So you have seen really all there
is to see with respect to glycogen synthesis
and glycogen breakdown. There is only
a handful of enzymes that are involved
in those entire pathways.
Now that allows for some simplicity in terms of
regulation. But as we will see that regulation has
a bit of complexity. But it's focused
completely on the enzymes involved
in the direct synthesis and the direct breakdown.
These, of course, are the glycogen phosphorylase
and the glycogen synthase.
Now the body works with glycogen metabolism
largely through hormonal action.
And hormones are involved in transferring
information of one part of body to another. So
for example a muscle
cell that is undergoing
a lot of energy burning from
contracting and so forth,
can release a signal that says
"Hey I am needing some glucose".
And that signal can travel to the liver, for example,
and then cause a process to release glucose.
The release of hormones is an organismal function.
It's important to remember that as we talk about
some of the pathways that I will be talking
about here for hormones stimulation.
And the reason is that's important is because
the needs of the body are quite varied.
Muscles have a different need than a liver has. Liver is
there to supply, muscles are there to use glucose for example.
So what we are focusing on
here are largely liver cells.
Liver cells supplying the glucose or in some
cases storing the glucose for the body.
The regulation of glycogen metabolism occurs
through one of hormones that you see here.
Now there are couples of
hormones that play role in
telling the liver, "Hey, the
body is needing some glucose."
These include epinephrine and
a peptide hormone called glucagon.
Epinephrine is also known
as adrenaline, for example.
The binding of either
one of these hormones
to the receptor in the cell membrane
that you see in the upper left
causes a change in the receptor. A slight
change in structure of the receptor
and that change is communicated inside
of the receptor to the inside of the cell.
Now that's a very critical
step in this process; because,
what's called signal transduction
that I am talking about here
is an essential way that the outside part of the world
connects with inside the part of the world of a cell.
In the signal transduction, the inside of the
receptor, and the receptor here that I am talking
about is called the beta adrenergic receptor.
The beta adrenergic receptor interacts
with a protein called a G-protein
and you see that below in orange.
That's label with an α, a β and a γ.
That protein has three subunits
and the functional part of
that protein, for our purposes,
is the part that has the
nucleotide GDP located in it.
And it's the GDP that actually gives the protein the name of
a "G" protein. It means it contains guanine nucleotides.
The action of the binding of the
hormone that changes the receptor
changes the interaction between
the receptor and the G protein
and that two causes two things to happen.
One thing that happens, is that GDP is released
from the α subunit and replaced by GTP.
Second the interaction between the α subunit
and the β, γ subunit is interrupted.
So the β, γ subunit is released
and the release of the β, γ subunit allows
the G-protein to travel from the receptor
over to a membrane bound enzyme
called adenylate cyclase.
Adenylate cyclase is an enzyme,
as it's name suggest, and what it
does is it catalyzes the conversion of
ATP into a molecule called cyclic AMP.
Now cyclic AMP is an example what
we call a signaling molecule.
And cyclic AMP is involved in many signaling pathways
we are looking at one of the pathways right here.
Well the reason cyclic AMP is important
is it is an allosteric effectors
on protein kinase A.
Now as we will see in this presentation
and subsequent presentations,
protein kinase A is central to
phosphorylation of many
proteins and those proteins
have significant changes that happen in their
activity as a result of that phosphorylation.
So the addition of cyclic AMP to protein kinase A
converts it from the inactive form on the right
to the active form on the left.
That active form on the left then is
able to start phosphorylating proteins
and the inactive form it is not able to do
that. So in absence of cyclic AMP,
proteins kinase A will
not phosphorylate anything.
The phosphorylation by proteins
kinase A, I wanna focus
on the arrows moving down first and then I
will talk about the one that into the left later.
Protein kinase A, phosphorylates
proteins, that's how it gets its name.
And the phosphorylation that it does first is
on an enzyme called phosphorylase kinase.
Again whenever you see the
name kinase you should think
puts phosphate onto. And
so what phosphorylase kinase does
is when it's activated, it puts
a phosphate onto another enzyme.
Phosphorylase kinase is converted
from the inactive form on the right
to the active form on the left
by that phosphorylation.
And that active phosphorylase kinase
converts glycogen phosphorylase B
which is relatively inactive, into glycogen
phosphorylase A which is very active.
And so what the glycogen phosphorylase A does is it
goes and catalyzes the reactions that we have already seen,
that is the breakdown of glycogen to make
glucose-1-phosphate that can
then be used later for energy.
A second thing that protein kinase A
phosphorylates, is it phosphorylates
the enzyme glycogen synthase
that we have already seen.
Now glycogen synthase, of course, is
involved in the synthesis of glycogen.
The effect of phosphorylating glycogen
synthase it to do exactly the opposite thing.
In the case of glycogen synthase,
the B form is the active form
and the A form which is
phosphorylated in inactive.
As a result of this, glycogen synthase
is converted into an inactive form.
So what's happened here is what
we call reciprocal regulation.
Protein kinase A has started what
we call a phosphorylation cascade
that is resulted in the different effects
on catabolic and anabolic pathways.
Breakdown is activated
and the synthetic pathway is inhibited.
So as we have seen this system is designed then to
put phosphate onto glycogen enzymes and these
additional phosphate on the glycogen enzyme is
activated by the hormone stimulation and you have
seen little bit of the effects
that these can have on the activity.
Glycogen synthase, a synthetic enzyme,
is less active with phosphate
and glycogen phosphorylase it breaks down
glycogen is more active with phosphate.
Now this reciprocal regulation
is very very important for
these metabolic pathways and
reciprocal regulation as a principle
is very important for catabolic
and anabolic pathways in general.
Now you can see here the phosphorylation that's
happened on there and the phosphorylation
or the addition of those phosphates must
be removed in some way; because,
cells are control freaks, as I like to say,
cells if they wanna do something they wanna
also be to reverse what they do
and they have to be able to
reverse what they do; because,
is really important here.
Glycogen is a resource of the body
and the activity of a glycogen breakdown
enzyme is such that it could very readily
breakdown the glycogen and waste all the glycogen
if it was doing that when the glycogen was not needed.
So it's important that this breakdown be
controlled and the breakdown is controlled
by removal of phosphates as we shall
see by an enzyme called phosphatase.
Now another interesting consideration occurs
at the top. So when we are talking about
reversing and stopping this pathway,
if we stop the lower part of the pathway but
we don't stop the upper part of the pathway,
then this signaling will continue
to activate glycogen breakdown.
So it's important that these internal things
inside the cell be turned off at all levels.
And this is a very interesting process,
the G-protein that you see on the left
with a GTP bound to it. The G-protein
is a very inefficient enzyme
and because it's an inefficient enzyme
it is able to do what it does. Now
that may seem very odd but it's true.
What happens is, the G-protein besides
activating adenylate cyclase
has an enzymatic activity of its own.
And the enzymatic activity of its own is
that it cleaves GTP and leaves behind GDP.
Well when the G-protein has GDP on it, we have
already seen what happens to it. It goes back
to the receptor
and binds to the receptor and
the β and the γ bind to it.
So the G-protein has a
way of turning itself off.
But what's important is because
it's an inefficient enzyme
it doesn't cleave GTP too fast.
So by having an inefficient enzyme,
it takes a few seconds to a few minutes
for that conversion to
happen. So that it's able to
communicate the signal to the
adenylate cyclase to be active,
but it is able to turn itself
off automatically by that.
Now the other molecule that is interesting
in this respective, cyclic AMP;
because, cyclic AMP must be dealt with.
Otherwise it will continue to
activate protein kinase A,
and that's what happens as we
can here in the next slide.
Cyclic AMP is broken down to AMP
by the enzyme phosphodiesterase.
And when that happens AMP will not
stimulate the process, as I have talked about,
and so the signal has been turned off.
Now you will notice above that enzyme
phosphodiesterase is inhibited by caffeine.
Now caffeine has numerous effects on the body
but I always like to remind people that
you think about that buzz you get from caffeine.
What's happening with that buzz? Well
part of that buzz comes from the fact that
the phosphodiesterase is being inactivated.
And when the phosphodiesterase is being inactivated
protein kinase A is being activated and
glycogen breakdown is being stimulated.
So what you are doing by drinking
caffeine at lease to a limited extent
is increasing your blood glucose.
That's part of your buzz.
Now so in summary here when glucose levels are low
the body signals the liver
with epinephrine or glucagon
and it increases the glucose concentration
by favoring glycogen breakdown
and inhibiting glycogen synthesis, the reciprocal
regulation that I have talked about before.