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Principles of Metabolic Regulation

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A) Why is it important for cells that proteins are degraded instead of remaining;indefinitely after being synthesized? (B) Name two ways cells control protein turn over?;Hints is in the attachment below;Attachment Preview;Lch15.1-4.pdf Download Attachment;CHAPTER 15;Principles of Metabolic Regulation;Key topics;Metabolic Pathways;The biochemical reactions in the living cell the;metabolism is organized into metabolic pathways;The pathways have dedicated purposes;Principles of regulation in biological systems;Glycolysis vs. gluconeogenesis?;Chemistry and regulation of glycogen metabolism;Metabolic Pathways;The pathways can be represented as a map;Map of Metabolic Pathways;The biochemical reactions in the living cell the metabolism is;organized into metabolic pathways;The pathways have dedicated purposes, some are dedicated;to extraction of energy;to storage of fuels;for synthesis of important building blocks;to elimination of waste materials;The pathways can be represented as a map;Follow the fate of metabolites and building blocks;Identify enzymes that act on these metabolites;Identify points and agents of regulation;Identify sources of metabolic diseases;http://www.genome.jp/kegg/;Homeostasis;Organisms maintain homeostasis by keeping the;concentrations of most metabolites at steady;state;Principles of Regulation;The flow of metabolites through the pathways is regulated;to maintain homeostasis;Sometimes, the levels of required metabolites must be;altered very rapidly;increase the capacity of glycolysis during the action;reduce the capacity of glycolysis after the action;increases the capacity of gluconeogenesis after successful action;Homeostasis;Organisms maintain homeostasis by keeping the;concentrations of most metabolites at steady;state;In steady state, the rate of synthesis of a;metabolite equals the rate of breakdown of this;metabolite;Regulate fluxes to maintain concentration of;metabolite (control enzyme);Feedback Inhibition;In many cases, ultimate products of metabolic pathways directly;or indirectly inhibit their own biosynthetic pathways;ATP inhibits the commitment step of glycolysis;Feedback Inhibition;Flux Control Coefficient for AD;Intermediate (branch point) or;cofactor (NADPH) can integrate;pathways by controlling enzyme;early in pathway;negative coefficient because;branchpoint competes for B;relative contribution of each enzymes in a pathway to flux J;through pathway, C=0, no impact on J, C=1 total control on;pathway;Note the Sum = 1 for any system of enzymes analyzed as a group;Reactions Far From Equilibrium Common Points of;Regulation;Living systems thrive by keeping some metabolic reactions far;from equilibrium while the levels of metabolites are in steady state;Rates of a Biochemical Reactions;Rates of a biochemical reactions depend on;many factors;Concentration of reactants (segregation, transporters);Activity of the catalyst;Concentration of the enzyme;(protein stability, rate of transcription/translation, mRNA/;protein degradation);Intrinsic activity of the enzyme;(covalent modification, binding of regulatory proteins;expression of isozymes (isoforms) w/ different kinetics and;regulation);Rates of a Biochemical Reactions;Factors that Determine the Activity of Enzymes;Rates of a biochemical reactions depend on;many factors;Michaelis Menten kinetics;Rate is Vmax when;[S]=Km;Enzyme is saturated w/;reactant associate;Concentration of reactants;Activity of the catalyst;Concentration of the enzyme;Intrinsic activity of the enzyme;Concentrations of effectors;hyperbolic response to;concentration;Allosteric regulators;Competing substrates;pH, ionic environment;Sensitive to small changes;in [substrate];Temperature;Km;These experimental data yield a Km for ATP of 5 mM.;The concentration of ATP in animal tissues is ~5 mM.;Enzymes from rat liver [E] enzyme;C= 0.79;concentration;Types of Pathway Management;metabolic regulation-processes that serve to;maintain homeostasis (at molecular level;maintain concentration of a metabolite);example, yeast PFK-1 regulation;C= 0.21;C=0;metabolic control-process that leads to;change in output of pathway in response to a;signal (change flux through pathway);example, insulin up regulates glycolytic enzymes transcription;Purified enzymes from rat liver added;in the amounts shown on the x axis;Factors that Determine the Activity of Enzymes;transcriptome;microarray;proteome;2D gel;Active Protein Molecules have a Finite Lifespan;Different proteins in the same tissue have very different;half-lives;less than an hour to about a week for liver enzymes;The stability correlates with the sequence at N-terminus;Some proteins are as old as you are;crystallins in the eye lens;Metabolome of E.coli;Phosphorylation of Enzymes Affects their Activity;Protein phosphorylation is catalyzed by protein kinases;Dephosphorylation can be spontaneous, or catalyzed by protein;phosphatases;Typically, hydroxyl groups of Ser, Thr, or Tyr are phosphorylated;extracellular signal >;regulatory cascade >;Phosphorylated within seconds;Some Enzymes in the Pathway Limit the Flux of;Metabolites More than Others;Hexokinase and phosphofructokinase are appropriate targets for;regulation of glycolytic flux;Both far from equilibrium G, so rate sensitive to small changes in;[substrate] or [product];WAS thought;to be the rate;determining;step;allosterically;regulated by;fructose 2,6bisphosphate;Increased hexokinase activity enables activation of glucose;Increased phosphofructokinase-1 activity enables catabolism of;activated glucose via glycolysis;Control of Glycogen Synthesis;hexokinase I or II isoform;Km 0.1mM so high affinity;Increased hexokinase activity enables;activation of glucose;glucose 6-phosphate produced in;excess E activity turned down;Glycogen synthase makes glycogen;for energy storage;Insulin signaling pathway;increases glucose import into;muscle;stimulates the activity of muscle;hexokinase;activates glycogen synthase;4-5mM;glucose;metabolite;regulation;inhibited by;glucose 6phosphate;Regulation of Hexokinase;Four isozymes (isoenzymes, isoforms) of hexokinase in;humans;Differ in transcriptional control, distribution in tissues;kinetic and regulatory properties and co-factors required;Liver- Hexokinase IV, glucokinase, Km 10mM while;[Blood glucose] = 4-5mM so low affinity prevents;hepatocytes from holding glucose for internal use unless;concentrations are high and activity is sensitive to;changes at relatively high [glucose];Regulation of Hexokinase IV by Sequestration in Hepatocyte;1) Glut 2 efficient receptor always on membrane so [blood glucose]= [liver cell glucose];Rate of Reaction Depends on the Concentration of;Substrates;The rate is more sensitive to concentration at low concentrations;2) hexokinase IV activity;responsive to high [blood glucose];Frequency of substrate meeting the enzyme matters;At 1/2 Vmax enzyme is half saturated;The rate becomes insensitive at high substrate concentrations;The enzyme is nearly saturated with substrate;3) hexokinase IV not;product inhibited so if;excess glucose is;around will mop up;4) reversibly bound;negative regulator;held in nucleus.;allosteric +effector of;binding is fructose 6phosphate while;effector is glucose;5) as [fructose 6-phosphate] increases hexokinase activity decreases;to allow other tissues to get glucose;6) transcriptional regulation hexokinase IV, !ATP, glucogon "low blood glucose, AMP;Isozymes may Show Different Kinetic Properties;Isozymes are different enzymes that catalyze the same reaction;They typically share similar sequences;Their regulation is often different;muscle isoform on and saturated;liver not retaining glucose;liver isoform sigmoidal;blood glucose and very responsive to;changes in [ ];Elasticity Coefficient Measures the Responsiveness to;Substrate;Enzyme w/ Typical Michaelis-Menten Kinetics;Elasticity coefficient;tangent to plot of rate;change vs [substrate];At [substrate] below the;Km, each increase in [S];produces large increase in;the reaction velocity, v.;Here enzyme has an of;about 1.0.;At [S] >> Km, increasing [S] has;little effect on v, here is close;to 0.0.;Glycolysis vs. Gluconeogenesis;Regulation of Phosphofructokinase-1;The conversion of fructose-6-phosphate to fructose 1,6bisphosphate is the commitment step in glycolysis;ATP is a negative effector;Do not spend glucose in glycolysis if there is plenty of ATP;Allosteric regulation, muscle PFK-1;At low [ATP];the K0.5 for fructose 6-phosphate is low;enabling the enzyme to function at a;high rate for relatively low [fructose 6phosphate].;Regulation of Phosphofructokinase 1 and;Fructose 1,6-Bisphosphatase;Go glycolysis if AMP is high and ATP is low;Go gluconeogenesis if AMP is low;When [ATP] is high;K0.5 for fructose 6phosphate is;greatly increased;as indicated by the;sigmoid relationship;between substrate;concentration and;enzyme activity.;Regulation by Fructose 2,6-Bisphosphate;F26BP activates phosphofructokinase (glycolytic enzyme);F26BP inhibits fructose 1,6-bisphosphatase (gluconeogenetic enzyme);F26BP activates phosphofructokinase Glycolysis;F26BP inhibits fructose 1,6-bisphosphatase- Gluconeogenesis;25um [inhibitor] lowers;affinity for substrate and;enhances AMP inhibition;without activator;enzyme is not active;at physiological;[fructose 6phosphate];Regulation by Fructose 2,6-Bisphosphate;Glycolysis if F26BP is high;Gluconeogenesis if F26BP is low;Regulation of 2,6-Bisphosphate Levels in the Liver;Insulin/ glucogon hormones;Xyluloase 5-phosphate from pentose phosphate;pathway/ Phosphoprotein phosphatase* **;Adenylate cyclase;Single protein;phosphofructokinase-2 (PFK-2);fructose 2,6-bisphosphatase (FBPase-2);Phosphoprotein phosphatasevariable regulatory subunits for substrate;specificity;no PO3;Adenylate cyclase;Xylulose 5-phosphate;Pentose phosphate pathway;Molecular Origin of Enzyme Regulation;Regulation of catalysis typically involves;Binding of inhibitors, often to the active site;Binding of regulatory protein subunits;phosphoprotein phosphatase 2A;(PP2A);determines substrate;specificity;Microcystin-LR;shown here in red;is a specific inhibitor;of PP2A;Dephosphorylates bifunctional;phosphofructokinase-2;(PFK-2)/ fructose 2,6bisphosphatase (FBPase-2);stimulating glycolysis;Regulation of Pyruvate Kinase;Signs of abundant energy supply allosterically inhibit all pyruvate;kinase isoforms;Signs of glucose depletion (glucagon) inactivate liver pyruvate;kinase via phosphorylation;Glucose from liver is exported to brain and other vital organs;Two Alternative Fates for Pyruvate;Pyruvate can be a source of;new glucose;Store energy as glycogen;Generate NADPH via;pentose phosphate pathway;Pyruvate can be a source of;acetyl-CoA;Store energy as body fat;Make ATP via citric acid;cycle;Acetyl-CoA stimulates glucose;synthesis by activating pyruvate;carboxylase;Glycogen structure and metabolism;Glycogen Metabolism;Glucogen phosphorylase (glucogen break down);Phosphoglucomutase glucose-1P # glucose -6P;Debranching enzyme;Dealing with Branch Points in Glycogen;Glycogen;phosphorylase works;on non-reducing;ends until it reaches;four residues from an;(1 6) branch point;Debrancing enzyme;transfers a block of;three residues to the;non-reducing end of;the chain;Debrancing enzyme;cleaves the single;remaining (1 6);linked glucose;Epinephrine and Glucagon Stimulate Breakdown;Glycogen Synthesis;Chapter 15: Summary;In this chapter, we learned that;living organisms regulate the flux of metabolites via;metabolic pathways by;increasing or decreasing enzyme concentrations;activating or inactivating key enzymes in the pathway;the activity of key enzymes in glycolysis and;gluconeogenesis is tightly regulated via various activating;and inhibiting metabolites;glycogen synthesis and degradation is regulated by;hormones insulin, epinephrine, and glucagon that report;on the levels of glucose in the body

 

Paper#16601 | Written in 18-Jul-2015

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