3 16 15 Biochemistry 401 Lecture 29 Cholesterol Function Synthesis Regulation Cholesterol Derivatives Function Synthesis Cholesterol 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 Site of fatty acid addition Flexible tail 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 1 3 16 15 Two Sources of Cholesterol Dietary Cholesterol Ingested Packaged in Intestines Chylomicrons Endogenous Cholesterol Synthesized de novo Packaged in liver Very low density lipoprotein particles VLDL Cholesterol Synthesis Counting by 5s 5 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 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 dimethylallyl Step 5 Cyclization to lanosterol Modification in several steps to form cholesterol Enzyme HMG CoA Synthase Condensation reaction HMG Co A is also an intermediate in ketone body synthesis 2 3 16 15 Synthesis of Mevalonate Reduction reactions Enzyme HMG Co A Reductase 1 NADPH Aldehyde 2 NADPH Alcohol Integral membrane protein Catalyzes the rate limiting step The next step uses 3 molecules of ATP Activity is highly regulated One monomer of the tetrameric enzyme NADPH binding HMG CoA binding Catalytic site Cytosol ER Membrane ER Eva S Istvan Washington University School of Medicine 3 3 16 15 Next 3 reactions require ATP 3 Molecules of ATP are used to make an activated 5C unit loss of CO2 Pi 1 2 3 Decarboxylation Loss of Pi 6C Activated Isoprene units used for Cholesterol synthesis Steroid synthesis Lipid additions for membrane insertion 5C Activated Isoprene Unit 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 4 3 16 15 A 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 Lanosterol 5 3 16 15 30C difference in saturation loss of 3C 27C HMG CoA reductase Monomer Sterol Sensor Sterol Sensor Sterol Sensor 6 3 16 15 What 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 3 Oxidize C24 2 Shorten the Hydrophobic tail 4 Add CoA at C24 5 Add a hydrophilic group at C24 7 3 16 15 1 7 dehydrocholesterol Pre VitD 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 Progesterone Testosterone Cortisol Aldosterone Estradiol 8 3 16 15 Progesterone 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 These corticosteroids are synthesized in the adrenal cortex Glucocorticosteroid Mineralcorticosteroid These corticosteroids are synthesized in the adrenal cortex Glucocorticosteroid Mineralcorticosteroid 9 3 16 15 Glucocorticosteroid 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 Mineralcorticosteroid 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 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 sexes 10 3 16 15 Estrogens 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 glands liver This is the end of Lecture 29 Have a great day 11
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