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Download Cholesterol Synthesis Regulation of cholesterol synthesis pathway
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Cholesterol Synthesis Main function: formation of steroid nucleus Regulation of cholesterol synthesis pathway • HMG CoA reductase catalyzes the rate-limiting step. Substrate: cytoplasmic acetyl CoA • The synthesis and the activity of the HMG-CoA reductase enzyme is controlled in the liver cell. Endproduct: cholesterol Location: cytoplasm Cholesterol biosynthesis cyto.acetyl CoA NADP:H HMG CoA mevalonate isopentenyl PP (5C) farnesyl PP (15C) geranylPP (10 C) CH2-C ~ S-CoA O HMG-CoA 2 NADP:H + 2 H+ OH CH3-C-CH2-COO HMG-CoA OH CH3-C-CH2-COO CH2-CH2 OH mevalonate 2 NADP+ CH3-C=O acetoacetyl CoA CH2-C ~S-CoA O (30C) HMG CoA reductase CH3-C-CH2-COO O CH3-C ~ S-CoA c. acetyl CoA squalene cholesterol OH Cholesterol synthesis pathway CH2-C ~ S-CoA O Regulation of HMG CoA reductase activity • cholesterol and mevalonate directly inhibit HMG-CoA reductase activity • insulin binding indirectly stimulates HMG-CoA reductase activity • glucagon binding indirectly inhibits HMG-CoA reductase activity Inhibition of HMG CoA reductase synthesis Inhibition of HMG CoA reductase synthesis 1 cholesterol esters in blood bind to Low Density Lipoprotein LDL-chol. 2 LDL-cholesterol complex binds LDL receptor protein in liver cell membrane. liver cell Control of enzyme synthesis • 3. LDL-cholesterol-ester complex is transported into liver cell by LDL receptor protein in liver cell membrane . • 4. LDL-chol.ester drops off LDL receptor protein and binds to cytoplasmic receptor protein. Control of enzyme synthesis LDL membrane receptors LDL-cholesterol cytoplasmic receptor protein Controlling enzyme synthesis 5. Cholesterol derivative and c. recept. protein enter nucleus, bind to DNA and prevent RNA polymerase from transcribing the gene coding for HMG-CoA reductase . Hormonal regulation of cholesterol synthesis • Glucagon binds to receptor in liver cell membrane, stimulating cAMP formation LDL-cholesterol binds to cyto. receptor protein and enters nucleus cholesterol binds to DNA; inhibits transcription of gsene coding for HMG CoA reductase • cAMP activates PROTEIN KINASE which inactivates rate-limiting HMG CoA reductase enzyme, decreasing cholesterol synthesis Hormone action Hormonal regulation of cholesterol synthesis • Insulin binds to its receptor protein in liver cell membrane, and stimulates irs-1 formation. insulin binds cAMP irs-1 • irs-1 activates HMG CoA reductase enzyme, increasing rate of cholesterol synthesis HMG CoA reductase active form glucagon binds G ATP Glucagon binding results in cAMP formation inactive P P form P P inactive protein kinase HMG ~ S-CoA 2 NADP:H + H+ mevalonate + 2 NADP+ Insulin binding decreases [cAMP] in cell inactive active form P P form P P cAMP HMG CoA Protein reductase kinase HMG ~ S-CoA P P 2 NADP:H P P + H+ Insulin binding to cell stimulates cholesterol synthesis inactive insulin binds irs-1 G no product adenyl cyclase phosphocAMP diesterase AMP ATP active form P P form P P HMG CoA protein reductase kinase HMG ~ S-CoA 2 NADP:H + H+ mevalonate 2 NADP+ Activated isoprenes Activated isoprenes isopentyl pyrophosphate isopentyl pyrophosphate mevalonate O O O-P-O~P-O O O O O O-P-O~P-O O O O O O-P-O~P-O O O O O O-P-O~P-O O O dimethylallyl pyrophosphate dimethylallyl pyrophosphate Condensation of activated isoprenes geranyl PP O O O-P-O~P-O O O O O O-P-O~P-O O O P~P + cholesterol HO Derivatives of cholesterol pathway intermediates O O O-P-O~P-O O O • • • • ubiquinone retinal (Vit. A) cholecalciferol (Vit.D) menadione (Vit. K) cholesterol ester CH3 - ( CH ) 14 - C - O 2 || O cholesterol palmitate Steroid hormones Bile acids testosterone OH HO cholesterol C= O O cholic acid HO O HO CH3 progesterone HO OH OH C=O estradiol - bile acids are derivatives of cholic acid HO HO O C= O - Bile acids HO OH - glycine is condensed through COO - to produce glycocholic acid - 80% of cholesterol made in liver is converted to bile acids and stored in gall bladder + NH3 | CH2 | COO- Function of bile acids - bile acids are secreted from liver and stored in the gall bladder liver gly Function of bile acids stomach liver - glycocholic acid emulsifies triglycerides in the small intestine Function of bile acids fatty acids in blood stream cause gall bladder to contract releasing bile liver gall bladder small intestine Fatty acids absorbed into blood through stomach wall stimulate gall bladder to contract, releasing bile. stomach gall bladder - glycocholic acid (bile acid) emulsifies triglycerides small intestine Gall stones - gall stones are cholesterol & bile acids - stones pass into hepatic duct hypercholesterolemia (too much cholesterol in blood stream) High cholesterol levels may be due to: liver 1. defective gene for LDL receptor protein - affected individuals are slow to clear cholesterol from blood stream - passage of large gall stones is extremely painful normal liver cell hypercholesterolemic liver cell LDL receptor protein 2. other factors: smoking, age, inactivity Atherosclerosis • atherosclerosis is the formation of plaques in arteries and arterioles • plaques are complex deposits of cholesterol esters and dead cells embedded in walls of artierioles chol.-LDL chol.-LDL chol.-LDL chol.-LDL chol.-LDL Plaque formation Atherosclerosis PLAQUE • damaged regions in arteriole walls trigger inflammatory response • plaques form at these inflamed areas more often in persons with high blood cholesterol • plaques form and remain when circulation of blood is sluggish damage & inflammation of arteriole wall healthy vessel 90% blocked Pentose shunt Pentose shunt (phosphogluconate pathway) • Main function: formation of NADP:H and pentose PO4 • Location in cell: enzymes found in cytoplasm • Regulation: 1st enzyme, glu-6-P DHase catalyzes rate-limiting step OH 6-phosphoglucolactone NADP:H + H+ G-6-P DHase O - C=O H -C-OH O = C =O HO-C - H H -C-OH + H -C-OH NADP H -C-O-P=O H O NADP:H + H+ =O OH 6-phosphogluconolactone .. H:O:H .. - O - C=O H -C-OH HO-C-H H -C-OH H -C-OH H -C-O-P=O H O 6-phosphogluconate rxn probably occurs spontaneously in cell 6-Phosphogluconate DHase - O OH OH g-6-P NADP+ in rapidly dividing cells, pentose -PO4’s are required for DNA synthesis (Lactonase) =O OH in adipose cells, NADP:H is required for lipid synthesis H HC-OP=O H HC-OP O H HC-OP O OH :H • Substrate: glucose - 6 - P • End-product: depends on cell needs H H -C-OH O=C H -C-OH H -C-OH H -C-O-P=O H O ribulose-5-P Hereditary deficiency of G-6-P DH • at least 2 different G-6-P DHase isozymes in humans • one isozyme is absent in many persons whose ancestors lived in malarial regions (S. Italy, parts of Africa, S.E. Asia) • these individuals are asymptomatic until large demand for NADP:H NADP:H provides reducing power in r.b.c. LIPIDS Classes G-6-P DHase g-6-P + NADP+ NADP:H + H+ 6-phosphogluconate NADP:H + H+ NADP+ oxidant oxidant .H.H (reduced acetyl salicylate) (acetyl salicylate) glycogen glu glu g-6-P f-6-P Carbon skeleton r-5-P Components • fatty acids • triglycerides acetyl units 3 f. a. + glycerol • phosphoglycerides • steroids 2 f.a. + glycerol-P • sphingolipids sphingosine + f.a. glycogen glu glu g-6-P f-1,6-diP OAA malate pyr pyr malate OAA glu pyr malate 3-PG acetyl Co A citrate OAA isocitrate NADP:H malate r-5-P c.citrate glu OAA OAA PEP malate malate OAA isocitrate glu g-6-P NADP:H G c. acetyl CoA r-5-P f-6-P c.citrate gly.P f-1,6-diP DHAP gly.P pyr malate m. acetyl Co A citrate OAA succinate succ.CoA gly.P pyr pyr glycogen f-1,6-diP 3-PG pyr pyr c. acetyl CoA f-6-P cAMP PEP c.citrate gly.P DHAP Insulin glycogen g-6-P OAA malate G c. acetyl CoA phosphitidate DHAP succinate succ.CoA Glucagon r-5-P f-1,6-diP DHAP gly.P PEP NADP:H f-6-P gly.P 3-PG acetyl units pyr malate DHAP 3-PG acetyl Co A citrate OAA succinate succ.CoA isocitrate G OAA PEP malate malate DHAP gly.P pyr pyr OAA pyr malate DHAP acetyl Co A citrate OAA succinate succ.CoA isocitrate G