Transcript Control Mechanisms: Hormones

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
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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
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•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
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* [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
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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

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*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)
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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
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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
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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:

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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




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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
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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
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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
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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)

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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

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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
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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
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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
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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
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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.
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Integration of metabolism