Biochemistry 301 Week 10 Notes
Biochemistry 301 Week 10 Notes BBMB 301
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This page Class Notes was uploaded by Emily on Tuesday March 8, 2016. The Class Notes belongs to BBMB 301 at Iowa State University taught by Robert Thornburg in Spring 2016. Since its upload, it has received 17 views. For similar materials see Survey of Biochemistry in General Science at Iowa State University.
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Date Created: 03/08/16
Biochemistry 301 Survey of Biochemistry Professor Robert Thornburg LECTURE 25 CHAPTER 25 GLYCOGEN METABOLISM II By Emily Settle Glycogen Synthesis Glucose Unit Donor o UDPGlucose is the glucose unit donor to elongated a glycogen chain 0 Glc1P UTP l UDPGlcuose UDP PPi Catalyzed by UDPglucose pyrophosphorylase Glycogen Branching Enzymes 0 Introduce cx16 branch linkage gycoside bonds Cleave a linear chain at an cx14 bond Transfer released portion temporarily to enzyme Donate the released portion to a C6 hydroxyl group elsewhere in the chain or in a neighboring chain Phosphorylation Regulates Glucose Storage in Glycogen 0 When glucose supply is low Storage of glucose in glycogen should cease Glycogen synthase should be inactive Release of glucose from glycogen should increase Glycogen phosphorylase should be active 0 Low glucose supply results in glucagon release This initiates the cAMPprotein kinase A PKA signal transduction pathway 0 Thus PKA activity stimulates glycogen breakdown inhibits glycogen synthesis PKA is active when glucose supply is low Removal of Phosphate Groups Reverses Metabolism o Phosphorylated state Phosphorylase kinase glycogen phosphorylase a on Glucose release stimulated Glycogen synthase off Glucose storage repressed o Dephosphorylated state Protein Kinase A phosphorylase kinase and phosphorylase a are in the off state Glucose release inhibited Glycogen synthase on 0 Synthesis stimulated 0 Protein phosphatase 1 PP1 is the dephosphorylation enzyme PP1 stimulates glycogen synthesis blocks glycogen breakdown Reciprocal Regulation 0 PP1 forms a complex with phosphorylase a in R form PP1 does not bind T form of phosphorylase disassociates Once phosphorylase a is released the PP1 can act upon it PP1 dephosphorylates phosphorylase a to convert it to phosphorylase b inactive 0 Released PP1 can also work on glycogen synthase Dephosphorylation by PP1 activates glycogen synthase 0 Resu High glucose cuases inactive phosphorylase and active glycogen synthase Inhibitors of Protein Phosphatase 1 o PP1 forms a scaffolding complex with a Gprotein that differs in different tissues GM in muscle GL in liver 0 Therefore different modes of regulation in different tissues 0 High Glucose Level Stimulates Glycogen Synthase o Glycogen synthase is inhibited when the glucose level is low As noted on a previous slide PKA phosphorylates glycogen synthase and inactivates it o A different kinase glycogen synthase kinase also phosphorylates glycogen synthase and inactivates o lnsulin is produced when glucose is high Signal transduction pathway activated Glycogen synthase kinase phosphorylated lnactivated o Glucagon is produced when glucose is low Signal transduction pathway activated Glycogen synthase inactivated Phosphorylase a is activated 0 Resu When blood glucose is high Glycogen synthesis activated breakdown inactivated When blood glucose is low glycogen synthesis inactivated breakdown activated Glucose levels are maintained in the normal range 0 Type 1 Diabetes 0 Insulin not made 0 Overexpression of glucagon Occurs in young people Transport of glucose into liver cells does not occur Liver cells perceive that glucose supply is low even though it is not Gluconeogenesis stays on glycolysis stays off 0 Normally the insulin signal shuts off gluconeogenesis and stimulates glycolysis ln type 1 diabetes F26BP levels stay low because the insulin signal to synthesize this molecule is not present 0 This keeps glycolysis off and gluconeogenesis on Glycogen breakdown stimulated even when glucose is high Glycogen synthase kept inactive even when glucose is high 0 ATP levels kept low even though there is plenty of fuel 0 Type II Diabetes 0 Most common type of diabetes older people 0 Insulin de ciency Insulin not produced in pancreas pancreatic Bcells die Insulin produced but receptors not present 0 Hyperglycemia high glucose in blood Glucose exists in the open chain form 1 of time Aldehydes react with free amines Can be a problem with proteins 0 Glucose reacts with lysines on proteins to form a quotSchiff Basequot 0 The body cannot break down a quotSchiff Basequot Body doesn39t have the biochemistry to deal with these compounds Schiff Bases accumulate to high levels in protein molecules throughout the body These Schiff Bases destroy the normal biochemistry of these proteins Diabetic complications 0 Regulation of Protein Phosphate amp Protein Kinase A PP1 inactivates Phosphorylase Kinase by dephosphorylation PP1 inactivates Phosphorylase a by dephosphorylation PP1 activates Glycogen synthase by dephosphorylation PKA activates Phosphorylase kinase PKA inactivates Glycogen synthase OOOOO Biochemistry 301 Survey of Biochemistry Professor Robert Thornburg LECTURE 26 CHAPTER 26 PENTOSE PHOSPHATE PATHWAY PPP By Emily Settle OVERVIEW 0 Oxidation Reactions Alternative means of oxidizing carbon in glucose NADPH produced 0 Interconversion of sugars 5 carbon sugars for DNARNA synthesis modular nature of metabolic pathways 0 Combine modules of various pathways to serve different functions depending on metabolic conditions Pentose Phosphate Pathway vs Calvin Cycle 0 Comparison of Calvin Cycle with Pentose Phosphate Pathway These pathways are mirror images of each other 0 Calvin cycle begins with the xation of C02 and goes on to use NADPH in the synthesis of glucose PPP begins with the oxidation of glucose to C02 and generates NADPH Role of PPP in central metabolism 0 The cell can change the pathways that it uses depending upon the biochemistry required at any particular time o For example using the same starting materials the cell Can make both ATP and NADPH When the cell requires extra energy Reductive biosynthesis within the cell NADPNADPH ratio high so new NADPH synthesis is needed Low ADPATP ratio so new ATP synthesis is needed Afterwards the nonoxidative phase uses glycolysis rather than gluconeogenesis Can many only NADPH When the cell is beginning to divide Synthesis of fatty acids in adipose tissue Can make both ribose5P and NADPH When the cell is growing RNA production and energy NADPNADPH ratio high so new NADPH synthesis required Growth ongoing so ribose5P needed for DNA replication ATP in adequate supply Omit the nonoxidative phase Can make only ribose5P When the cell is beginning to divide DNA replication NADPHNADP ratio high so new NADPH synthesis not required Ribose5P needed for cell division DNA replication ATP supply adequate Start with glycolysis 0 Then run pentose phosphate pathway reactions back to ribose5P o Allows the cell to be highly adaptable 0 Can adapt to different conditions 0 A hallmark of robust life Pentose Phosphate Pathway 0 Partial oxidation of glucose distinct from glycolysis 0 Overall reaction Glucose6P converted to 6 C02 1 Pi 12 NADP reduced to 12 NADPH 12 H o No ATP produced operates when ATP level is high 0 NADPH used in anabolic reactions Oxidized carbon converted to larger reduced biomolecules fatty acids NADP regenerated when NADPH donates electrons to carbon Source of biosynthetic reducing power 0 Also can produce ribose5P and other sugars from glucose Component of nucleotides nucleic acids NADH Compared to NADPH o NADH used to eventually reduce 02 Respiration ATP H20 produced 0 NADPH sued to eventually reduce carbon ATP used Polymers produced alkane part of fatty acids Pentose Phosphate Pathway oxidative phase 0 Two oxidation steps Aldehyde to carboxylic acid D NADPH Carboxylic acid to C02 D NADPH o NADPH produced at each oxidation step 0 Product is ribulose5P Pentose Phosphate Pathway nonoxidative phase 0 lnterconversion of Fivecarbon Compounds 0 Ribulose5P converted to ribose5P or xylulose5P Ribose5P and xylulose5P used for rearrangement back to glucose Some ribos5P can be used for nucleic acid biosynthesis 0 After six complete oxidative phase reactions 6 Glc6P converted to 6 ribulose5P 6 C02 0 Transketolase and transaldolase reactions Similar to Calvin cycle in photosynthesis 6 ribulose5P 30 carbons converted to 5 Glc6P 30 carbons plus 1 Pi Gluconeogenesis used Converts fructose6P to glucose6P Converts two glyceraldehyde3P into Glc6P Pi o Transaldolase and transketolase shuf e 2 or 3 carbon atoms around to rearrange the carbon skeletons of the pentoses to make 6carbon and 3carbon units 0 First Transketolase o C5C5C3C7 Transaldolase o C3C7C6C4 Second Transketolase o C4C5C6C3 PPP Complete Pathway o Oxidative phase reactions run six times Consume 6 glucose6P 12 NADP 6 H20 Produce 6 C02 12 NADPH 6 ribulose5P 0 Six ribulose5P converted to ve glucose6P one Pi 0 Net reaction 6 Glc6P 12 NADP 6 H20 l 6 C02 12 NADPH 12 H 6 Ribulose6P 6 Ribulose6P D 5 Glc6P Pi Glc6P 12 NADP 6 H20 l 6 C02 12 NADPH 12 H Pi 0 Purpose Oxidize glucose to C02 using electrons to reduce NADP to form NADPH for later use in biosynthesis To produce ribose5P for nucleic acid biosynthesis and DNA replication 0 Use of NADPH from the PPP 0 One of many uses of NADPH is to detoxify harmful compounds Indirect Glutathione reduces peroxides becomes oxidized NADPH then reduces oxidized glutathione Reconverting it to the functional form Biochemistry 301 Survey of Biochemistry Professor Robert Thornburg LECTURE 27 CHAPTER 27 FATTY ACID SYNTHESIS By Emily Settle Overview 0 Breakdown of triacylglycerol in stored fat Fatty acids and glycerol produced Regulation by PKA Fate of glycerol Transport of FAs to tissues 0 Oxidation of FAs to aceylCoA B oxidation pathway Special steps for unsaturated FAs odd number FAs o Ketone bodies Fuel source during prolonged starvation How does fatty acid breakdown occur 0 Adipose cells store triacylglycerols TAG in lipid droplets o TAG hydrolyzed in response to lowglucose signals Epinephrine glucagon released when blood glucose is low Target enzyme phosphorylated and acrtivated by signal transduction cascade Hormonesensitivelipase 0 FA and glycerol produced Glycerol to liver enters glycolysis or gluconeogenesis FA through blood to other tissues Eventually oxidized to acetylCoA Signal Transduction Activates Lypolysis o Glucagon and epinephrine signal the quotstarvedquot state low glucose CAMP generated as second messenger PKA activated PKA phosphorylates perilipin lipid droplet associated protein PKA phosphorylates and activates hormonesensitive lipase HSL Phosphorylated perilipin binds to adipose triglyceride lipase ATGL ATGL binds coactivator CA binds to phosphorylated HSL Perilipin phosphorylated causes activation of ATGL These two lipases hydrolyze two of the acyl groups releasing free fatty acids Monoacylglycerol lipase MAG lipase removes the nal fatty acid from monoacylglycerol Fate of Glycerol from TAG o Glycerol backbone of TAG after all three fatty acids released Can be oxidized to C02 Converted to pyruvate D PDH complex Produces acetylCoA D citric acid cycle 0 ATP C02 H20 produced Or reduced to glucose Gluconeogenesis o Pathway Glycerol D glycerol3phosphate ATP expended Glycerol3phosphate D dihydroxyacetone phosphate NAD reduced to NADH Dihydroxyacetone phosphate D glyceraldehyde3phosphate To pyruvate through glycolysis then into respiratory pathway 0 To glucose through gluconeogenesis Transport of Fatty Acids through Bloodstream 0 Fatty acids move to bloodstream pass through membranes 0 Bound by serum albumin held in hydrophobic environment 0 Released to tissues where reduced carbon from fat is used for ATP production 0 Fatty acid transport into mitochondria 0 Serum Albumin transports fatty acids through the blood to the tissues throughout the body 0 Step 1 Activation by formation of AcylCoA activated form of acyl group AcylCoA synthase located in the mitochondrial outer membrane Acyl adenylate is an important intermediate in this reaction Hydrolysis of PPi to 2Pi drives reaction forward 0 Step 2 Carnitine shuttle transport of Acyl group into mitochondrial matrix FA oxidation occurs in mitochondrial matrix but FAs exist in cytoplasm Carnitine shuttle moves FAs from cytosol into mitochondria AcylCoA synthesis occurs on outer membrane Acyl group transferred to carnitine carrier 0 Inner side of outer membrane Acylcarnitine crosses inner membrane Acyl group transferred back to CoA SH AcylCoA now located in matrix 0 Step 3 BOxidation breakdown of Acyl group 1 oxidation 2 hydration 3 oxidation 4 thiolation Conversion of Fatty Acids to AcetylCoA Overview BOxidation pathway AcylCoA cleaved into acetyICoA and a new shorter fatty acyICoA O O O 0 New acyICoA 2 carbons shorter than starting moecue Cyclical reaction pathway Shorten acyICoA by 2 carbons each round of the cycle For example the 16 C fatty acid palmitoylCoA forms 8 acetylCoA in 7 turns of cycle BOxidation Biochemistry 0 oxidation acyICoA dehydrogenase o hydration enoyICoA hydratase 0 oxidation BhydroxyacyICoA dehydrogenase o cleavage thioase BOxidation Pathway 0 Step 1 acyICoA dehydrogenase Integral inner membrane protein Proton and e are removed from the or and B carbons FAD reduced to FADH2 FADH2 donates e Coenzyme Q of the electron transfer chain Trans double bond forms between the or and B carbons Analogous to succinate dehydrogenase of the citric acid cycle complex II of the electron transport chain Redox reaction 0 Step 2 enoyICoA hydratase H20 added to the double bond 0 OH to the B carbon Proton to the or carbon Lyase reaction 0 Step 3 BhydroxyICoA dehydrogenase B hydroxyl group oxidized to ketone Forms B ketro acid NAD reduced to NADH NADH donate electron to Complex of electron transport chain 0 Step 4 thioase CoASH attacks ketone group of the B keto acid Produces acetylCoA and new acylCoA Boxidation Pathway Summary 0 Each turn of the cycle yields 1 FADH2 1 NADH and 1 acetylCoA 2 acetylCoA on the last turn of the cycle Yield for palmitate 8 acetylCoA 80 ATP 7 FADH2 105 ATP 7 NADH 175 ATP 108 ATP generated 0 2 ATP used to generate acylCoA Net production is 106 ATP per palmitate molecule BOxidation of Unsaturated Fatty Acids 0 Extra step allows oxidation of unsaturated fatty acids Monounsaturated FAs C16 degraded as usual until double bond is between carbons B and Y lsomerase moves the double bond to between the cxB carbons B oxidation continues as normal 0 Other mechanisms for polyunsaturated FAs Oxidation of FAs with Odd Numbers of C o For odd number carbon FAs last cycle produces 1 acetylCoA 2 carbons 1 propionylCoA 3 carbons o PropionylCoA is carboxylated Four carbon compound formed Converted to succinylCoA by two metabolic steps Citric acid cycle intermediate Ketone Bodies o Ketone bodies compromise three primary compounds Acetone 3hydroxybutyrate acetoacetate Watersoluble compounds easily transported to tissues from liver 0 Produced from excess acetylCoA More than can be handled by the citric acid cycle Form during starvation diabetes 0 Why is there excess acetylCoA in starvation or diabetes 0 No glucose uptake into cells diabetes or glucose not available OAA used to make glucose by gluconeogenesis Citric acid cycle not working because of low OAA AcetylCoA accumulates Ketone bodies made sent through blood 0 Brain can use ketone bodies instead of glucose Converted back to acetylCoA 0 Continued release of FAs from TAGs even when glucose level is high lnsulin is necessary to deactivate the release of FAs from TAGs 0 Diabetic shock Too high concentration of acetoacetate Blood pH drops can be lethal Conversion of Fatty Acids to AcetylCoA OVERVIEW 0 o Carbonyl group created at 3 carbon Bketo acid susceptible to nucleophilic attack by CoASH between the or and B carbons o Oxidation of alkane to thioester Accompanied by reduction of FAD and NAD
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