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Chapter 15

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CHY 205
Mario Estable

Chapter 15: Principles of Metabolic Regulation (Overview) -All metabolic pathways are intertwined. Metabolic regulation is essential in that all rxns are regulated in some form. Eg. Possible fate of glc 6-P in hepatocytes (liver) 1. Breakdown by glycolysis for ATP & NADH production 2. Breakdwon in the pentose P pathway making NADPH & pentose P 3. Used in synthesis of compley polysacchs in extracellular matrix 4. Hydrolysis to glc & P to replenish blood glc 5. Synthesis of many sugars 6. Use in pro glycosylation 7. Partially degraded to provide acetyl-coA for FA & sterol synthesis *When any cell uses glc 6-P for 1 purpose, that affects all other pathways it’s a precursor in, in that any change in the allocation of glc 6-P to 1 pathway, in/directly affects the flow of metabolites through all others. -Cells & organisms maintain a dynamic steady state: Cells & organisms exist in metabolic homeostasis, eg. 5mM [blood glc]. The failure of homeostatic mechanisms is often the root of human disease. In the course of evolution, organisms have acquired a collection of regulatory systems from maintaining homeostasis at the molecular, cellular & organismal levels. A typical eukaryote has the capacity to make 30,000 diff pro which catalyze 1000s diff rxns involving many 100s of metabolites, most shared by more than 1 pathway creating this metabolic map. -Both the amt & catalyctic activity of enzyme can be regulated: such changes occur from msec to hours: The total activity of an enzyme can be changed by: Adjusting the # of enzyme molecules/ Modifying activity of existing molecules effective activity in a subcellular compartment 1. Extracellular signals may be hormonal or 7. Enzyme binds to substrate depending on neuronal, growth factors or cytokines. The # [substrate] which can make a rxn of molecules of a given enzyme in a cell is a endo/exergonic. func of relative rates of synthesis & 8. Enzyme binds ligand: Enzyme activity can degradation of that enzyme be inc/dec by an allosteric effector. A small 2. The rate of synthesis can be adjusted by change in the [substrate/allosteric effector] activation of a transcription factor which are can have a large impact on rxn rate. nuclear pro that when activated bind 9. Enzyme undergoes de/phosphorylation: response elements near the gene’s promoter Covalent modifications of enzymes & other & activate/repress the expression of that pro occur w/in sec/min of a regulatory signal, gene. eg. extracellular signal via 3. The stability of mRNAs which is their de/phosphorylation. To be usefl, cell must be resistance to degradation varies & amt of able to restore the altered enzyme to its mRNA in the cell is a function of its rates of original activity state. synthesis & degradation. Their stability 10. Enzymes combine w/ regulatory pro: influences gene expression. many enz are regulated by assoc/dissoc 4. The rate at which mRNA is translated into from another regulatory pro/ a pro by ribosomes is also regulated. 5. Protein turnover differs from enzyme to enzyme & depends on the conditions in the cell. Some pro are tagged by ubiquitin for degradation in proteasomes. 6. Sequester enzyme & its substrate in diff compartments. The rate of transport of substrate across intracellular membranes may be the limiting factor in enzyme action. *By these several mechanisms for regulating enzyme level, cells can dramatically change their complement of enzymes in response to changes in metabolic circumstances, eg. in vertebrates, liver is the most adaptable tissue so when there’s a change from a high carb to high fat diet, transcription of 100s of genes & thus 100s of pro are affected. These changes can be quantified by using DNA microarrays that display transcriptome (entire complement of mRNAs present in a given cell/organ) or by 2-gel electrophoresis that displays proteome (pro complement of cell type/organ). The effect of changes in the proteome is often a change in the total ensemble of low molecular weight metabolites, metabolome. *Metabolic regulation refers to processes that serve to maintain homeostasis at the molecular level to hold the metabolite at a steady [ ] overtime even as the flow of metabolite through the path changes. Metabolic control refers to a process that leads to a change in the output of a metabolic pathway over time in response to an outside signal or changing conditions. Reactions far from equilibrium are frequently regulated Summary -Various signals activate/inactivate transcription factors which act in the nucleus to regulate gene expression. Changes in the transcriptome lead to changes in proteome & ultimately in the metabolome of a cell/tissue. -Rates of biochemcical reactions depend on many factors, eg. [reactants], activity of catalyst (depends on [ ] & intrinsic activity of enzyme) & [effectors] (eg. allosteric regulators, competing substrates, pH & ionic environment. PFK-1 is the rate determining step in glycolysis Examples of regulation/control of glycolysis & gluconeogenesis A. Glc to Frc 6-P: There is not usually a single rate-determining step in a pathway. Hexokinase & PFK-1 are appropriate targets for regulation of glycolytic flux b/c inc hexokinase activity enables activation of glc & inc PFK-1 activity enables catabolism of activated glc via glycolysis. Increasing amts of both were assoc’d w/ inc rates of glycolysis whereas phosphohexose isomerase (step 3 of gluconeogenesis) was w/o effect. Flux control in a pathway is distributed among enzymes in the pathway & flux inc through a pathway can be achieved by inc the amt of all enzymes in the pathway. B. Control of glycogen synthesis from blood glc: 5-step pathway from glc in the blood to glycogen in myocytes, aka insulin signalling pathway: 1) Pancreas beta cells detect high [glc] in the blood. 2) Insulin is secreted in response to high [glc] stimulating the inc of glc import into muscle cells via GLUT4. 3) Glc enters the cell stimulating the activity of muscle hexokinase, 4) undergoes a series of steps, ultimately activating glycogen synthase producing glycogen. *Metabolic control analysis suggests that when blood [glc] rises, insulin acts on muscle to inc glc transport into cells by conveying GLUT4 to the pm, induce synthesis of hexokinase & activate glycogen synthase by covalent alteration. The 1 2 effects of insulin inc glc flux through the pathway (control) & the 3 serves to adapt the activity of glycogen synthase so metabolite levels will no change dramatically w/ inc flux (regulation) C. Hexokinases: Hxk which catalyzes the entry of glc in glycolysis is a regulatory enzyme. Humans have 4 isoszymes encoded by 4 diff genes (Hxk I-IV). *When blood [glc] rises, Hxk IV activity inc but Hxk I-III are already operating near their maximal Vmax & can’t respond to further inc in [glc] but are sensitve to small amts of glc in which they are activated. a. Hxk I-III, predominant in myocytes has high glc affinity & is ½ saturated at 0.1mM. B/c glc from blood (5mM) produces intracellular [glc] high enough to saturate hxk I-III, enzyme normally acts at/near its maximal rate. They are allosterically inhibited by glc 6-P so when [glc 6-P] rises, Hxk I-II are temporarily/reversibly inhibited bringing homeostasis. Stimulated by activation of GLUT4 transporter. b. Hxk IV is the predominant hxk enzyme in the liver, aka glucokinase which differs from Hxk I-III. Hxk IV is regulated by GLUT2 transport, has low glc affinity & is ½ sat at [glc] of 10mM, much higher than blood [glc]. When blood [glc] is high as after a meal, hxk IV activity inc converting excess glc to glc 6- P stimulating glycolysis. B/c Hxk IV is not fully saturated at 10mM, its activity still continues to inc as [glc]>10mM; but not very active at low [glc] . HxkIV is not inhibitied by glc 6-P so it can continue to operate when accumulation of glc 6-P inhibits Hxk I-III. Hxk IV is subject to inhibition by irreversible binding of a liver-specific pro which is allosterically controlled. D. Allosteric regulation of Hexokinase IV in liver: The binding of Hxk IV to a specific regulator pro is much tighter in the presence of an allosteric effector, frc 6-P. Glc competes w/ frc 6-P for binding to the regulatory pro so when there’s high [glc], glc causes dissociation of the regulatory pro from Hxk IV relieving inhibition. Immediately after a rich meal, glc enters hepatocyte via GLUT2 & activates Hxk IV this way & thus proceeding to glycolysis. During a fast, when blood glc drops, frc 6-P triggers inhibition of Hxk IV by the regulatory pro so the liver doens’ compete w/ other organs for scarce glc. E. Transcriptional regulation of hxk activity: Increased transcription of Hxk IV gene in the liver stimulate glycolysis in the liver in response to low ATP, vigorous muscle contraction & high blood [glc] to inc glc consumption. Increased transcription of glc 6- P stimulates gluconeogenesis in the liver in response to low blood [glc] & glucagon signalling to inc production of glucose. F. 3 (PFK-1) commits to glycolysis: a. Allosteric regulation of PFK-1: PFK-1 is regulated by [ATP], its substrate & an end product of glycolysis. The PFK-1 rxn is the step that commits glc to glycolysis. Low [ATP], high [ADP/AMP], PFK-1 is more active. High [ATP], low [ADP/AMP, PFK-1 is less active b/c ATP
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