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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] 2. allosterism 3. [enzyme] 4. hormones concentration of 1 substrate is rate-limiting activity of key (control) enzyme modulated noncovalent; covalent concentration of key enzyme varied, usually by controlling its rate of synthesis intercellular signal factors that regulate & coordinate intracellular processes Control mechanisms 4. hormones pathway/process limiting factor glucose uptake activated by inhibited by transport protein insulin (muscle, adipose) (GLUT4) amino acid uptake (muscle) transport proteins insulin glycogenolysis phosphorylase glycogenesis synthase epi (muscle) glgn (liver) insulin lipolysis lipase epi, glgn epi = epinephrine; glgn = glucagon 1 cortisol cortisol insulin epi (muscle) glgn (liver) insulin 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 acids steroids peptides epinephrine, thyroxine cortisol insulin, glucagon 2 Receptor(s) target cell protein that: binds a signal molecule (ligand) becomes activated passes the signal along 100 so as to produce a response for ligand usually high response usually varies hyperbolically with [ligand] sometimes varies sigmoidally saturation behavior 3 80 % response affinity 60 40 20 0 0 50 [ligand] nM 100 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 4 •enters the nucleus •binds to DNA at a sequence called a hormone (or steroid) response element (HRE or SRE) •activates transcription of one or more genes Hormones: intracellular HO O OH cortisol corticosteroidbinding globulin steroid hormone + cytosol + 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 OH O glucocorticoid receptor protein 5 * [glucose]-regulating adrenal cortex hormones nucleus Intracellular hormones: nuclear effects in the nucleus, the complex binds to DNA at HRE called the glucocorticoid response element (GRE) numerous genes activated e.g., for transamination, gluconeogenesis enzymes DNA GRE receptor's DNA binding domain nucleus has recognition helices that are part of motifs called zinc fingers numerous other hormones & signal factors exert their effects via similar mechanism: the other steroid hormones vitamin D hormones group 6 thyroxine l carotenoids l of receptors called the nuclear receptor superfamily DNA-binding domain of hormone receptor F3 recognition helix major groove F2 F1 Zinc finger motif Stryer, 4 ed., Figs. 37-33, 37-34 (cf. 5 ed., Fig. 31.22) 7 ds DNA recognition helices of 3 Zn fingers (F1, F2 & F3) bound to DNA Hormones: cell-surface receptor protein spans plasma membrane member of receptor family called 7TM* receptors hormone binding site interfaces with extracellular fluid hormone binds reversibly via complementary noncovalent interactions (NCIs) binding activates G protein, causing GTP to replace GDP bound to a subunit 8 *seven-TransMembrane-helix (see Fig. 15.3) 7TM receptor protein a b from Fig. 21.14 g 7TM receptors: structure & functions Fig. 15.3 9 Adenylate cyclase activation a subunit (Ga) dissociates from the other subunits (Gbg) Ga diffuses anchored to to membrane, binds to & activates adenylate cyclase a small fraction of ATP is converted to cyclic AMP (cAMP) cyclic AMP is called a second messenger (intracellular messenger) 10 adenylate cyclase ATP Ga GTP cAMP + PPi from Fig. 21.14 Protein kinase A cyclic AMP activates protein kinase A by binding to its inhibitory subunits, allosteric which dissociate (S9L1slide17) control site catalytic subunit can now C phosphorylate target enzymes R at specific ser/thr side chains (S9L1slide18) tissue adipose liver, muscle 11 target enzyme lipase (S7L1) glycogen synthase & phosphorylase kinase (S6L2) C R + 4 cyclic AMP C ATP target enzyme R R ADP target enzyme -P C Activation of glycogenolysis protein kinase A (C subunit) ATP phosphorylase kinase ADP phosphorylase kinase-P ATP in ADP glycogen glycogen liver & muscle, phosphorylase-P activated protein kinase A phosphorylase activates phosphorylase Pi + glycogen (glc)n kinase activated phosphorylase glycogen (glc)n–1 + glc 1-phosphate kinase activates glycogen phosphorylase glc 6-phosphate activated phosphorylase removes glycogen’s glc units GLYCOLYSIS as glucose 1-phosphate 12 Deactivation of glycogenesis protein kinase A ATP glycogen synthase is active in unphosphorylated form activated protein kinase A phosphorylates synthase phosphorylated synthase is not active glycogen synthase ADP glycogen synthase-P UDP-glc + glycogen (glc)n UDP + glycogen (glc)n+1 result: 13 when protein kinase A is active, glycogenesis stopped net result of hormone binding is coordinated: activation of glycogenolysis inhibition of glycogenesis Cell-surface hormones: reversal of effects processes 14 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) Fig. 21.14 Summary of glycogen mobilization by hormoneactivated signal transduction cascade 15 Signal amplification x molecules of hormone results in downstream: 100x 1000x 10,000x Summary of Fatty Acid Mobilization (S7L1slide8) Fig. 22.6 note that the steps are the same through activation of protein kinase 16 Hormones: cell-surface receptor site via insulin bound to receptors tyr kinase activation Lehninger hormone (insulin) binds at receptor sites on a subunits this activates intracellular tyr kinase domains on b subunits these domains phosphorylate one another et al., 3rd ed., Fig. 13-6 plasma membrane #1 phosphorylates #2 #2 phosphorylates #1 cross-phosphorylation (autophosphorylation) result: these domains’ tyr kinase activity is increased 17 2 1 P tyrosine kinase domains crossphosphorylation site 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) 18 phosphorylated state slowly reversed by specific protein phosphatases ATP 2 1 Tyr P P ADP target protein P Tyr produces intracellular insulin effects Insulin & GLUT4 at high [glc], facilitated diffusion mediated by GLUT4 (muscle & adipose) similar mechanism operates for transport of amino acids into muscle insulin binding activates exocytosis 19 GLUT4 (glucose transporter) GLUT4 “stored” in vesicles as [insulin], endocytosis removes GLUT4 budding fusion endosome Lehninger et al., 3rd ed., p. 414 Major metabolic hormones: overview hormone source stimulus general function epinephrine adrenal medulla alarm (neural) mobilize fuels glucagon a cells of pancreas blood [glucose] maintain blood [glucose], [fatty ac] cortisol adrenal cortex blood [glucose] maintain blood [glucose] & (via ACTH) [fatty acids] blood [glucose] stim. anabolism (synthesis, fuel storage) insulin 20 b cells of pancreas Major catabolic hormones hormone molec. mechanism targets effects epinephrine muscle glycogenolysis adipose lipolysis glucagon cell-surface receptor/cAMP liver glycogenolysis adipose lipolysis cortisol liver enzymes for aa glc cell-surface receptor/cAMP intracellular receptor/ transcription adipose enzymes for lipolysis most cells protein synthesis 21 Major anabolic hormone: insulin molec. mechanism targets effects cell-surface receptor/ tyr kinase activation muscle amino acids, glc uptake* adipose glc uptake*, lipolysis most cells glycogenesis protein synthesis glycogenolysis gluconeogenesis { * via stimulation of fusion of vesicles containing transmembrane GLUT4 with cell membrane 22 Control of metabolism: fill in the blanks GLYCOGEN FATS pyruvate acetyl CoA ADP + Pi O2 oxaloacetate e– CO2 v oxidative phosphorylation amino acids NAD+ H2O glucose 6-P fatty acids+ glycerol ATP PROTEINS Krebs cycle CoA v 23 Web links Peptide hormones Resource 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 hormones Companion 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 Diabetes This 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 Next: Integration of metabolism