. Add Hydrophilic Hydroxyl groups to give the molecule an amphipathic nature 2. Shorten the Hydrophobic tail 3. Oxidize C24 4. Add CoA at C24 5. Add another hydrophilic group at C24 1. Add Hydrophilic Hydroxyl groups 2. Shorten the Hydrophobic tail 3. Oxidize C24 4. Add CoA at C24 5. Add a hydrophilic group at C243/16/1581 Vitamin D Site of Synthesis: Skin: uv photolysis of Function: Important for bone growth and remodeling. Regulates calcium and phosphorus levels in the blood: • promotes absorption the intestines • promotes re-absorption of calcium in the kidneys 7-dehydrocholesterol Pre-VitD Cortisol Aldosterone Progesterone Testosterone Estradiol3/16/159Progesterone Site of Synthesis: • ovarian follicle cells • placenta • in many non-reproductive tissues as well. Function: • precursor for all other steroid hormones • in reproduction, preparation and maintenance of pregnancy. Mineralcorticosteroid Glucocorticosteroid These corticosteroids are synthesized in the adrenal cortex Mineralcorticosteroid Glucocorticosteroid These corticosteroids are synthesized in the adrenal cortex3/16/1510Glucocorticosteroid 3 Main Functions: 1.Increases and Maintains serum glucose levels. • Stimulates gluconeogenesis especially in the liver from amino acids and fats. • Stimulates fatty acid breakdown • Stimulates amino acid transport to the liver. • Prevents uptake of glucose in adipose and muscle tissue. 2.Anti-inflamatory - reduces tissue inflammation 3.Immunosuppressant - reduces the immune response to antigens Main Function: Increases Blood volume, and blood pressure Acts on the kidneys to cause retention of sodium in the system rather than excretion in the urine. Because of this, water is also reabsorbed rather than excreted. This increase of water in the blood increases blood volume and thus blood pressure. Excretion of potassium ions is also affected by aldosterone. Mineralcorticosteroid Androgens Testosterone Function: • Promotes male secondary sexual characteristics • Affects Libido, energy levels, immune response, and is thought to protect against osteoporosis Sites of synthesis: • Leydig cells of the testes in males, • follicle cells in ovaries in females • to a small extent, by the adrenal cortex in both sexes3/16/1511Estrogens 2 Main types, Estrone, Estradiol Function: promotes female secondary sexual characteristics regulation of menses. Sites of synthesis: • primary site: follicle cells of the ovary • in the placenta during pregnancy • to lesser extent in - breast tissue - adrenal
View Full Document
Unlocking...