Download Glycogen metabolism: synthesis, degradation, regulation

Glycogen metabolism: synthesis,
degradation, regulation
Glycogen storage diseases
The glycogen is helical,
branched, spherical
particle, it is full of water
many-many nonreducing
free 4-OH ends where
it is elongated and
degraded
1-1piece of reducing
glycosidic 1.OH, it is bound
to glycogenin protein dimer,
glycogenin makes the first
about 8 glucose containing
part of glycogen, the protein
remains in the middle.
Glycogen is a storage form of glucose,
every other carbohydrate can be formed from glucose,
when glucose is degraded, ATP or NADPH or
UDP-glucuronic acid can be produced
lactose in lactating
mammary gland
UDP-glucuronate
amino sugars
Glycogen degradation = glycogenolysis in cells
1 enzyme
2 kind of activity:
bifunctional E
Remember: every carbohydrate degrading enzyme in gut is a hydrolase
Glycogen phosphorylase
PLP: general
acid-base catalist
homodimer
phosphorolysis =
cleavage by Pi and
Pi builds in,
it occurs without water
Debranching enzyme = α-1,6-glucosidase
produces free glucose
hexokinases
out of cell to blood
from liver and
kidney cortex
glucose-6P
extrahepatically,
converted further in the cell
Fate of glucose depends on the organ
phosphoglucomutase
to other organs
↑
glucose to blood
GLUT-2
glycolysis - everywhere,
PDHC,
if mt.
citric acid cycle,
oxidat. phosph. exist
ATP
only: liver,
kidney cortex
Absorption of glucose, fructose, and galactose. Glucose (glu),
fructose (fru) and galactose (gal) derived from ingested carbohydrate
containing foods enter the portal vein and are carried to the liver. The
liver rapidly clears fru and gal from the circulation and a large proportion
is stored as glycogen. Glucose on the other hand goes through the liver into
the peripheral circulation where it stimulates insulin secretion
Journal of the American College of Nutrition, Vol. 26, No. 2, 83–94 (2007
UDP-glucose formation before:
uronic acid pathway, glycogen synthesis or lactose synthesis
glucose from blood
↓hexokinases
glu-6P
phosphoglucomutase
epimeráz
UDP-gal
glu-1P
gal-1P-uridyltransferase
UDP-glu
gal-1P
galactokinase
gal from blood
stored glycogen
↓
glu-1P
UTP
glu-1P-uridyltransferase
PP
UDP-glu
Fate of glu, gal, fru can be: degradation to
ATP, glycogen synthesis or lipogenesis
In liver
GLUT-2
transports
all the 3
hexoses,
only glucose
goes into
both direction
with high
capacity
Pathways of glucose, galactose and fructose metabolism in liver. Glucose, galactose and
fructose all serve as substrates for glycogen synthesis. In addition, as indicated in Fig. 1, all
regulate the activity of glycogen synthase
Journal of the American College of Nutrition, Vol. 26, No. 2, 83–94 (2007
Glycogenesis: glycogen synthase
primer: existing glycogen
Glycogen de novo synthesis after it was consumed,
or if we produce more glycogen particles
The first 8 glucose unit is joined by glycogenin dimer
one after each other, similarly to glycogen synthase,
but glycogenin Tyr OH remains covalently bound to
the 1. glucose in the middle of the particle
Glycogen branching enzyme =
glycan-4→6-transferase
Next α-1,6-glycosidic branch is made
at least 4, rather 6-8 glucose unit
further from existing branchpoint
Many branches, lot of free 4-OH ends
make fast synthesis and fast
degradation possible.
Energetics of glycogen metabolism
90 %
10 %
glucose
glu-6P
ATP ADP
glycolysis
oxid. foszf.
glu-1P
UTP
UDP-glu
PP
glycogen(n)
glycogen(n+1)
UDP
2P
ADP ATP
ATP is necessary for phosphorylation of glucose taken up from blood and liberated from
α-1,6-branchpoints and to phosphorylate UDP,
inorganic phosphate is used for degradation of glycogen!!
It is worth to store much glucose in such form, free glucose would case so high osmotic pressure
that the cell could not survive, rather burst.
Why do we need glycogen?
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Free glucose would increase the osmotic pressure to so high value that is
intolerable.
Energy demand of the muscle can increase suddenly in the beginning of
contraction or during strenous exercise, muscles’ own glycogen can be
degraded very fast, the even anaerobically degraded glucose can fulfil the ATP
demand
There are obligate glucose consuing organs, cells:
red blood cell: does not contain mitochondria
brain: fatty acid can not penetrate through blood brain barrier, only glucose and
ketone bodies can yield energy, but k.b. are produced in significiant amount after
several days starvation or prolonged exercise
white muscle fibers, kidney medulla...: few mitoch.
Liver and kidney cortex regulate blood sugar level, only here one can find
glucose-6-phosphatase. Enough glucose is needed for obligate glucose
consuming organs. High bood glucose cc. causes protein glycosylation, ROS
formaion, so it is important to decrease blood glucose level quickly after meal
During hypoxia, blood vessel occlusion the brain own glycogen can supply
glucose and energy demand for some minutes
Comparison of glycogen synthesis and degradation
glycogen synthesis
glycogen degradation
happens
well-fed, [glucose] ↑,
during rest in muscle
starvation – liver
contraction – muscle
hypoxia – brain
ATPdemand ↑ - extrahepatically
regulated enzyme
glycogen synthase
glycogen phosphorylase
substrates
glycogen(n) + UDP-glucose
glycogen(n) + Pi
products
glycogen(n+1) + UDP
glycogen(n-1) + glucose-1phosphate
phosphorylates the
rate-limiting enzyme
PKA (act. glucagon, adrenalin)
GPK (act. glucagon, adrenalin)
GSK-3 (inhibited by insulin)
CK-1 (= casein-kinase)
GPK = glycogen phosphorylasekinase
(activated by glucagon, adrenalin)
regulated enzyme
is active, if
non-phosphorylated
phosphorylated
rate-limiting enzyme is
dephosphorylated by
PP1 = phosphoprotein
phosphatase-1
PP1
Glycogen-phosphorylase
100% active ,
phosphorylated
contraction, synthesis...
inactive,
non-phosphorylated,
allosterically not
ATP + AMP
activated 2 ADP
Glycogen-phosphorylase homodimer
has 3 kinds of isoenzymes:
M – skeletal and heartmuscle
B – brain
L – liver and many other places,
almost everywhere
adenylate kinase
glycolysis, oxidat. phosphoryl.
Regulation of glycogen phosphorylase by
phosphorylation and allosterically in muscle
80 % act.
R = relaxed
2 ADP
ATP + AMP
AMP
0 % activity
T = tight
conformation
ATP,
glu-6P
glycogen phosphorylase-kinase
phosphorylated active
PP1
100 % activity
PKA
AMP
ATP,
glu-6P
less active than R-conf.
PP1
Comparison of glycogen
phosphorylase L és M isoenzymes
[ATP] ↑ in rest and well-fed
[AMP] ↑ glu/ATP/O2/FA absence
[glu-6P] ↑ after glucose food in muscle
[glu] ↑ after glucose food, because
GLUT-2 and glucokinase can work
only in that case in liver
tight conformation,
less active
relaxed
conformation,
80 %-os activity
in muscle
The liver glycogen phosphorylase
isoenzyme is not sensitive for AMP,
but it is a glucose-sensor: glucose
allosterically inhibits and makes it as
a better substrate for dephosphorylating
phosphoprotein phosphatase,
so it is completely inactivated.
Glycogen phosphorylase kinase is a tetramer of a
heterotetramer: (αβγδ)4
glucagon: liver, adipocyte
adrenalin β1-3 rec.: (liver), skeletal, heart, smooth muscle...
γ
δ
other hormons
α
γ
α
sympathic activation
liver adrenalin α1 receptor
Note: γ-subunit is the catalytic part, mistake in Stryer figure
Each signal transduction step of hormonal regulation
in glycogen degradation amplifies the signal
= adrenalin
Molecules that supply energy,
speed of glycogen degradation, speed of glycogenesis
Everywhere after glucose meal
or during rest in muscle
inactive
active,
dephosphorylated
Regulation of phosphoprotein phosphatase-1
glucagon is only in liver
and adipocyte, not in muscle
in liver GL is the glycogen-binding
scaffold protein, that brings to close
proximity: glycogen, PP1 and its
substrates (glycogen phosphorylase,
phosphorylase kinase, glycogen synthas
Insulin activates glycogen synthesis and
inhibits glycogen degradation
pancreas β-cells
blood sugar ↑
PI3K = phosphatidyl-inositol-3-kinase
PDK -1 = phosphatidyl-inositol dependent kinase
PKB = akt = protein-kinase B
insulin receptor
with tyrosin kinase
activity
insulin receptorsubstrate
Switching from
glycogen degradation
to glycogen synthesis
is very fast if glucose
-P inact. is added to blood
-P inact.
Insulin activates glycogen synthesis, GLUT-4 translocation to
plasmamembrane (the glucose uptake) and also glycolysis
Effect of cortisol,
a glucocorticoid hormon
on liver:
signal transduction of
insulin is not material
to study!!
Regulation of phosphoprotein phosphatase-1 in liver
muscle
liver
goal of glycogen
degradation
ATP for contraction
to maintain blood sugar
level
hormon that stimulates
glycogenolysis
adrenalin β-receptors
(absent glucagon receptor!)
glucagon
adrenalin α1 (and β)-rec.
glycogenolysis neural
acetylcholine nicotinic rec.
stimulation, GPK activation → Ca2+ liberation from SR
noradrenalin α1-rec. → Ca2+
liberation from ER
phosphorylase is
allosterically regulated by
AMP activates
glucose inhibits and
promotes
dephosphorylation
promotes glycogenesis
insulin (GSK-3 inact. /AC inhib..
insulin (GSK-3 inact. /AC inhib.
/cAMP degrad./PP1 act.)
/cAMP degrad./PP1 act.)
eating after glycogen consumption because of excercise
blood sugar level ↑ after
meal, cortisol
glycogen synthase is
phosphorylated and
inactivated by
PKA, GSK-3,
GPK, CamK, PKCαβ, CK1
PKA, GSK-3,
GPK, CamK, PKCαβ, CK1
glycogen-binding protein
that joins to PP1
GM : binds to glycogen,
GL: binds to glycogen,
phosphoprotein phosphatase and to
enzyme’s substrate
phosphoprotein phosphatase and to
enzyme’s substrate
Glycogen storage diseases
In every lysosome
Muscle glycogen phosphorylase
hereditary deficiency = Mc Ardle-disease α-1,4-glikosidase
hereditary deficiency =
Pompe-disease