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Chapter 9 Regulation of Metabolism Metabolism: Metabolism in the living organism contains many pathways. Catabolism: to generate energy Anabolism: to use eneragy Cells maintain a dynamic homeostasis, the living organism modulates various metabolisms in intensity, direction and velocity, in order to adapt changes of enviroment inside and outside the body. Metabolism regulation is an important character of life, being an adaptation formed in evolution over a long –term. There are three hierarchies in metabolism regulations: 1) Metabolism regulation in the cell level 2) Hormone regulation of metabolism 3) Regulation of metabolism in level of the whole Section 1 Metabolism Regulation in Cell Level 1. Basic manner of metabolism regulation in cells 1) Integration and orientation of metabolism enzymes and pathways ⅰ. Regional distribution of enzymes in cells Eukaryote cells have many inner-membrane systems, so enzyme distribution presents compartmentation, which not only avoids interference among enzymes in different metabolism pathways but also benefits harmonious operation of enzymes. Table 1 Compartment distribution of main metabolism pathways (enzymes in eukarote cell) Metabolism pathways distribution Metabolism pathways distribution Cictric acid cycle Mitochondrion Urea synthesis Mit, Cytosol Protein synthesis Cytosol DNA synthesis Nucleus mRNA synthesis Nucleus Glycolysis P.P.P Cytosol Glycogenolysis Cytosol Glycogenesis Cytosol Gluconeogenesis Cytosol FA β-oxidation FA synthesis Respiratory chain Mitochondrion Cytosol Mitochondrion Oxidative phosphrylation Mitochondrion tRNA synthesis rRNA synthesis Ch synthesis PL synthesis Heme synthesis Hydrolytic enzymes ER, Cytosol Nucleoplasma Nucleus ER, Cytosol ER Cytosol, Mit Lysosome ⅱ. Multienzyme System and Multifunctional Enzyme Monomeric enzyme Oligameric enzyme Multienzyme System: Pyruvate dehydrogenase complex Multifunctional Enzyme: FA synthase system ⅲ. Isoenzyme Isoenzymes (isozymes ) : are different forms of an enzyme which catalyze the same reaction, but which exhibit different physical or kinetic properties, such as isoelectric point, pH optimum, substrate affinity or effect of inhibitors. Examples: LDH (lactate dehydrogenase ) H4 H3M H2M2 HM3 M4 Heart Muscle Different tissues express different isoenzyme forms (by regulating tissues express different isoenzyme forms) , as appropriate to their particular metabolic needs. 2) Basic manner of metabolism regulation Metabolism speed or direction often lies up on activities of some key enzymes. The enzyme that catalyzes the reaction at the slowest speed, whose activities is modulated by substrates, metabolites(products or effectors), is called regulatory enzyme, key enzyme or rate-limiting enzyme. Table 2 Rate-limiting enzymes of some important metabolism pathways Metabolism pathway Rate-limiting enzymes Glycolysis HK , PFK-1, PK P.P.P G6PD Gluconeogenesis Pyr carboxylase, PEP carboxykinse, FBPase, G6Pase Cictric acid cycle Citrate synthase, Isocitrate DHase, α-KG DHase Glycogenesis Glycogen synthase Glycogenolysis Glycogen phosphorylase Triacylglycerol hydrolysis Triacylglycerol lipase FA synthesis Acetyl CoA carboxylase Ketogenesis HMG CoA synthase Cholesterol synthesis HMG CoA reductase Urea synthesis Argininosuccinate synthase Heme synthesis ALA synthase ⅰ. Feedback Regulation The substrates or products in metabolism pathways often affect the initial enzymes in the pathway. Feedback regulation is one of the finest acting manners of regulatory enzymes. Negative feedback: Positive feedback: Glucogenolysis : Gn Glycogen synthase Glycogen phosphorylase UDPG (—) G1P G6P (+) G ⅱ. Substrate Cycle In a metabolism pathway, the direction of reversible reaction is controlled by different enzyme. ATP (+) F-6-P AMP (-) Pi ADP FPK-1 (-) F-2,6-2P F-1,6-2P (+) Fructose biposphatase-1 ⅲ. Cascade Reaction In a chain reaction, when an enzyme is activated, other enzymes are activated in turn to bring primal signal amplifying. hormones(glucagon 、epinephrine)+ receptor Adenyly cyclase (inactive) Adenyly cyclase (active) ATP cAMP PKA (inactive) Phosphorylase b kinase Phosphorylase b inactive PKA (active) Phosphorylase b kinase-P Phosphorylase a-P active 2. Regulation of Enzymatic Activity in Cells 1) Allosteric Regulation ( rapid regulation) when some metabolites combine reversibly to an regulating site of an enzyme and change the conformation of the enzyme, resulting in the change of enzyme activity. • allosteric enzyme • allosteric site Allosteric activator • allosteric effectors Allosteric inhibitor Table 3 Metabolism pathway Glycolysis Cictric acid cycle Gluconeogenesis Glycogenolysis Glycogenesis FA synthesis Some allosteric enzymes and effectors in enzyme systems of metabolism pathways Allosteric enzymes Activator Inhibitor HK PFK-1 PK Citrate synthase AMP, ADP, FBP, Pi G6P FBP Citrate FBP ATP, Acetyl CoA AMP ATP, long-chain fatty acyl CoA Isocitrate DHase AMP, ADP ATP Pyr carboxylase Acetyl CoA, ATP FBPase Citrate AMP Glycogen phosphorylase AMP, G1P, Pi ATP, G6P Glycogen synthase G6P Acetyl CoA carboxylase Citrate, Isocitrate long-chain fatty acyl CoA Cholesterol synthesis HMG CoA reductase Cholesterol Amino acid metabolism GLDH ADP, Leu, Met ATP, GTP, NADH General Properties of Allosteric Enzymes Key points: An allosteric enzyme is regulated by its effectors (activator or inhibitor). Allosteric effectors bind noncovalently to the enzyme. Allosteric enzymes are often multi-subunit proteins. A plot of V0 against [S] for an allosteric enzyme gives a sigmoidal-shaped curve. The binding of allosteric enzyme with an effector will induce a conformational change Allosteric effect of fructose-1,6-biphosphatase FDP FDP FDP FDP FDP AMP (allosteric inhibitor) AMP FDP FDP Glyceraldehydes-3-phosphate Fatty acid –carrier protein Citrate AMP (allosteric activator) T state (high activity) AMP AMP FDP R state (low activity) 2). Covalent Modification(rapid regulation) It means the reversible covalent attachment of a chemical. Types of Covalent Modification: phosphorylation / dephosphorylation adenylylation/deadenylylation methylation/demethylation acetylation/deacetylation -SH / -S-S , etc Covalent Modification Pi Protein phosphatase H2 O Protein-OH O- ATP Protein kinase Protein-O-P=O O- The reversible phosphorylation and dephosphorylation of an enzyme ADP Table 4 Regulation of covalent modification in enzyme activities Enzyme Reactive type Effect PFK-1 Phosphorylation/dephosphorylation Inactivity/activity Pyr DHase Phosphorylation/dephosphorylation Inactivity/activity Pyr decarboxylase Phosphorylation/dephosphorylation Inactivity/activity Glycogen phosphorylase Phosphorylation/dephosphorylation Activity/inactivity Phosphorylase b kinase Phosphorylation/dephosphorylation Activity/inactivity Protein phosphatase Phosphorylation/dephosphorylation Inactivity/activity Glycogen synthase Phosphorylation/dephosphorylation Inactivity/activity Triacylglycerol lipase Phosphorylation/dephosphorylation Activity/inactivity HMG CoA reductase Phosphorylation/dephosphorylation Inactivity/activity Acetyl CoA carboxylase Phosphorylation/dephosphorylation Inactivity/activity Key points: Change of a covalent bond The most common is the phosphorylation or dephosphorylation. Enzymes----protein kinases or phosphatases The activity of an enzyme after the modification can increase or decrease. The modification is a rapid, reversible and effective process. Covalent modification of phosphorylase 2ATP 2Pi Phosphorylase b (dimer) Inactivity Phosphorylase b kinase phosphatase 2ADP P P Phosphorylase a (dimer) High activity P P P P Phosphorylase a (tetramer) Activity 3. Regulation of Enzyme Content in Cells (Genetic Control) The amount of enzyme present is a balance between the rates of its synthesis and degradation. The level of induction or repression of the gene encoding the enzyme, and the rate of degradation of its mRNA, will alter the rate of synthesis of the enzyme protein. Once the enzyme protein has been synthesized, the rate of its breakdown (half-life ) can also be altered as a means of regulating enzyme activity. 1) Induction and repression of Enzyme Protein Synthesis Induction: the activation of enzyme synthesis. Repression: the shutdown of enzyme synthesis. Genetic control of enzyme activity means to controlling the transcription of mRNA needed for an enzyme’s synthesis. In prokaryotic cells, it also involves regulatory proteins that induce or repress enzyme’s synthesis. Regulatory proteins bind to DNA, and then block or enhance the function of RNA polymerase. So, regulatory proteins may function as repressors or activators. ⅰ. Repressor Repressors are regulatory proteins that block transcription of mRNA, by binding to the operator that lies downstream of promoter. This biding will prevent RNA polymerase from passing the operator the and transcribing the coding sequence for the enzymes.------Negative control. Regulatory proteins are allosteric proteins. Some special molecules can bind to regulatory proteins and alter their conformation, and then affect their ability to bind to DNA. They work by two ways: Some repressor readily bind to the operator and block transcription: lac operon When no lactose: Promotor Operator gene Structural gene I Z repressor gene A RNA polymerase mRNA mRNA repressor protein Y NH2 When there is lactose: I repressor gene P O Structural gene A Y Z RNA polymerase mRNA mRNA NH2 NH2 NH2 repressor protein lactose Z Y A Some repressor can not bind to the operator directly : Trp operon When Trp trpR P Structural gene O RNA polymerase mRNA repressor protein When Trp Structural gene trpR P O RNA polymerase mRNA repressor protein Trp ( corepressor ) ⅱ. Activators Activators promote the transcription of mRNA. Activator is an allosteric protein which can not bind to the activator-binding site normally. When no inducer: activator-binding site P Structural gene O mRNA activator RNA polymerase When inducer: activator-binding site P Structural gene O mRNA RNA polymerase activator inducer ⅲ. Bacteria also Use Translational Control of Enzyme Synthesis The bacteric produces antisense RNA that is complementary to the mRNA coding for the enzyme. When the antisense RNA binds to the mRNA by complementary base paring, the mRNA cannot be translated into protein. 2) Regulation on Enzyme Protein Degradation Cellular enzyme proteins are in a dynamic state of turn over, with the relative rates of enzyme synthesis and degradation ultimately determining the amount of enzymes. In many instances, transcriptional regulation determines the concentrations of specific enzyme, with enzyme proteins degradation playing a minor role. In other instances, protein synthesis is constitutive, and the amounts of key enzymes and regulatory proteins are controlled via selective protein degradation. In addition, it also involves the abnormal enzyme proteins ( biosynthetic errors or post-synthetic damage). There are two pathways to degrade enzyme protein in cells: ⅰ. Lysosomal pathway ATP independent ⅱ. Proteasome pathway ATP, Ubiquitin dependent Section 2 Hormone Regulation of Metabolism Hormones are secreted by certain cells, usually located in glands, either by simple diffusion or circulation in the blood stream, to specific target cells. By these mechanisms, hormones regulate the metabolic processes of various organs and tissues; facilitate and control growth, differentiation, reproductive activities, learning and memory; and help the organism cope with changing conditions and stress in its environment. Hormonal regularion depends upon the transduction of the hormonal signal across the plasma membrane to specific intracellular sites, particularly the nucleus. Many steps in these signal across the signalling pathway involve phosphorylation of Ser, Thr, and Tyr residues on target proteins. According to receptor’s location in a cell, hormones are divided into two classes: Hormones associating transmembrane receptors Hormones associating intracellular receptors 1. Regulation Hormones Associating Transmembrane Receptors Hormones associating transmembrane receptors, as the first messenger, which act by binding to membrane receptors, activate various signal transduction pathways that mobilize various second messengers-----cAMP, cGMP, Ca2+, IP3 , DG that activate or inhibit enzymes or cascade of enzymes in specific ways. The first messenger: Peptide or protein hormones: GH, Insulin, etc Amino acid derivatives: epinephrine, norepinephrine H 腺苷酸环化酶 cAMP R R β β γ α γ AA CC GDP GTP ATP Hormone receptor G protein Enzyme The second messenger Protein kinase Enzyme or other protein Biological effects 2. Regulation Hormones Associating Intracellular Receptor Hormones associating intracellular receptor: Steroid hormones: Glucocorticoids Mineralococorticoids Vit D Sex hormones Amino acid derivatives: T3, T4 Section 3 Regulation of Metabolism in Relation to the Whole Living in an ever-changing environment, human must have the ability to adapting to the environment, the body regulates metabolism through neurohumoral pathways to satisfy energy needs and maintain homeostasis of the internal environment. 1. Metabolism Regulation in Stress Stress is a tense state of an organism in response to unusual stimulus. Effect: Stimulus injury pain frostbite oxygen deficiency toxicosis Excitation of sympathetic nerves Adrenal medullary/cortical hormones Epinephrine, glucagons, wrowth hormone Insulin Metabolism of carbohydrates lipids infection change proteoins out-of-control rage Catabolism Anabolism 1). Change of Carbohydrate Metabolism Hyperglycemia catecholamine glucagon growth hormone corticosteroid Glycogenolysis Gluconeogenesis Stress hyperglycemia Stress glucosuria Insulin Blood glucose If exceeds renal threshold of glucose (8.96 mmol/L) Glucosuria In the beginning phase of stress: Liver Gluconeogenesis Muscle Glycogens Most tissue utilizes glucose In brain, it utilizes glucose normally. Glycogens 2). Change of Triacylglycerol Metabolism Adrenaline Noradrenaline Glucagon Fat mobilization Fatty acid Ketone bodies Tissue utilize FA as energy 3). Change of Protein Metabolism Protein hydrolysis Amino acid: as material for Gluconeogenesis Urea synthesis Equilibrium of negative nitrogen Liver Glycogenolysis Glycerophosphate Ketogenesis Stress Sympathetic excitation Adrenal cortex/ medulla hormone FA LA glucose Gluconeogenesis Pyruvate Ureogenesis Alanine NH3 FA LA Alanine Urea Glucose Glycerophosphate Kidney Blood vessel Glucosuria Muscle glycogenolysis TAG hydrolysis Lipocyte Muscle Protein degradation 2. Change of Metabolism in Starvation 1) Starvation in Short-term (1-3 days) Glycogen reserve Blood Glucose Insulin glucagon corticosteroid a series of metabolic changes ⅰ. Protein Metabolism Protein degradation , Protein Amino acid Glucose Glucose degradation gluconeogenesis Amino acid Pyruvate deamination transamination Pyruvate transamination Alanine Alanine Muscle Blood Liver ⅱ. Carbohydrate Metabolism Gluconeogenesis Lactic acid 30% Glycerol 10% Amino acids 40% Liver : 80% Renocortical : 20% Tissue utilize glucose In brain , glucose is still the main fuel source. ⅲ. Triacylglycerol Metabolism Fat mobilization Fatty acidG Ketone bodies Heart Skeletal muscle Renal cortex 2) Starvation in Long-term ⅰ. Protein Metabolism Muscle protein degradation Amino acid , but Glu deamination In urine Urea NH3 Acidism ( by ketosis ) ⅱ. Carbohydrate Metabolism In kidney : Gluconeogenesis ( almost equal to that in liver ) The main materials of gluconeogenesis in liver: Lactic acid Pyruvate ⅲ. Triacylglycerol Metabolism Fatty acidG Ketone bodies Skeletal muscle: FA as an energy source to ensure that adequate amounts of ketone bodies are available in brain. Fat mobilization Brain: gradually adapts to using ketone bodies as fuel. This may reduce utilization of glucose and gluconeogenesis of amino acid, so decrease the breakdown of protein.