- [Instructor] At its most simplistic level,
regulation of metabolic pathways inside
of the body is really just a fancy word
for a balancing act that's occurring in the body.
So, to illustrate this, I have a seesaw
and we've been learning about two metabolic pathways:
glycolysis, which is the process of breaking down
glucose into pyruvate; and gluconeogenesis,
which is essentially the opposite in which we start out
with pyruvate and through a little bit
of a different route we end up back at glucose.
And when we're talking about the regulation of these
particular pathways, we're essentially asking ourself,
"When is glycolysis the predominant pathway
and when is gluconeogenesis the predominant pathway?"
The body wants to make sure that we either have a net
breakdown of glucose, in the case of glycolysis,
or that we have a net production of glucose,
in the case of gluconeogenesis.
So now the next question is, "How does the body
"accomplish this balancing act?"
And to answer this question, the way I like to think
about it is to think about it along a spectrum.
There are very fast-acting forms of regulation
that take place on the order of seconds,
and there are very very slow forms of regulation
that can take up to hours or even days to occur.
So let's talk about each of these
in a little bit more detail.
The major principle that helps me understand fast-acting
forms of regulation is a good old principle
from general chemistry: Le Chatelier's Principle.
So if you remember, Le Chatelier's Principle talks
about anything that's in equilibrium
and it says that if there's any change to this equilibrium,
let's say more products are added
or reactants are taken away, the equilibrium will adjust
to essentially counter that change
and return the system back to equilibrium.
So what does this mean in the context of metabolic pathways
like glycolysis and gluconeogenesis?
So let's remind ourselves that in glycolysis,
glucose is converted to pyruvate through several reactions
that are all in equilibrium with one another,
and so we can essentially think about this
metabolic pathway as a series of equilibria.
And so imagine, for example, if we had
an influx of glucose, let's say we've just eaten a big meal,
and a huge bunch of glucose has entered
our body and our blood stream.
What will happen to this equilibrium?
Well, we can return to Le Chatelier's Principle
and say that if we have a rise in glucose,
it will essentially push this entire equilibria
towards the production of pyruvate.
And so you can see that in this example,
Le Chatelier's Principle allows this equilibrium
to adjust within seconds to just
a simple influx of glucose to promote glycolysis.
Le Chatelier's Principle also applies to gluconeogenesis.
So remember that in gluconeogenesis,
something unique starts to happen after blood glucose
levels have been low for a while.
Amino acids being to break down and form this metabolite
called oxaloacetate, and remember that oxaloacetate
plays its unique role in its conversion of pyruvate
back to glucose which occurs in gluconeogenesis.
Remember that it's kind of this intermediary.
So pyruvate is converted to oxaloacetate
and then essentially reenters
the equilibria to form glucose.
So you can imagine that if we have
an influx of oxaloacetate, the equilibria will be
pushed towards the opposite direction, that is,
towards the production of glucose.
Now in addition, I wanna briefly mention another form
of fast-acting regulation,
which is call allosteric regulation.
So what is allosteric regulation?
Recall that all metabolic pathways have unique enzymes
that catalyze or facilitate each step
of the reactions along the metabolic pathways.
So you can imagine that if we have an enzyme here,
I'm just drawing a simple structure,
it has what's called an active site,
where it actually binds the substrate of interest
so it binds the, let's say, glucose molecule here,
but in addition there are also molecules within a cell
that we call allosteric regulators and these,
by definition, bind to a portion of the enzyme
that is not the active site.
So let's say we have an allosteric molecule that binds
to a separate portion like right here.
Now this allosteric molecule can have one of two effects.
We say that allosteric molecules can be inhibitory,
that is, by inhibiting enzymes, inhibit the pathway
that utilizes those enzymes, or these allosteric
interactions can be positive, that is,
promote the action of enzymes and therefore promote
the overall reaction in which those enzymes are involved.
So to put this in context with glycolysis
and gluconeogenesis above, it turns out that ATP
is actually a big allosteric regulator
of one of these two pathways.
So recall that gluconeogenesis requires ATP,
a net amount of ATP, to produce glucose.
It's an anabolic building up pathway.
On the other hand, in glycolysis, there is
a net release of ATP and the oxidative breakdown of glucose.
And so we have a lot of ATP in a cell,
think about, for a moment, which of these
two pathways would be favored.
Indeed, gluconeogenesis would probably
be favored because it requires ATP.
On the other hand, if there's a lot of ATP,
that's kind of a sign to the cell to say,
"Hey, we don't need to perform as much glycolysis
"because we already have enough ATP available."
And it does turn out that ATP is actually an allosteric
regulator of a couple enzymes in glycolysis.
And specifically, it's a negative allosteric regulator,
or an inhibitor, of these couple enzymes.
Essentially it's putting the breaks on glycolysis
and saying, "We have enough energy
"and we don't need to produce any more."
On the other hand, it turns out that there is also
a molecule, AMP,
in the body which is basically a sign
that the cell has used up all of its ATP, in other words,
ATP has been dephosphorylated,
and turned into AMP
which is a sign that that cell is running out of ATP.
So if the cell is running out of ATP, the cell probably
won't want to be performing energy-requiring
processes such as gluconeogenesis, and indeed,
AMP is a negative
allosteric regulator of one
of the enzymes in gluconeogenesis.
Alright, so that kind of finishes up our discussion
of fast-acting forms of regulation.
So now let's talk briefly about slow-acting
forms of regulation.
So these types of regulation often take advantage
of transcriptional changes within the cell.
So what do I mean by that?
So let's first remind ourselves what transcription is.
So remember that transcription is a process
of taking DNA and making an mRNA transcript
and then translating this in the cytosol of the cell
to a protein product and when we're talking about proteins
oftentimes we're talking about enzymes.
So I'm just gonna go write that here
since it's relevant for our discussion.
And so you can imagine for example that this
might be very useful if the organism
is in a longterm fasting state.
It will want to essentially up-regulate the transcription
of enzymes that promote something like gluconeogenesis
so that it can dump glucose into the blood.
And notice here that even visually as it's implied here
this process of going from DNA to mRNA to enzymes
is going to take much longer than a simple Le Chatelier
or allosteric regulation and so that's why this process
is more of an adaptive process that allows the organism
to adapt to more of long term changes
that it experiences in its environment.
Now finally I want to add in one more form of regulation
between fast- and slow-acting regulation
which is called hormonal regulation.
So what is hormonal regulation?
Well it's exactly what it sounds like.
It's the ability for the body to essentially produce
specific hormones which are simply molecules
that travel in the blood to regulate whether glycolysis
or gluconeogenesis is on or off.
And the two hormones that the body uses to regulate
glycolysis and gluconeogenesis and pretty much, actually,
all metabolic pathways, are insulin
and another hormone called glucagon.
And depending on whether there is more insulin
or more glucagon, the body will be more likely
to do glycolysis or more likely to do gluconeogenesis.
So let's talk about how that decision is made.
Now hormones, like insulin and glucagon, are usually
released by the body whenever the body
deviates from a particular set point.
Now in the case of regulation of metabolism,
the set point that we're interested in
is the blood glucose level, and if we return
back to our analogy here, this seesaw here,
this pivot point we can think about as our set point.
The blood glucose level: it's a specific amount
of glucose that the body wants to have
in the blood at all times.
Now to get more specific, if the blood glucose level rises
it actually stimulates the body
to release the hormone insulin,
and if the blood glucose levels decrease,
it stimulates the body to release the hormone glucagon.
And so with that in mind, take a moment to think
about which hormone, insulin or glucagon,
promotes glycolysis, and which of these
two hormones promotes gluconeogenesis.
Basically this is actually a macro-application
of Le Chatelier's Prinicple, right?
If we have too much blood glucose level,
we want to get rid of it.
How do we get rid of it?
We break it down.
And so indeed, insulin promotes glycolysis.
On the other hand, when blood glucose levels are low,
we want to return the equilibrium to normal,
we want to pump more glucose back into the blood
and we know that gluconeogenesis can accomplish that for us.
And so glucagon indeed promotes gluconeogenesis.
Now briefly at the end I want to talk about why I decided
to put hormonal changes between fast-
and slow-acting forms of regulation.
So to talk about this, we need to understand a little bit
how hormones interact with target cells.
So cells in our body have particular receptors
that will bind to the hormones that are
floating around in the blood stream.
So once these receptors bind to a particular hormone,
whether it be insulin or glucagon,
it actually causes a series of particular reactions to occur
inside of the cell to modify
oftentimes enzymes that are involved in metabolic pathways.
So I'll just abbreviate that with the letter E.
And these modifying reactions that occur in the cell
are oftentimes phosphorylation reactions, that is,
either the gain or the loss of a phosphate group
oftentimes on an enzyme in a metabolic pathway.
And so with that in mind, you can appreciate how
modification by phosphorylation is a lot faster
than starting with a DNA transcript and then going
to mRNA and then translating into enzymes,
but it is indeed a bit slower than the second-to-second
Le Chatelier and allosteric regulation
that can occur in a cell as well.