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UA BIOC 460 - Lipid Metabolism

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PowerPoint PresentationSlide 2Slide 3Review of Pathway QuestionsSlide 5Slide 6Acetyl-CoA carboxylase catalyzes the commitment step in fatty acid synthesis which converts acetyl-CoA to malonyl-CoASlide 8The swinging arm mechanism of acetyl-CoA carboxylaseThe fatty synthesis reaction cycleSlide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Summary of the fatty synthesis pathwaySlide 19The citrate shuttle transports acetyl-CoA equivalents from the matrix to the cytosol and generates NADPHSlide 21Slide 22Regulation of fatty acid synthesisMetabolic regulation of acetyl-CoA carboxylaseHormonal regulation of acetyl-CoA carboxylaseRegulation of acetyl-CoA carboxylase activityAMPK is an important metabolic sensorSlide 28Three Metabolic Control Points of FA SynthesisSlide 30Lipid Metabolism 2:Acetyl-CoA carboxylase, fatty acid synthase reaction, and regulation of fatty acid synthesisBioc 460 Spring 2008 - Lecture 36 (Miesfeld)AMP-activated kinase (AMPK) is a regulator of acetyl-CoA carboxylaseC247 is a fatty acid synthase inhibitor that reduces breast cancer incidence in miceThe fatty acid synthase enzyme in eukaryotes is dimer of two very large polypeptide chains, each encoding seven functional units C247•Fatty acid synthesis and degradation have several similarities and many differences. Both require carrier molecules and the enzymology of adding or subtracting acetate units to a hydrocarbon chain are similar. However, synthesis takes place in the cytosol, uses NADPH as coenzyme in redox reactions, and the building block is malonyl-CoA. •Acetyl-CoA carboxylase is the key regulated enzyme in fatty acid synthesis and is responsible for generating malonyl-CoA in a carboxylation reaction using acetyl-CoA. Acetyl-CoA carboxylase activity is regulated by both allostery (metabolic signaling) and phosphorylation (hormonal signaling).•The fatty acid synthase protein complex consists of six enzymatic activities and the acyl carrier protein (ACP). Seven reaction cycles are required to synthesize palmitate (C16) from 1 acetyl-CoA and 7 malonyl-CoA at cost of 14 NADPH. •The citrate shuttle is responsible for moving acetyl-CoA equivalents from the mitochondrial matrix to the cytosol when glucose levels are high and the citrate cycle is feedback inhibited by a high energy charge in the cell. Key Concepts in Lipid MetabolismComparison of fatty acid synthesis and degradationWhile the chemistry of the four core reactions required for the removal or addition of C2 acetyl groups to the hydrocarbon chain are similar between fatty acid degradation and synthesis, the two pathways are in fact quite distinct in terms of the required enzymes, subcellular location and source of redox energy. Fatty acid degradation occurs in the mitochondrial matrix and utilizes FAD and NAD+ as the oxidants in two oxidation reactions, whereas, fatty acid synthesis occurs in the cytosol and is dependent on NADPH serving as the reductant in the two corresponding reduction reactions. Other differences are listed below. Difference FA Synthesis FA Degradation subcellular location cytosol mitochondrial matrix carrier protein acyl carrier protein (ACP) Coenzyme A (CoA) enzymes all activities on a single polypeptide chain multiple enzymes required redox reductant is NADPH oxidants are NAD+ and FAD building block malonyl CoA (formed from Acetyl CoA) acetyl CoA1. What purpose does fatty acid synthesis serve in animals?–Fatty acid oxidation in mitochondria is responsible for providing energy to cells when glucose levels are low. Triacylglycerols stored in adipose tissue of most humans can supply energy to the body for ~3 months during starvation.–Fatty acid synthesis reactions in the cytosol of liver and adipose cells convert excess acetyl CoA that builds up in the mitochondrial matrix when glucose levels are high into fatty acids that can be stored or exported as triacylglycerols. Review of Pathway Questions2. What is the net reaction in the synthesis C16 palmitate? Fatty acid oxidation:Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP → 8 acetyl CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H+Fatty acid synthesis:8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ → Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O Review of Pathway Questions3. What are the key enzymes in fatty acid synthesis?Acetyl CoA carboxylase - catalyzes the commitment step in fatty acid synthesis using a biotin-mediated reaction mechanism that carboxylates acetyl-CoA to form the C3 compound malonyl-CoA. The activity of acetyl CoA carboxylase is regulated by both reversible phosphorylation (the active conformation is dephosphorylated) and allosteric mechanisms (citrate binding stimulates activity, palmitoyl-CoA inhibits activity). Fatty acid synthase - this large multi-functional enzyme is responsible for catalyzing a series of reactions that sequentially adds C2 units to a growing fatty acid chain covalently attached to the enzyme complex. The mechanism involves the linking malonyl-CoA to an acyl carrier protein, followed by a decarboxylation and condensation reaction that extends the hydrocarbon chain. Review of Pathway QuestionsAcetyl-CoA carboxylase catalyzes the commitment step in fatty acid synthesis which converts acetyl-CoA to malonyl-CoAMalonyl-CoA serves as the donor of C2 acetyl groups during each round of the fatty acid synthesis reaction cycle. The E. coli acetyl CoA carboxylase enzyme consists of three subunits which encode a biotin carboxylase, a biotin carrier protein and a transcarboxylase.In the first step, the biotin carboxylase subunit of the enzyme uses ATP to form carboxyphosphate which is then dephosphorylated to drive the formation of carboxybiotin. The carboxybiotin arm then swings across the enzyme complex and positions the carboxyl group in a second active site where the transcarboxylase subunit transfers the carboxyl group from carboxybiotin to acetyl CoA to form the reaction product malonyl CoA.This same carboxyl group used to form malonyl CoA from acetyl CoA is removed by decarboxylation in step 4 of the fatty acid synthesis reaction cycle (decarboxylation is a highly exergonic reaction). Therefore, malonyl CoA essentially serves as the "activated" carboxylated form of acetyl CoA.Acetyl-CoA carboxylase catalyzes the commitment step in fatty acid synthesis which converts acetyl-CoA to malonyl-CoAThe swinging arm mechanism of acetyl-CoA carboxylaseThe four core reactions of fatty acid degradation and fatty acid


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UA BIOC 460 - Lipid Metabolism

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