section 9: control of metabolism 2. control via hormones 12/9/05
TRANSCRIPT
Section 9: Section 9:
Control of MetabolismControl of Metabolism
2. Control via hormones2. Control via hormones
12/9/0512/9/05
How are metabolic pathways regulated?How are metabolic pathways regulated?
4 major control mechanisms4 major control mechanisms
control typecontrol type main featuresmain features
1. [substrate]1. [substrate] concentration of 1 substrate is rate-limitingconcentration of 1 substrate is rate-limiting2. allosterism2. allosterism activity of key (control) enzyme modulatedactivity of key (control) enzyme modulated
noncovalent; covalentnoncovalent; covalent
3. [enzyme]3. [enzyme] concentration of key enzyme varied,concentration of key enzyme varied,usually by controlling its rate of synthesis usually by controlling its rate of synthesis
4. hormones4. hormones intercellular signal factors that regulate & intercellular signal factors that regulate & coordinate intracellular processescoordinate intracellular processes
Control mechanisms 4. hormonesControl mechanisms 4. hormones
pathway/processpathway/process limiting factorlimiting factor activated byactivated by inhibited inhibited byby
glucose uptakeglucose uptake transport proteintransport protein insulininsulin cortisolcortisol(muscle, adipose)(muscle, adipose) (GLUT4) (GLUT4)
amino acid amino acid transporttransport insulininsulin cortisolcortisoluptakeuptake (muscle) (muscle) proteins proteins
glycogenolysisglycogenolysis phosphorylasephosphorylase epiepi (muscle) (muscle) insulininsulinglgnglgn (liver) (liver)
glycogenesisglycogenesis synthasesynthase insulininsulin epiepi (muscle) (muscle)glgnglgn (liver) (liver)
lipolysislipolysis lipaselipase epi, glgnepi, glgn insulininsulinepi = epinephrine; glgn = glucagonepi = epinephrine; glgn = glucagon
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HormonesHormones act by processes called act by processes called signal transduction cascadessignal transduction cascades
signal is conveyed & amplified by varied types of moleculessignal is conveyed & amplified by varied types of molecules a type of signal factor produced in very small amountsa type of signal factor produced in very small amounts carried in the blood from secretion site to target cellscarried in the blood from secretion site to target cells bind to bind to receptorsreceptors produce a response appropriate to the function of many cells produce a response appropriate to the function of many cells
or the body as a wholeor the body as a whole
Structural types of main metabolic hormonesStructural types of main metabolic hormones
derivatives of amino acidsderivatives of amino acids epinephrine, thyroxineepinephrine, thyroxine
steroidssteroids cortisolcortisol
peptidespeptides insulin, glucagoninsulin, glucagon22
Receptor(s)Receptor(s) target cell protein that:target cell protein that:
binds a signal molecule (ligand)binds a signal molecule (ligand) becomes activatedbecomes activated passes the signal alongpasses the signal along
so as to produce a responseso as to produce a response affinity for ligand affinity for ligand
usually highusually high response usually varies response usually varies
hyperbolicallyhyperbolically with [ligand]with [ligand]sometimes variessometimes varies
sigmoidallysigmoidally saturation behaviorsaturation behavior
0
20
40
60
80
100
0 50 100[ligand] nM
% r
esp
on
se
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Hormones with intracellular receptorsHormones with intracellular receptors sites of action (location of receptor binding site):sites of action (location of receptor binding site):
intracellularintracellular or or cell-surfacecell-surface (extracellular) (extracellular) "intracellular" hormones"intracellular" hormones
lipophilic or amphiphiliclipophilic or amphiphilic transported in blood bound to plasma proteintransported in blood bound to plasma protein enter cytosol of target cell by diffusionenter cytosol of target cell by diffusion bind to a bind to a receptor proteinreceptor protein the hormone-receptor protein complexthe hormone-receptor protein complex•enters the nucleus enters the nucleus •binds to DNA at a sequence called abinds to DNA at a sequence called ahormone (hormone (oror steroid) response element (HRE steroid) response element (HRE oror SRE) SRE)
•activates transcription of one or more genesactivates transcription of one or more genes44
Hormones: intracellularHormones: intracellular cortisol: cortisol:
main metabolic hormone that main metabolic hormone that acts intracellularly acts intracellularly
major major glucocorticoid*glucocorticoid* in humans in humans transported in plasma transported in plasma
~90% protein-bound~90% protein-bound free hormone diffuses free hormone diffuses
across plasma membraneacross plasma membrane hormone binds to hormone binds to
receptor protein in cytosolreceptor protein in cytosol complex enters nucleuscomplex enters nucleus
glucocorticoid glucocorticoid receptor proteinreceptor protein
OH
O
OH OH
O
cortisol
* [glucose]-regulating adrenal cortex hormones* [glucose]-regulating adrenal cortex hormones
steroid steroid hormonehormone
corticosteroid-corticosteroid-binding globulinbinding globulin
nucleusnucleus
cytosolcytosol++
++
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Intracellular hormones: nuclear effectsIntracellular hormones: nuclear effects in the nucleus, the complex binds in the nucleus, the complex binds
to DNA at HRE called the to DNA at HRE called the gluco-gluco-corticoid response elementcorticoid response element (GRE) (GRE)
numerous genes activatednumerous genes activatede.g.e.g., for transamination,, for transamination,gluconeogenesis enzymesgluconeogenesis enzymes
receptor's DNA binding domain receptor's DNA binding domain has has recognition helicesrecognition helices that are that arepart of motifs called part of motifs called zinc fingerszinc fingers
numerous other hormones & signal factors exert their effects numerous other hormones & signal factors exert their effects via similar mechanism:via similar mechanism:the other steroid hormonesthe other steroid hormones thyroxine thyroxinevitamin D hormonesvitamin D hormones carotenoids carotenoids
group of receptors called the group of receptors called the nuclear receptor superfamilynuclear receptor superfamily
GREGRE
DNADNA
nucleusnucleus
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DNA-binding domain of hormone receptorDNA-binding domain of hormone receptor
Stryer, 4 ed., Stryer, 4 ed., Figs. 37-33, 37-34Figs. 37-33, 37-34(cf. 5 ed., Fig. 31.22)(cf. 5 ed., Fig. 31.22)
majormajorgroovegroove
F2
F3
F1
recognition helices of recognition helices of 3 Zn fingers (F1, F2 & F3)3 Zn fingers (F1, F2 & F3)bound to DNAbound to DNA
ds DNA
Zinc finger motif
recognition recognition helixhelix
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Hormones: cell-surfaceHormones: cell-surface receptor proteinreceptor protein
spans plasma membranespans plasma membrane member of receptor familymember of receptor family
called 7TM* receptorscalled 7TM* receptors hormone binding site hormone binding site
interfaces with extracellular fluidinterfaces with extracellular fluid hormone binds reversibly viahormone binds reversibly via
complementary noncovalentcomplementary noncovalentinteractions (NCIs)interactions (NCIs)
binding activates G protein, binding activates G protein, causing GTP to replace GDPcausing GTP to replace GDPbound to bound to subunit subunit
*seven-TransMembrane-helix *seven-TransMembrane-helix ((see Fig. 15.3see Fig. 15.3))88
from from Fig. 21.14Fig. 21.14
7TM receptor7TM receptorproteinprotein
7TM receptors: 7TM receptors: structure & functionsstructure & functions
seven-transmembrane-helix seven-transmembrane-helix Fig. 15.3Fig. 15.3
Fig. 15.3Fig. 15.3
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Adenylate cyclase activationAdenylate cyclase activation subunit (Gsubunit (G) dissociates) dissociates
from the other subunits (Gfrom the other subunits (G)) GG diffuses anchored to to diffuses anchored to to
membrane, binds to & membrane, binds to & activates adenylate cyclase activates adenylate cyclase
a small fraction ofa small fraction ofATP is converted toATP is converted tocyclic AMP (cAMP)cyclic AMP (cAMP)
cyclic AMP is called acyclic AMP is called asecond messengersecond messenger(intracellular messenger)(intracellular messenger)
ATP
cAMP + PPi
from from Fig. 21.14Fig. 21.141010
GTP
adenylateadenylatecyclasecyclase
GG
Protein kinase AProtein kinase A cyclic AMP activates protein kinase A cyclic AMP activates protein kinase A
by binding to its inhibitory subunits, by binding to its inhibitory subunits, which dissociate (which dissociate (S9L1slide17S9L1slide17))
catalytic subunit can now catalytic subunit can now phosphorylate phosphorylate target enzymestarget enzymes at specific at specific serser//thr thr side chainsside chains ( (S9L1slide18S9L1slide18))
tissuetissue target enzymetarget enzymeadiposeadipose lipase (lipase (S7L1S7L1))
liver, muscleliver, muscle glycogenglycogen synthase & synthase &phosphorylasephosphorylase kinase ( kinase (S6L2S6L2)) targettarget
enzymeenzyme
ATPATP ADPADP
targettargetenzymeenzyme -P-P
CC
R R
CR R
+ 4 cyclic AMP+ 4 cyclic AMP
allosteric control site
C
1111
Activation of Activation of glycogenolysisglycogenolysis
in liver & muscle, in liver & muscle, activated protein kinase A activated protein kinase A activates phosphorylase activates phosphorylase kinasekinase
activated phosphorylaseactivated phosphorylasekinase activates glycogen kinase activates glycogen phosphorylasephosphorylase
activated phosphorylase activated phosphorylase removes glycogen’s glc units removes glycogen’s glc units as glucose 1-phosphateas glucose 1-phosphate
protein kinase Aprotein kinase A(C subunit)(C subunit)
phosphorylasephosphorylase phosphorylasephosphorylasekinasekinase kinasekinase--PP
glycogenglycogen glycogenglycogenphosphorylasephosphorylase phosphorylasephosphorylase--PP
ATPATP ADP
ATPATP ADPADP
Pi + glycogen (glc)Pi + glycogen (glc)nn
glycogen (glc)glycogen (glc)nn–1–1 + glc 1-phosphate + glc 1-phosphate
glc 6-phosphateglc 6-phosphate
GLYCOLYSISGLYCOLYSIS
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Deactivation ofDeactivation ofglycogenesisglycogenesis
glycogen synthase is active glycogen synthase is active in in ununphosphorylated formphosphorylated form
activated protein kinase A activated protein kinase A phosphorylates synthasephosphorylates synthase
phosphorylated synthase phosphorylated synthase is is not not activeactive
result:result:when protein kinase A is active, glycogenesis stoppedwhen protein kinase A is active, glycogenesis stopped
net result of hormone binding is coordinated:net result of hormone binding is coordinated: activation of activation of glycogenolysisglycogenolysis inhibition of inhibition of glycogenesisglycogenesis
proteinproteinkinase Akinase A
glycogenglycogen glycogenglycogensynthasesynthase synthasesynthase--PP
ATPATP ADPADP
UDP-glc + UDP-glc +
glycogen (glc)glycogen (glc)nn
UDP + glycogen (glc)UDP + glycogen (glc)nn+1+1
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Cell-surface hormones: reversal of effectsCell-surface hormones: reversal of effects processes activated by hormone binding are reversed byprocesses activated by hormone binding are reversed by
hormone dissociation & degradationhormone dissociation & degradation second messenger destruction by second messenger destruction by phosphodiesterasephosphodiesterase::
cyclic AMP + Hcyclic AMP + H22O → 5'-AMPO → 5'-AMP G protein inactivation:G protein inactivation:
• slow hydrolysis of slow hydrolysis of -subunit-bound GTP to-subunit-bound GTP toGDPGDP• GGGDPGDP subunit then rebinds to subunit then rebinds to subunits subunits
protein phosphatasesprotein phosphatases catalyze removal of phosphoryl catalyze removal of phosphoryl groups (groups (insulin-activated)insulin-activated)
protein-protein-PP + H+ H22O O → → protein + Pprotein + Pii
e.g., glycogen phosphorylase-e.g., glycogen phosphorylase-PP +H +H22O →O →
glycogen phosphorylase (inactive)glycogen phosphorylase (inactive)1414
Summary of glycogen mobilization by hormone-activated signal transduction cascade
100x
10,000x
1000x
Signal amplificationx molecules of hormoneresults in downstream:
Fig. 21.14
15
Summary of Fatty Acid Mobilization (S7L1slide8)Summary of Fatty Acid Mobilization (S7L1slide8)
note that the steps are the same through activation of protein kinase note that the steps are the same through activation of protein kinase 1616
Fig. 22.6
Hormones: cell-surface receptor site via Hormones: cell-surface receptor site via tyrtyr kinase activation kinase activation hormone (insulin) binds at hormone (insulin) binds at
receptor sites on receptor sites on subunits subunits this activates intracellular this activates intracellular
tyrtyr kinase domains kinase domains on on subunits subunits
these domains phosphorylate these domains phosphorylate one anotherone another #1 phosphorylates #2#1 phosphorylates #2 #2 phosphorylates #1#2 phosphorylates #1 cross-phosphorylation cross-phosphorylation
(autophosphorylation)(autophosphorylation)
result:result: these domains’ these domains’ tyrtyr kinase kinase activity is increasedactivity is increased PP
tyrosinetyrosinekinasekinasedomainsdomains
insulin bound to receptorsinsulin bound to receptors
cross-cross-phosphorylationphosphorylation
site site
1 2
plasmamembrane
Lehninger et al., 3rd ed., Fig. 13-6
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tyrtyr kinase activity: effects kinase activity: effects activated activated tyrtyr kinase domains kinase domains
phosphorylate intracellular phosphorylate intracellular signal factors signal factors (target proteins)(target proteins)
target proteins cause:target proteins cause: activation of transportactivation of transport
(next slide)(next slide) activation/deactivation of activation/deactivation of
specific pathwaysspecific pathways
(see Table on slide 22)(see Table on slide 22) phosphorylated state slowly phosphorylated state slowly
reversed by specific protein reversed by specific protein phosphatasesphosphatases
PP
PP
TyrTyr
TyrTyr
ADPADP
ATPATP
produces produces intracellularintracellularinsulin effectsinsulin effects
targettargetproteinprotein
PP
1 2
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Insulin & Insulin & GLUT4GLUT4 at high [glc],at high [glc],
facilitated facilitated diffusiondiffusionmediated by mediated by GLUT4GLUT4(muscle & (muscle & adipose)adipose)
similar similar mechanismmechanismoperates foroperates fortransport of transport of amino acidsamino acidsinto muscleinto muscle
GLUT4(glucosetransporter)
GLUT4 “stored”in vesicles
insulin binding activates exocytosis
as [insulin], endocytosis removes GLUT4
endo-some
fusion
budding
Lehninger et al.,3rd ed., p. 4141919
Major metabolic hormones: overviewMajor metabolic hormones: overviewhormonehormone sourcesource stimulusstimulus general functiongeneral function
epinephrineepinephrine adrenaladrenal alarmalarm mobilize fuelsmobilize fuelsmedullamedulla (neural)(neural)
glucagonglucagon cells of cells of blood blood maintain bloodmaintain bloodpancreas pancreas [glucose][glucose] [glucose],[glucose], [fatty ac][fatty ac]
cortisolcortisol adrenaladrenal bloodblood maintain bloodmaintain bloodcortexcortex [glucose] [glucose] [glucose] &[glucose] &
(via ACTH)(via ACTH) [fatty acids][fatty acids]
insulininsulin cells of cells of blood blood stim. anabolismstim. anabolismpancreas pancreas [glucose] [glucose] (synthesis,(synthesis,
fuel storage) fuel storage)
2020
Major catabolic hormonesMajor catabolic hormoneshormonehormone molec. mechanismmolec. mechanism targets targets effects effects
epineph-epineph- cell-surfacecell-surface musclemuscle glycogenolysis glycogenolysisrinerine receptorreceptor//cAMPcAMP
glucagon glucagon cell-surfacecell-surface liverliver glycogenolysis glycogenolysis receptorreceptor//cAMPcAMP
cortisolcortisol intracellularintracellular receptorreceptor// transcriptiontranscription
adiposeadipose lipolysis lipolysis
adiposeadipose lipolysis lipolysis
most cellsmost cells protein protein synthesis synthesis
adiposeadipose enzymes for enzymes for lipolysis lipolysis
liverliver enzymes enzymes for aa for aa glcglc
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Major anabolic hormone: insulinMajor anabolic hormone: insulinmolec. mechanismmolec. mechanism targetstargets effectseffects
cell-surfacecell-surface musclemuscle amino acids, glc uptake* amino acids, glc uptake* receptorreceptor//
tyrtyrkinasekinaseactivation activation glycogenesis glycogenesis
mostmost protein synthesis protein synthesis cells cells glycogenolysis glycogenolysis gluconeogenesisgluconeogenesis
{* via stimulation of fusion of vesicles containing* via stimulation of fusion of vesicles containing transmembrane GLUT4 with cell membrane transmembrane GLUT4 with cell membrane
adiposeadipose glc uptake*, glc uptake*, lipolysis lipolysis
2222
Control of metabolism: Control of metabolism: fill in the blanksfill in the blanks
FATSFATS GLYCOGENGLYCOGEN PROTEINSPROTEINS
fatty acids+ glycerolfatty acids+ glycerol glucose 6-Pglucose 6-P
pyruvatepyruvate
amino acidsamino acids
acetyl CoAacetyl CoA
KrebsKrebscyclecycle
ee––
COCO22
oxidativeoxidativephosphorylationphosphorylation
CoACoAATP ATP ADP + PADP + Pii
HH22O OO O22
vv
vv
2323
oxaloacetateoxaloacetate
NAD+
Web linksWeb links Peptide hormonesPeptide hormones
Resource on the structure & function of various families of hormones, Resource on the structure & function of various families of hormones, which induce many important signal-transduction cascades. Also included which induce many important signal-transduction cascades. Also included are a summary table of structures and functions, as well as descriptions of are a summary table of structures and functions, as well as descriptions of hormone receptors, second-messenger molecules, & related diseases. hormone receptors, second-messenger molecules, & related diseases.
Medical Biochemistry Page, Terre Haute Cntr for Medical EducationMedical Biochemistry Page, Terre Haute Cntr for Medical Education Steroid hormonesSteroid hormones
Companion to Peptide Hormones site (above), this site covers the Companion to Peptide Hormones site (above), this site covers the important characteristics of steroids such as testosterone and cortisol important characteristics of steroids such as testosterone and cortisol and their role in signal transduction.and their role in signal transduction.
Insulin and DiabetesInsulin and Diabetes This Web site defines and describes the many forms of diabetes, one of 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 best-known metabolic diseases. It includes a thorough discussion of the clinical aspects of the disease, as well as its biochemical and the clinical aspects of the disease, as well as its biochemical and physiological characteristics.Created by Michael King of the Terre Haute physiological characteristics.Created by Michael King of the Terre Haute Center.Center.
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