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