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Biochem Study Guide Test 2


Biochem Study Guide Test 2 BIOL 5311

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Regulation and Citric Acid Cycle
Biochemistry: Metabolism
Dr. Vogel
Study Guide
biochem, biochemistry, metabolism
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This 88 page Study Guide was uploaded by an elite notetaker on Monday February 29, 2016. The Study Guide belongs to BIOL 5311 at Southern Methodist University taught by Dr. Vogel in Winter 2016. Since its upload, it has received 28 views. For similar materials see Biochemistry: Metabolism in Biology at Southern Methodist University.


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Date Created: 02/29/16
Glycogen Metabolism and Regulation Chapter 15.4 and 15.5 Glycogen metabolism Glycogen breakdown from the nonreducing end, catalyzed by glycogen phophorylase In all organisms, excess glucose is converted to polymeric forms for storage: glycogen in vertebrates and some microorganisms, starch in plants Glycogen mostly found in liver (10 % of weight) and skeletal muscle (1-2 % weight). Glycogen in liver corresponds to about 0.4M glucose monomers. Muscle glycogen provides quick energy source and can be exhausted in < 1 hour during exercise. Liver glycogen as reservoir for dietary glucose Glucose from glycogen can enter glycolysis or replenish blood glucose • Phosphoglucomutase converts glucose-1-P to glucose-6-P → enter glycolysis. • To leave into blood, glucose-6-phosphatase in hepatocytes cleaves the phosphate of G6P Only in liver: when blood glucose is low: glucose-6-phosphatase cleaves phosphate Glycogen synthesis isexpensive: Glucoseneeds to be activated for glycogen synthesis The positive Δ G of the reaction is compensated by PPi hydrolysis. The reaction is made metabolically irreversible. UDP-glucose and glycogen synthesis Glycogen synthesis is expensive! Adding UDP to glucose increases the overall size of the molecule and interactions with glycogen synthase. Enhanced binding interaction will result in added free energy of binding and contribute to catalytic activity. UDP is a good leaving group. But even before that: Glucose + ATP is phosphorylated by hexokinase to glucose-6-P. G6P is converted to G1P by phosphoglucomutase. G1P + UTP react to UDP-glucose + PPi Glycogen synthase only adds glucose molecules to the 4 position. Glycogen branching enzyme transfers a terminal fragment of 6-7 glucose to a more interior 6 position. Glucose can be added to all branches at the 4 (non-reducing) position. Glycogen synthesis needs to be primed by glycogenin. Glycogen break down: Regulation of glycogenphosphorylase through phosphorylation cascade Glycogen synthesis: Regulation of glycogensynthase through phosphorylation/dephosphorylation Insulin stimulates dephosphorylation of glycogen phosphorylase, making it inactive, no glycogen degradation Insulin inhibits glycogen synthase phosphorylation and activates glycogen synthase dephosphorylation Resulting in formation of active glycogensynthase α and glycogen synthesis ↓ Principles of Metabolic Regulation CHAPTER 15.1 through 15.3 Regulation happens at different levels - different time scales Michaelis Menten Kinetic vo = v * [S]/(K + [S]) max m Allosteric enzymes don’t follow Michaelis Menten kinetics, they often follow sigmoidal curves Allosteric enzymes don’t follow Michaelis Menten kinetics, they often follow sigmoidal curves More pronounced change in velocity with smaller change in [S]. Hill coefficient defines how drastically velocity changes with changes in [S] Regulation on different levels •Transcription •Substrate levels; Km, •Stability of mRNA affinity, relationship [S] and •Translation Km •Degradation of proteins (rapid •Allosteric effectors changes of [protein] is •Covalent modifications expensive but allows fast •Regulatory proteins adjustment, responsiveness) •Sequester either enzyme or substrate •Or combinations of all of → changes in transcriptome, the above! proteome, metabolome Not all reactions are at equilibrium, small changes in [S] or [P] can change direction of net flow If k’eq and Q are within 1 or 2 orders of magnitude, the reaction is close to equilibrium. Cells need to keep reactions from reaching equilibrium to be able to perform work (phosphorylation power ofATP, not have excessive concentrations of some metabolites). ATP concentrations need to remain relatively constant to allow Enzymes who useATP to proceed at significant velocities [ATP]/[ADP] and [AMP] are major control factors, AMP results from adenylate kinase: 2ADP↔ ATP +AMP AMP-activated Protein kinase Responds to high [AMP] by phosphorylating key proteins Regulation to: •Maximize efficiency of fuel utilization •No simultaneous pathways in opposite direction •Partition metabolites appropriately between alternative pathways •Draw fuel best suited for immediate needs, i.e. glucose vs. fatty acids vs. glycogen, etc. •Slow down pathways when products accumulate Contribution of each enzyme can be measured Enzymes respond to varying [S] differently Coordinated regulation of glycolysis and gluconeogenesis Irreversible reactions in Glycolysis: • Hexokinase • Phophofructokinase • Pyruvate kinase Bypasses in gluconeogenesis: • Pyruvate carboxylase + PEP carboxykinase • Fru-1,6-bisphosphatase • Glucose-6-phosphatase i.e. ifATP +Fru-6-P → Fru-1,6-bis-P + ADP PFK and Fru-1,6-bis-P + H2O → Fru-6-P + Pi FBPase Were simultaneous, then the sum of the reaction would be:ATP + H O →ADP+ Pi + heat 2 No work would be performed, futile cycle or substrate cycle Isozymes in different cell types are differently affected by their Substrates and products: • Hexokinase I and II in muscle have high affinity for glucose, but are allosterically inhibited by glu-6-P, slowing the reaction when much product formed. • Hexokinase IV in liver cells has Km higher than [glucose] blood GLUT2 rapidly equilibrates, so increase in activity with increasing [glucose] blood At low blood glucose, the glucose from gluconeogenesis can leave cell before being phosphorylated. Also: Hexokinase IV inhibitor helps sequester HKIV in nucleus at High Fru-6-P concentrations and releases to cytosol when glucose high Phosphofructokinase key regulator of glycolysis ▯ High [ATP] inhibit PFK by allosterically lowering affinity for Fru-6-P ▯ ADP, AMP relieve that inhibition ▯ High [citrate] increases ATP inhibitory effect In the opposite way: ▯ AMP inhibits fructose- bisphosphatase, FBPase Fructose-2,6-bisphosphate, a special regulator in liver glucose handling Liver maintains constant blood glucose level → special regulation needed. • When blood [glucose]↓, glucagon signals glucose production through gluconeogenesis and glycogen break down and stop to glycolysis. • When blood [glucose]↑, insulin signals use of glucose in glycolysis and storage as glycogen and triacylglycerol. • Mediator is F2,6BP which is synthesized by PFK-2 and hydrolyzed by FBPase-2, a distinct protein with two distinct enzymatic activities and regulated by glucagon and insulin. • F2,6BP allosterically binds to PFK-1 and reduces affinity for inhibitors ATP and citrate, but reduces affinity of FBPase –1 for its substrate Hormonal regulation of F2,6BP Glucagon stimulates adenylyl cyclase of liver to form cAMP: •[cAMP]↑ stimulates cAMP-dependent protein kinase to phosphorylate PFK-2/FBPase-2. •Phosphorylation stimulates FBPase-2 activity and inhibits PFK-2 activity → F2,6BP↓, gluconeogenesis stimulated Insulin stimulates phosphoprotein phosphatase to remove the phosphate from PFK-2/FBPase-2. •Not phosporylated PFK-2/FBPase-2 has high PFK-2 activity and low FBPase-2 activity, F2,6BP↑, glycolysis stimulated Other regulatory mechanisms, also through cAMP dependent kinase and phosphoprotein phosphatase action, mostly in liver Other regulatory mechanisms: Transcriptional regulation Carbohydrate Response Element Binding Protein: Coordinates synthesis of enzymes needed for carbohydrate and fat synthesis Example of insulin regulating transcription • Insulin stimulates signaling cascade that activates protein kinase B • Activated PKB phosphorylates FOXO1. • Phosphorylated FOXO1 is tagged for degradation through proteasome • Unphosphorylated FOXO1 migrates into nucleus and stimulates gene expression. • → insulin signaling causes less FOXO1 in nucleus, less PEP carboxykinase, G6Pase expression, less gluconeogenesis The Citric Acid Cycle (Krebs cycle, TCA cycle) CHAPTER 16.1 through 16.3 Three stages of cellular respiration Under aerobic conditions, pyruvate from glycolysis as well as fatty acids and some amino acids are completely oxidized to CO 2nd H O.2 Almost all pathways feed through acetyl-CoA, (activated acetate) into the citric acid cycle. Two CO ar2 released for every C-2 (acetate) that then enters the citric acid cycle and electron carriers NADH and FADH ar2 formed. The last step is the electron transfer onto O 2o make water to provide the energy to synthesize ATP Before entering the citric acid cycle, pyruvate is oxidized and decarboxylated to acetyl-CoAin the pyruvate dehydrogenase complex: Pyruvate dehydrogenase complex Number and size of complex varies with different copy number of enzymes. In mammals about 50 nm diameter. Entry to the citric acid cycle withAcetyl-CoA: Thioester of acetic acid and coenzyme A Five coenzymes are needed in the pyruvate dehydrogenase complex to make acetyl-CoA Three enzymes in the complex: Pyruvate dehydrogenase Dihydrolipoyl transacetylase Dihydrolipoyl dehydrogenase Coenzymes of the pyruvate FAD dehydrogenase complex Thiamine (TPP, Vit. B1), riboflavin (FAD, Vit. B2), niacin (NAD), pantothenate (CoA, Vit. B5), Lipoate as food supplement (meta lipoate) 5-step reaction of pyruvate dehydrogenase through substrate channeling: 1) TPP aided decarboxylation of pyruvate 2) Oxidation of hydroxyethyl (activated acetaldehyde) group to acid level, reducing -S-S- group of lipoyl-group 3)Acylthioester with lipoyl is transferred to CoA 4 + 5) electrons are transferred through FAD to NAD+ to regenerate oxidized lipoyl Pyruvate dehydrogenase complex E1: Pyruvate dehydrogenase, TPP bound E2: Dihydrolipoyl transacetylase, bound lipoyl group E3: Dihydrolipoyl dehydrogenase, FAD and NAD+ cofactors E1: catalyzes decarboxylation of pyruvate and then oxidation to acetyl group and acetyl transfer to thioester with reduced lipoyl rest. E2: catalyzes acetyl transfer to CoA, forming acetyl-CoA E3:regeneration of oxidized lipoyl rest by transferring e- through FAD to NAD+ Similar complex arrangements in other enzyme complexes Remember Endosymbiosis Hypothesis Cadillac song Step 1: Citrate synthase: Conformational change upon substrate binding arranges amino acids for the chemical reaction to happen and creates reaction surface Large negative ΔG’ needed because [oxaloacetate] usually low CoSH released is re-used in PDH complex Step 2: Tri carboxylic acid TCAcycle Step 3: Oxidative decarboxylation of isocitrate leads to α-ketoglutarate, first CO of the cycle lost (second C of pyruvate) 2 Step 4: Oxidative decarboxylation and reaction with CoSH leads to succinyl-CoA Who can find the error in this figure? Conserved reaction mechanims in step 4 Step 5: Step 6: Malonate is strong competitive inhibitor of succinate Dehydrogenase when added to cells Step 7: Fumarase is highly stereospecific in both directions Step 8: Some anaerobic bacteria lack α- ketoglutarate dehydrogenase Cannot carry out complete citric acid cycle Α-ketogluterate and succinyl CoA from carboxylation of pyruvate and reverse citric acid cycle as biosynthetic precursors Central role of citric acid cycle also in anabolism Anaplerotic reactions replenish biosynthetic precursors that are removed from the citric acid cycle Role of biotin in adding CO in 2 Carboxylation reactions, i.e. pyruvate carboxylase Co-enzymes attached with long tethers for flexibility Lipoate and biotin are linked through amide bond with a catalytic site lysine residue CoA precursor has long pantothenate- mercaptoethanolamine tether linked to serine In CoASH Ser is substituted for AMP-3’Pi


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