Now, two organs I want to talk about that play important roles in
hormonal control which is what we're getting ready to talk about here
are the adrenal gland, which is where epinephrine is synthesized.
Epinephrine is a hormone that is also known as adrenaline
and is synthesized when the body
is trying to produce a lot of glucose.
Insulin, is a sort of a counter hormone to epinephrine.
Insulin is produced when the body is trying to
lower its concentration of glucose in the bloodstream
and it is synthesized in the pancreas.
Now it's very important that the body maintain
relatively constant levels of glucose.
Glucose exist in the body kind of like a poison.
Too much of it, not good.
And so if the blood glucose levels get too high,
then there's gonna be problems. That's why insulin is there.
Well too low is also a problem because you can be hypoglycemic.
And that's why hormones like epinephrine and glucagon
that stimulate the production of glucose
are essential in a multicellular organism for balancing that.
So the hormonal control that we're going to see is largely
balanced by the different activities of these two hormones
and the effects that they have on the enzymes in metabolism.
Now in the scheme I showed earlier,
glycolysis and gluconeogenesis.
I showed this molecule fructose 2.6-biphosphate or F2.6BP
as being an important reciprocal regulator.
What turns out to that molecule is almost the most important
reciprocal regulator of the two pathways.
So it's important for us to understand
how it is that it accomplishes what it does
and how it is that it's made and broken down.
Now F2.6BP is an activator of PFK,
the most important regulatory enzyme in glycolysis.
It's an inhibitor of fructose 1.6-bisphosphatase,
the corresponding enzyme in gluconeogenesis.
So it's therefore important to understand
well what happens to fructose 2.6-bisphosphatase,
because if you make it, you're gonna favour one path,
while if you break it down, you're going to favour the other.
This molecule is made by a very interesting enzyme.
It's made by one enzyme, but this one enzyme has two activities.
So it's made and broken down by the same enzyme
and the two activities work in conjunction with each other.
This shows the synthesis of fructose 2.6-bisphosphate
from fructose 6-phosphate.
Now this is not a reaction of glycolysis even though
fructose 6-phosphate is in fact an intermediate in glycolysis.
This reaction is catalyzed by this enzyme that you see here
and I've drawn with a yin and yang
because that's really the way that the enzyme is.
You'll notice that there's a blue part on the top
and it says PFK 2.
And so PFK 2 catalyses the addition of phosphate at position 2
on the fructose 6-phosphate to make fructose 2.6-bisphosphate.
Now, fructose 2.6-bisphosphate is broken down
by the yellow part of the enzyme.
It's broken down by this enzyme called FBPase 2.
If you look carefully at these two enzymes,
you'll see that they are different.
The difference is they've got a P in those little circles there.
That P refers to a phosphate.
In this case, the addition of a phosphate to this enzyme
is determining which of these two activities is actually going on.
When the phosphate is absent, the PFK 2 is active,
and when the phosphate is present, the fructose bisphosphatase 2,
the enzyme catalyzing the leftward reaction is active.
This slide shows then how the phosphate gets put on to
and taken off of this yin and yang enzyme.
There's a protein called protein kinase A
that puts the phosphate on to the yin and yang enzyme.
This pathway where the phosphate is put on is activated
by the hormone epinephrine or the hormone glucagon.
They work in very similar fashions. Both of them alternately
trying to increase the concentration of glucose in the body.
The phosphate on the FBPase 2 enzyme is removed
by a protein called phosphoprotein phosphatase.
And if you've been thinking what I said earlier,
you'll probably realize it's activated by insulin stimulation.
So epinephrine is gonna favour the phosphorylation
and insulin favours the dephosphorylation.
And we'll see there's a common pattern in
some of the pathways I'm going to talk about here.
Under conditions where epinephrine or glucagon
is binding to a liver cell
fructose 2.6-bisphosphate is broken down. And under these conditions
as we saw on the regulation before, glycolysis is inhibited.
Well when glycolysis is inhibited, gluconeogenesis is favoured,
and remember that epinephrine and glucagon were being produced
in order to stimulate the body's levels of glucose.
On insulin, when insulin is being bound to a liver cell,
what we see is that fructose 2.6-bisphosphate is made.
Now under those conditions, PFK will be stimulated,
glycolysis will be favoured
and insulin is there to try to reduce the body's level of glucose.
So burning getting glycolysis makes very good sense.
We've talked in other presentations about the pathway
whereby hormone stimulation outside the cell
communicates information inside the cells.
So now I'm gonna bring this back to that to see
how this affects the enzymes that we've been talking about.
In this case, we're looking at a liver cell that has been bound
by either epinephrine or glucagon at its receptor.
At the receptor, when that happens,
the G protein that's bound to the receptor becomes activated
and it becomes activated by letting go of a couple of its subunits
and replacing its GDP with GTP.
When that happens, the G protein stimulates
an enzyme in the membrane called adenylate cyclase
to convert ATP into cyclic AMP.
That cyclic AMP then becomes
an allosteric effector of protein kinase A.
Protein kinase A becomes active at that point and
it stimulates the activation of fructose bisphosphatase 2
thus removing the phosphate from fructose 2.6-bisphosphate.
This is what happen in the process
that I described in the previous slide.
The lack of fructose 2.6-bisphosphate stops glycolysis
and allows gluconeogenesis to get going.
The circumstances that I described before with the epinephrine
or glucagon binding to the liver cell surface receptor
occurs when the glucose concentration in the blood stream is low.
When the glucose concentration in the blood stream is high,
then insulin is released.
And insulin as we'll see in that liver cell
reverses all the effects.
So the binding by insulin to the cell surface receptor for insulins,
called the insulin receptor causes several things to happen.
First of all, the G protein that was activated earlier
by the epinephrine is inactivated.
That means that the adenylate cyclase will not be activated,
and the adenylate cyclase which produce cyclic AMP
is no longer producing something to activate protein kinase.
Protein kinase therefore remains in an inactive state.
Well if protein kinase is remaining in an inactive state, that means
there's nothing putting phosphates onto our yin and yang enzyme.
Well in addition to that, binding of insulin to the
insulin receptors stimulates activity of another important enzyme
and that enzyme is shown here.
That's an insulin-stimulated phosphatase.
And what does a phosphatase do?
It removes phosphates from things.
As result of the action of the insulin-stimulated phosphatase,
fructose bisphosphatase 2 that was active
when the phosphates were on it is inactivated
and instead converted to the other form
of the yin and yang enzyme, PFK 2.
PFK 2 of course takes fructose 6-phosphate
and adds a phosphate to it to make F2.6BP.
F2.6BP activates the glycolysis enzyme PFK. And at the same time,
F2.6BP inhibits the gluconeogenesis enzyme F1.6BPase.
As a consequence, glycolysis starts
and gluconeogenesis stops.
And this makes very good sense because
glycolysis starting, burns glucose,
and the cell and the body are trying to
reduce glucose concentrations.