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revised - lipid synthesis

revised - lipid synthesis - Learning Objec-ves Lipid...

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Unformatted text preview: Learning Objec-ves: Lipid Synthesis Describe the reac,ons catalyzed by malic enzyme and acetyl CoA carboxylase For the fa9y acid synthase reac,on: list the substrates and key products, iden,fy the sources of NADPH for the reac,on, and describe its general mechanism. Discuss the regula,on of fa9y acid synthesis at the levels of cellular compartmentaliza,on, response to AMPK, allosteric s,mula,on, and hormonal regula,on. Describe AMPK and explain why it is an important regulator of metabolic pathways. Explain how cholesterol is synthesized from acetyl CoA, including the star,ng substrates, the major products, the four stages, and the commi9ed/regulated step. Name three classes of molecules that are deriva,ves of either cholesterol or of the isoprenoid intermediates generated during cholesterol biosynthesis. Discuss the different levels of regula,on of HMG CoA reductase and explain why inhibitors of this enzyme lower serum cholesterol levels. Outline (in general terms) the pathway for eicosnoid biosynthesis and explain why this pathway is a target for an,-inflammatory drugs. Reading Chapter 22 Sec-ons 22.5 and 22.6 Chapter 26 Sec-ons 26.2, 26.3, and 26.4 Problems Chapter 22: 6, 8, 11, and 19 (really good review for the final) Chapter 26 (758-759): 7, 10 plus problem set Lipogenesis (FaKy acid synthesis) is the opposite of lipolysis (faKy acid oxida-on) Lipogensis occurs primarily in the cytoplasm of adipose ,ssue and liver Adipose: FA stored as triacylglycerols via esterifica,on Liver: produces TAG packaged into VLDL and exported Fa9y acid synthesis requires acetyl CoA: Compounds metabolized to acetyl CoA can serve as a fat precursor Glucose is a source of carbons for fat synthesis. Difference subcellular location carrier protein enzymes redox building block FA Synthesis cytosol acyl carrier protein (ACP) all activities on a single polypeptide chain reductant is NADPH malonyl CoA (formed from Acetyl CoA) FA Degradation mitochondrial matrix Coenzyme A (CoA) multiple enzymes required oxidants are NAD+ and FAD acetyl CoA Fa9y acid synthesis: 8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O Acetyl-CoA carboxylase catalyzes the commitment step in fa9y acid synthesis by conver,ng acetyl-CoA to malonyl-CoA Acetyl CoA and Malonyl CoA are covalently a9ached to acyl carrier protein (ACP) in reac,ons catalyzed by the transferase domains of fa9y acid synthase The reac,ons on the right represent The first round of fa9y acid synthesis. In mammals this repeats 6 more ,mes To form C16-acyl ACP. C16-acyl ACP is hydrolyzed to palmitate and ACP. In animals, all of these reac,ons (7 different cataly,c ac,vates) are catalyzed by one polypep,de chain -- faKy acid synthase . Cartoon model of faKy acid synthase AT= acetyl transferase MT= malonyl transferase CE = condensing enzyme ACP= acyl carrier protein KR= -ketoacyl reductase ER= enolyl reductase DH= dehyratase TE = thioesterase Discuss when each of the ac,vi,es is needed during fa9y acid synthesis. Three dimensional structure of pig fa9y acid synthase in the ac,ve dimer form Image credit: Maier, T. et al. Science 321: 1315-1322 (2008) Note: the structure revealed two cataly,cally Inac,ve pseudodomains Denoted with The fa9y acid synthesis reac,on cycle ACP Acetyl-CoA is the priming group only in the first cycle, afer that, only malonyl-CoA is added to the ACP carrier protein each ,me. There are four reac,on steps required each cycle to result in the net addi,on two carbons to the growing fa9y acid chain. ACP ACP ACP ACP Courtesy of Dr. RL Miesfeld The fa9y acid synthesis reac,on cycle Each cycle of the fa9y acid synthase reac,on requires the input of one malonyl-CoA and the oxida,on of 2 NADPH molecules (4 e- total). The synthesis of C16 palmitate therefore requires 14 NADPH. Courtesy of Dr. RL Miesfeld The fa9y acid synthesis reac,on cycle In the final step, the enzyme palmitoyl thioesterase catalyzes a hydrolysis reac3on to release palmitate. Courtesy of Dr. RL Miesfeld Acetyl CoA is shu9led from the mitochondrial matrix to the cytoplasm via the citrate shu9le. This reac,on is one source Of NADPH used in fa9y acid synthesis Malate + NADP+ Pyruvate + CO2 + NADPH What is the other major source of NADPH? Regula-on of acetyl CoA carboxylase controls faKy acid synthesis Citrate s,mulates polymeriza,on of acetyl CoA carboxylase Phosphoryla,on of acetyl CoA carboxylase inac,vates the enzyme -through hormone s,mula,on OR Phosphoryla,on by AMP-ac,vated kinase (AMPK) AMP-ac-vated kinase (AMPK) acts as an energy charge sensor, regula-ng many metabolic pathways AMPK is s,mulated by High [AMP] as well as Extracellular signals. Regula,on by AMPK differs from allosteric regula,on by AMP because AMPK Covalently modified its targets. Acetyl CoA Carboxylase is controlled by AMPK Regula-on of acetyl CoA carboxylase -filament forma,on promotes ac,vity -citrate allosterically ac,vates acetyl CoA carboxylase by promo,ng filament forma,on -Phosphoryla,on completely inhibits in the absence of citrate, par,ally inhibits in the presence of citrate Cholesterol is synthesized from acetyl CoA and is used as the star-ng substrate for synthesis of many steroid hormones and other cholesterol deriva-ves Stage 1 Acetyl CoA (C2) HMG-CoA NADPH HMG-CoA Reductase NADP+ Mevalonate (C6) Stage 2 Mevalonate CO2 Ac,ve Isoprenoids (C5) Several NADPH Condensa,on Steps NADP+ Squalene (C30) 3ATP 3ADP ! ! ! ! rate-determining step cholesterol is feedback inhibitor mevalonate is feedback inhibitor target site for sta,n drugs Stage 4 Lanosterol (C30) O2 NADPH NADP+ (19 steps) Stage 3 Squalene (C30) O2 NADPH NADP+ Cycliza,on Squalene epoxidase/ cyclase Lanosterol (C30) (4-ring structure) 3 CH3 Cholesterol (C27) Courtesy of Dr. M. Tischler The four stages of cholesterol biosynthesis Isoprenoids are the star,ng substrate for the synthesis of a wide range of Biologically important molecules (from state 2 of cholesterol Biosynthesis) HMG CoA Reductase catalyzes the commi9ed and regulated step in cholesterol biosynthesis. Regula,on occurs on three levels 1. Feedback inhibi,on of HMG-CoA reductase 2. Modula,on of expression of mRNA encoding proteins in the cholesterol biosynthe,c pathway 3. Phosphoryla,on of HMG-CoA reductase by AMPK Expression of HMG CoA Reductase Responds to Intracellular Levels of Cholesterol Through The Ac-on of SREBP Sta,n drugs inhibit cholesterol biosynthesis by blocking the ac,vity of HMG-CoA reductase Courtesy of Dr. R.L. Miesfeld Remember, newly Synthesized cholesterol is not the only source cholesterol 4 1 3 2 Courtesy of Dr. R.L. Miesfeld Eicosanoids are lipid based messenger molecules. Cyclooxgenase is the target for many an--inflammatory drugs. Two isozymes of cyclooxgenase, COX1 and COX2 Asprin and ibuprofen inhibit both ...
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