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Section 9: Control of Metabolism

Section 9: Control of Metabolism. 2. Control via hormones. 12/9/05. How are metabolic pathways regulated?. 4 major control mechanisms control type main features 1. [substrate] concentration of 1 substrate is rate-limiting 2. allosterism activity of key (control) enzyme modulated

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Section 9: Control of Metabolism

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  1. Section 9: Control of Metabolism 2. Control via hormones 12/9/05

  2. How are metabolic pathways regulated? 4 major control mechanisms control type main features 1. [substrate] concentration of 1 substrate is rate-limiting 2. allosterism activity of key (control) enzyme modulated noncovalent; covalent 3. [enzyme] concentration of key enzyme varied, usually by controlling its rate of synthesis 4. hormones intercellular signal factors that regulate & coordinate intracellular processes 7

  3. Control mechanisms 4. hormones pathway/process limiting factor activated by inhibited by glucose uptake transport protein insulin cortisol(muscle, adipose) (GLUT4) amino acid transport insulin cortisoluptake (muscle) proteins glycogenolysis phosphorylase epi (muscle) insulin glgn (liver) glycogenesis synthase insulin epi (muscle) glgn (liver) lipolysis lipase epi, glgn insulin epi = epinephrine; glgn = glucagon 1

  4. Hormones • act by processes called signal transduction cascades • signal is conveyed & amplified by varied types of molecules • a type of signal factor produced in very small amounts • carried in the blood from secretion site to target cells • bind to receptors • produce a response appropriate to the function of many cells or the body as a whole Structural types of main metabolic hormones derivatives of amino acidsepinephrine, thyroxine steroids cortisol peptides insulin, glucagon 2

  5. Receptor(s) • target cell protein that: • binds a signal molecule (ligand) • becomes activated • passes the signal alongso as to produce a response • affinity for ligand usually high • response usually varies hyperbolicallywith [ligand] • sometimes variessigmoidally • saturation behavior 3

  6. Hormones with intracellular receptors • sites of action (location of receptor binding site):intracellular or cell-surface (extracellular) • "intracellular" hormones • lipophilic or amphiphilic • transported in blood bound to plasma protein • enter cytosol of target cell by diffusion • bind to a receptor protein • the hormone-receptor protein complex • enters the nucleus • binds to DNA at a sequence called ahormone (or steroid) response element (HRE or SRE) • activates transcription of one or more genes 4

  7. Hormones: intracellular • cortisol: • main metabolic hormone that acts intracellularly • major glucocorticoid* in humans • transported in plasma ~90% protein-bound • free hormone diffuses across plasma membrane • hormone binds to receptor protein in cytosol • complex enters nucleus corticosteroid-binding globulin Harper's 23 edp.528: 8% plasmacort unbound º + cytosol steroid hormone + º glucocorticoid receptor protein nucleus * [glucose]-regulating adrenal cortex hormones 5

  8. Intracellular hormones: nuclear effects • in the nucleus, the complex binds to DNA at HRE called the gluco-corticoid response element (GRE) • numerous genes activated e.g., for transamination,gluconeogenesis enzymes • receptor's DNA binding domain has recognition helices that arepart of motifs called zinc fingers • numerous other hormones & signal factors exert their effects via similar mechanism: • the other steroid hormones l thyroxine • vitamin D hormones l carotenoids • group of receptors called the nuclear receptor superfamily DNA GRE nucleus StryerF37-33&34 6

  9. DNA-binding domain of hormone receptor F3 recognition helix majorgroove F2 F1 Zinc finger motif Stryer, 4 ed., Figs. 37-33, 37-34(cf. 5 ed., Fig. 31.22) recognition helices of 3 Zn fingers (F1, F2 & F3)bound to DNA ds DNA 7

  10. receptor protein spans plasma membrane member of receptor familycalled 7TM* receptors hormone binding site interfaces with extracellular fluid hormone binds reversibly viacomplementary noncovalentinteractions (NCIs) binding activates G protein, causing GTP to replace GDPbound to a subunit Hormones: cell-surface 7TM receptorprotein a g b *seven-TransMembrane-helix (see Fig. 15.3) from Fig. 21.14 8

  11. 7TM receptors: structure & functions Table: from CD slide;negative, bkrnd trnsp wPhotoed, brit incr in PPT Fig. 15.3 F15.3A: fr CD gif Fig,80%, trnsp in Photoed F15.3B: fr CD slide,70%, trnsp in Photoed seven-transmembrane-helix Fig. 15.3 9

  12. Adenylate cyclase activation adenylatecyclase • a subunit (Ga) dissociatesfrom the other subunits (Gbg) • Ga diffuses anchored to to membrane, binds to & activates adenylate cyclase • a small fraction ofATP is converted tocyclic AMP (cAMP) • cyclic AMP is called asecond messenger(intracellular messenger) ATP cAMP + PPi GTP Ga from Fig. 21.14 10

  13. Protein kinase A allosteric control site • cyclic AMP activates protein kinase A by binding to its inhibitory subunits, which dissociate (S9L1slide17) • catalytic subunit can now phosphorylate target enzymesat specific ser/thr side chains (S9L1slide18) tissue target enzyme adipose lipase (S7L1) liver, muscle glycogen synthase & phosphorylase kinase (S6L2) C C R R + 4 cyclic AMP C R R C ADP ATP targetenzyme targetenzyme-P 11

  14. protein kinase A (C subunit) phosphorylase phosphorylasekinase kinase-P glycogen glycogen phosphorylase phosphorylase-P Activation of glycogenolysis ADP ATP • in liver & muscle, activated protein kinase A activates phosphorylase kinase • activated phosphorylasekinase activates glycogen phosphorylase • activated phosphorylase removes glycogen’s glc units as glucose 1-phosphate ADP ATP Pi + glycogen (glc)n glycogen (glc)n–1 + glc 1-phosphate ¯glc 6-phosphate¯GLYCOLYSIS 12

  15. Deactivation ofglycogenesis protein kinase A glycogen glycogensynthase synthase-P ADP ATP • glycogen synthase is active in unphosphorylated form • activated protein kinase A phosphorylates synthase • phosphorylated synthase is not activeresult:when protein kinase A is active, glycogenesis stopped • net result of hormone binding is coordinated: • activation of glycogenolysis • inhibition of glycogenesis UDP-glc + glycogen (glc)n UDP + glycogen (glc)n+1 13

  16. Cell-surface hormones: reversal of effects • processes activated by hormone binding are reversed by • hormone dissociation & degradation • second messenger destruction by phosphodiesterase: cyclic AMP + H2O → 5'-AMP • G protein inactivation: • slow hydrolysis of a-subunit-bound GTP toGDP • GaGDP subunit then rebinds to bg subunits • protein phosphatases catalyze removal of phosphoryl groups (insulin-activated) protein-P+ H2O → protein + Pi e.g., glycogen phosphorylase-P +H2O → glycogen phosphorylase (inactive) add F 15.9 ? Stryer, 596-8 14

  17. Summary of glycogen mobilization by hormone-activated signal transduction cascade Fig. 21.14 Signal amplification x molecules of hormoneresults in downstream: 100x 1000x 10,000x 15

  18. Summary of Fatty Acid Mobilization (S7L1slide8) note that the steps are the same through activation of protein kinase Fig. 22.6 16

  19. P Hormones: cell-surface receptor site via tyr kinase activation insulin bound to receptors Lehninger et al., 3rd ed., Fig. 13-6 • hormone (insulin) binds at receptor sites on a subunits • this activates intracellular tyr kinase domains on b subunits • these domains phosphorylate one another • #1 phosphorylates #2 • #2 phosphorylates #1 • cross-phosphorylation (autophosphorylation) • result: these domains’ tyr kinase activity is increased plasmamembrane 2 1 tyrosinekinasedomains cross-phosphorylation site 17

  20. P P P tyr kinase activity: effects • activated tyr kinase domains phosphorylate intracellular signal factors (target proteins) • target proteins cause: • activation of transport(next slide) • activation/deactivation of specific pathways (see Table on slide 22) • phosphorylated state slowly reversed by specific protein phosphatases 2 ATP 1 Tyr ADP targetprotein Tyr produces intracellularinsulin effects 18

  21. insulin binding activates exocytosis Insulin & GLUT4 • at high [glc],facilitated diffusionmediated by GLUT4(muscle & adipose) • similar mechanismoperates fortransport of amino acidsinto muscle GLUT4(glucosetransporter) GLUT4 “stored”in vesicles as [insulin]¯, endocytosis removes GLUT4 budding fusion endo-some produce intracellularinsulin effects Lehninger et al.,3rd ed., p. 414 19

  22. Major metabolic hormones: overview hormonesource stimulus general function epinephrine adrenal alarm mobilize fuels medulla (neural) glucagon a cells of  blood maintain blood pancreas [glucose] [glucose],[fatty ac] cortisol adrenal blood maintain blood cortex [glucose] [glucose] & (via ACTH) [fatty acids] insulin b cells of  blood stim. anabolism pancreas [glucose] (synthesis, fuel storage) 20

  23. Major catabolic hormones hormonemolec. mechanism targets effects epineph- cell-surface muscle  glycogenolysisrine receptor/cAMP glucagon cell-surface liver  glycogenolysis receptor/cAMP cortisol intracellular receptor/ transcription adipose  lipolysis adipose  lipolysis liver  enzymes for aa  glc adipose  enzymes for lipolysis most cells  protein synthesis 21

  24. Major anabolic hormone: insulin molec. mechanism targets effects cell-surface muscle  amino acids, glc uptake* receptor/tyrkinaseactivation  glycogenesis most  protein synthesis cells glycogenolysis gluconeogenesis adipose  glc uptake*,  lipolysis { * via stimulation of fusion of vesicles containing transmembrane GLUT4 with cell membrane 22

  25. Control of metabolism: fill in the blanks GLYCOGEN FATS PROTEINS    glucose 6-Ppyruvate fatty acids+ glycerol amino acids  NAD+ acetyl CoA  CoA ATP ADP + Pi oxaloacetate e–CO2 Krebscycle oxidativephosphorylation v  v 23 H2O O2

  26. Web links • Peptide hormonesResource on the structure & function of various families of hormones, which induce many important signal-transduction cascades. Also included are a summary table of structures and functions, as well as descriptions of hormone receptors, second-messenger molecules, & related diseases. Medical Biochemistry Page, Terre Haute Cntr for Medical Education • Steroid hormonesCompanion to Peptide Hormones site (above), this site covers the important characteristics of steroids such as testosterone and cortisol and their role in signal transduction. • Insulin and DiabetesThis Web site defines and describes the many forms of diabetes, one of the best-known metabolic diseases. It includes a thorough discussion of the clinical aspects of the disease, as well as its biochemical and physiological characteristics.Created by Michael King of the Terre Haute Center. 24

  27. Next:Integration of metabolism

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