15. Cell metabolism: regulation and integration of glucose metabolism
glucose has many options:
storage as glycogen, starch, and sucrose oxidation via glycolysis to make pyruvate oxidation via pentose phosphate pathway resulting in ribose 5-phosphate synthesis of structural polymer such as extracellular matrix and cell wall polysaccharides
so if cellular ATP levels are what they should be, the body will do what with glucose
store as glycogen in the liver
draw entire pathway
that was recreated in notes - slide 14
why isn't muscle just like the liver then?
the glucose cannot be delivered to the blood - muscle uses gluconeogenesis primarily to make glycogen
since they are irreversible, gluconeogenesis is forced to
use a different path around them with different enzymes
what does ribose-5-phosphate do
used to build nucleic acids and NADH to counter oxidative stress
what you do with glucose depends on
what tissues and the body's energy state
futile cycles
without regulation you can imagine that enzymes phosphofructokinase-1 and fructose 1,6-biphosphatase could just go back and forth
if you just ate a lot
you have excess glucose and it will end up as glycogen
so if you haven't eaten
your blood sugar is low and glucagon will be released
glycogenesis
convert glucose to glycogen for storage (liver) glucose to glycogen
multi subunits does what
cooperatively conformational change in one changes them all
gluconeogenesis
create glucose (liver) to provide fuel for brain and muscle ATP to glucose
if blood sugar is low, the liver
does not use it for its own needs thus lowers glycolysis
muscles and glucagon receptors
don't have them! glucagon is a signal to the liver to break down glycogen and to create more glucose so that glucose can be sent into the blood stream
2. compartmentalization
done by membranes to keep concentrations of reactants and products at different levels and so that tissue specific enzyme isoforms can have different biochemical properties
allosteric inhibitors of glycolysis are typically
downstream products - feedback regulation!
so fructose 6 phosphate + ATP --->
fructose 1, 6 biphosphate + ADP ATP and citrate prevent products AMP, ADP, and fructose 2, 6 biphosphate favor the products
High blood glucose -> insulin -> activation of enzyme ->
fuctose -> glycoysis Low blood sugar -> glucagon -> no enzyme to make fuctose -> gluconeogensis
low blood glucose stimulates ___ release: the liver...
glucagon increases glycogen breakdown and inhibits glycolysis
1. systemic messengers
glucagon, insulin, epinephrine act through signalling pathways to integrate metabolic responses
difference in liver?
glucose 6 phosphate goes into blood as glucose ALSO liver can have all the same responses to epinephrine as it does to glucagon because it has receptors unlike muscle
the different enzymes are
glucose-6-phosphatase fructore 1,6 biphosphatase-1 PEP carboxylase, pyruvate carboxylase
SO epinephrine stimulate both the liver and the muscle
glycogen goes to glucose 6 phosphate goes to pyruvate
if you are depleted of energy or epinephrine was released then
glycogen is being released as glucose to fuel glycolysis
insulin also directly stimulates
glycogen storage
PKA phosphorylation inhibits... activates...
glycogen synthase glycogen phosphorylase
PKA phosphorylates inhibitor and activator
glycogen synthase to inhibit glycogen phosphorylase to activate
major players in glycogen regulation (storage and release) in the liver
glycogen synthase, glycogen phosphorylase, epinephrine and glucagon, cAMP, cAMP dependent protein kinase, PKA phosphorylates
epinephrine or glucagon binds to their receptor ___
heterotrimeric G protein coupled receptor
three far from equilibrium reactions/regulatory points:
hexokinase phosphofructokinase-1 (PFK-1) pyruvate kinase
GLUT 2 -->
increase glucose concentration inside --> increase glycolysis
muscle needs energy so it continues to
increase glycolysis to make pyruvate and then ATP
if insulin in increased it can lead to
increase insulin sensitive protein kinase increase PKB synthesis of hexokinase II, PFK-1, pyruvate kinase
this overall ___ glycogenolysis and __ glycolysis and ___ gluconeogenesis
increase, decrease in liver and increase in muscle, increase
low blood glucose --> _ glucagon --> _ [cAMP] --> _ PKA
increase; increase; increase
high blood glucose stimulates ___ release and the liver...
insulin increases glycogen synthesis and glycolysis
how does liver divide its glucose?
it will raise blood glucose before using glucose for glycolysis or itself brain is super sensitive to glucose levels the liver can use fats for energy, the brain cannot
look at figure on page 20
its about regulation of glycolysis and gluconeogenesis
this gets really complicated...
just be able to draw out graph on page 16 actually you aren't responsible...just kinda know them
glycagon synthase
key enzyme in pathway that polymerizes glucose into glycogen
glycogen phosphorylase
key enzyme in pathway that releases glucose from glycogen
glycogenolysis
release glucose from glycogen (liver) for use glycogen to glucose
3. allosteric effectors
act to maintain nearly constant levels of metabolites and to generally sense the cell's energy needs
carbohydrate metabolism is finely regulated by
allosteric and hormonal signals
if you about to kill a bear...
einephrine will be released
what does citrate accumulation do?
energy needs are met allosterically inhibits PFK-1
hexokinase (...) isoforms in the muscle and liver are...
first step glycolysis biochemically tuned so that the liver will only process glucose when the other cells have what they need for glycolysis
glycogenolysis is increased in liver with
glucagon = release of glucose into the blood
gluconeogensis produces glucose when
glucose and glycogen stores are depleted
the liver stores glucose as
glycogen so it can release it when blood glucose is low
liver cells (___) respond differently/the same to glucagon and epinephrine as myocytes
hepatocytes differently
but ATP is also an allosteric...
inhibitor of PFK
glucose 6 phosphate cannot
leave the cell so it goes back to glucose to leave the cell
primary site of gluconeogenesis
liver
increase PKA can lead to
lower glycogen synthase thus lower glycogen synthesis OR higher glycogen phosphorylase thus higher glycogen breakdown
the liver does what
maintains constant blood glucose so other cells have a steady supply such as the muscle and brain
cAMP dependent protein kinase =
protein kinase A to activate PKA
allosteric effectors of glycolysis are typically
sensitive indicators of the cell's energy needs
draw and understand page 28
shows the layers of enzyme allostery of phosphofructokinase-1 (glycolysis) and fructose 1,6-biphosphatase (gluconeogensis) reciprocally regulate these two pathways, preventing a "futile cycle"
draw what is in your notebook
starting with extracellular signals binding the the receptor
who is the mom?
the liver because it stores glucose as glycogen and gives it out and produces glucose when needed
insulin means that
there is high blood glucose (such as after a meal)
glucagon means that
there is low blood glucose
how does the cell control which is on and off
through allosteric enzyme regulation
regulation of metabolism occurs on multiple ___, in localized ___, and across...
timescales regions (single cell or organelle) the body in integrated responses
how to reverse the following three
you can't
glycolysis
breakdown glucose to make ATP (all tissues) glucose to ATP
look at slide 29 too
draw that maybe
insulin breaks cAMP signal and
insulin binds to insulin receptor results in activation of phosphodiesterase PDE breaks down cAMP into AMP
glucagon
A hormone secreted by the pancreatic alpha cells that increases blood glucose concentration
epinephrine
Adrenalin
what is PFK-1's substrate
ATP
leads to conversion of some
ATP into cAMP
Fuctore 2, 6-biphosphate is an allosteric modulator In the liver Regulatory molecule Turns glycolysis on
Turns glycogenesis off Enzymes that makes it is activated in response to insulin
cAMP binds to
cAMP dependent protein kinase
cAMP binds to
cAMP dependent protein kinase to activate PKA
why do organs such as the brain depend on the liver for constant glucose supply?
cannot process fuels such as fats
how they integrate responses
change the concentration of particular enzymes by influencing rate of enzyme transcription, translation, or degradation (slow = hours) alter enzyme activity through ligand-binding, phosphorylation, ect (fast = minutes)
binding leads to
conversion of some ATP into cAMP
how do cells process glucose differently to keep metabolic responses integrated and homeostasis maintained? even during large scale physiological changes?
1. glucagon, insulin, and epinephrine are systemic messengers 2. metabolic reactions can be compartmentalized 3. enzymes are regulated by allosteric effectors
high ATP means high citrate means
ATP concentration is high so slow down glycolysis
high ADP means high AMP means
ATP concentration is low!
what do cells, such as muscle cells, use glucose for
ATP generation mostly
high blood glucose leads to
GLUT2 or increase in insulin
where is the commitment step of glycolysis
PFK-1 catalyzes the commitment step! therefore very regulated
AMP and ADP? activate or inhibit PFK-1?
activate
enzymes in glycolysis are regulated by...that act to ...
allosteric effectors maintain nearly constant levels of metabolites
phosphofructokinase-1 and regulation
allosterically regulated inhibited by its products
Precise control of flux through these metabolic pathways is required to
balance resources and needs
things in common between glycolysis and gluconeogenesis
basically the reverse of each other occur in cytoplasm share many enzymes except three
why do futile cycles not happen
because the cell isn't dumb when one pathway is on, the other is off
allosteric effectors
bind to a site on enzyme other than activate site and change conformation of active site
so what does ATP do to PFK-1?
binds to allosteric side which lowers its affinity for its substrate F-6-P
pancreas senses
blood glucose level and responds by releasing hormonal signals
what is special about muscle
muscle does have the enzyme glucose 6 phosphatase so it can carry out gluconeogenesis!
ICP#2
page 18 & 19
ICP #2
page 24 & 25
ICP #1
page 3-7
heterotrimeric G-protein-coupled receptor
receptor epinephrine or glucagon binds to