Session 21 - Regulation of Metabolism -- To now, 5.07 has been at the molecule to cell level -- Now we consider cell to organ and organ to organism levels athways (and sites of regulation) 1.) lycolysis (K / HK, / F16ase, K) 2.) T (DH; all steps that make NDH) 3.) N (, F16ase via F2,6, S / ) 4.) F atabolism (Malo T-I) 5.) F iosynthesis ( activated by Insulin) 6.) (DH stimulated by ND ) 7.) ET/xidative hosphorylation (D [ ] needed for H flow; NDH or FDH 2 needed for e flow to oxygen) Key organ systems and hormones Environment system responds to changes in environment Liver Kidney rain - integrates input from the environment Muscle -- Normal [] = 5 mm -- α-cell senses < 5mM - releases glucagon (liver N) -- β-cell senses > 5mM - releases insulin (fuel storage) ancreas drenals sense hunger α cells lucagon peptide hormones Insulin β cells sense "fed" state Epinephrine (drenaline) -- released from adrenal medulla in response to stress H HN 1 36 eneral aradigms of athway ontrol 1.) ovalent ("Hormonal") ontrol - covalent modification of enzyme affects activity - e.g., as we saw with in session 8 2.) llosteric ontrol - model = Hemoglobin - others: very sensitive to [M] (M activity) as well as F26 3.) "cceptor ontrol" - D = "cceptor" of i in ET/xidative hosphorylation - we already covered this in detail ovalent Regulation S rimary Regulator lycogen 1 I llosteric Regulation 1/2 2 2 H H 2 D i F16 F26 F1,6ase ET/xidative hosphorylation "cceptor ontrol" M NDH NDH ND D NDH NDH co NDH
aradigm I: ovalent ontrol S / S Regulation = rimarily by covalent post-translational modification of the enzymes inactive active Scenario = Stress revents "futile cycling" -- Liver (makes and stores fuel) - instructed to liberate from glycogen ( other organs) -- Muscle (run away or otherwise deal with stress) - instructed to absorb glucose and liberate from glycogen for local (in-muscle) use by glycolysis.) Second messenger initiates a "Kinase ascade" Mg 2 H R = Regulatory subunit = rotein kinase α 1 µm cm T 2 nd messenger Time 5 µm cm (2 mol) i R 4 cm (2 mol) 2 i Muscle or Liver ell - Top part of pathway is similar.) rimary messenger (Epinephrine) to secondary messender (cm) β γ cm δ SK δ SK (active) δ = calmodulin subunit (activated by a 2 ) α Epinephrine (~10-10 M) signal from brain signal from brain adrenals organs D signal 1 st messenger β-adrenergic receptor β, γ activates α T T denylate yclase i cm 2 nd messenger 2 i 1.) Hormone β-adrenergic receptor - signal transduced to -protein 2.) α subunit released - It is replaced by T - It is now "active" 3.) α-t activates 4.) makes cm (second messenger) lycogen (senses hunger) will do pretty much the same thing lycolysis in muscle glucose i H 2 In Liver exported ase M lycogen reakdown lycogen (n) (active) lycogen 1 (n - 1) Note that glycolysis is turned on & lycogen Synthase turned off (active) S lycogen Synthesis S hosphatase (-1) will remove residues to turn signal off 1.) cm dependent protein kinase K- 3.) - It is inhibited by R (its regulatory protein) 2.) K- phosphorylates SK SK Synthasephosphorylase kinase (Synthase = S ; hosphorylase = ) SK = active kinase 4.) In liver - glycogen other organs 1 37 5.) In muscle - use for energy (run away from stressor)
aradigm II: llostery (mostly) -- F2,6 / F16ase Scenario 2 (Liver post-stress) Regulation = rimarily by small molecule allosteric effector (or competitive inhibitor) = primary effector of glycolysis/n (M also has an effect) -- Made by omplicated enzyme M Kinase target (in muscle) F2,6 D F2,6 i K- target (α-anomer) (β-anomer) D F2,6 (β-anomer) -- Liver wants to turn on N to help muscles (& other organs) Stress cm cascade H 1 H H 2 2 1 H looks like F1,6! S i Scenario 1 (Liver, pre-stress state) α -- Net flux favors lycolysis Kinase site hosphatase site K F16ase H 2 This site is active (anomerization) F16... D N α β β-f2,6 F16ase lycolysis M ositive llosteric Effector - - - F16 Negative Effector (looks like substrate) = tetramer - suggests cooperativity clogs up the active site Scenario 3 (Muscle post-stress) D M Kinase D 6 H 1 38 1 H α-anomer Kinase K- activated K- hosphatase! ase destroys F26 β β-f2,6 H 2 i -- llosteric effector of is now absent - activity drops -- ctive site inhibitor of F16ase (F26) is destroyed - activity increases -- Net flux ( ) now favors gluconeogenesis This FK does the same thing as in anel FK but it is more active. MK = energy sensing kinase
Scenario 3 (Muscle post-stress) - continued lycolysis 1 39 -- favors lycolysis F16ase Muscle lacks F16ase because muscle does not do N (only liver and renal cortex do N) HK α F16 Energy!! cm cascade MK β - - otent generator of F26, which allosterically activates β-f2,6 M itrate ther Effectors -- is a tetramer, is subject to allosteric regulation, as well as covalent regulation -- = tetramer cooperativity -- lot is known about its activity in presence of M (senses energy need) and (energy surplus). ctivity 0.5mM M low or no (not realistic) 1mM (typical = 1-10 mm) condition plus 0.1mM M active enzyme in "relaxed" = R state -- M (allosteric activator) binds better to R than to -- Shifts to more active protein -- binds better to T state M inactive enzyme in "tense" = T state T T T T T
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