#第24回ケビン・アハーンのBB450/550のための生化学グルコネジェネシス講義 (#24 Biochemistry Gluconeogenesis Lecture for Kevin Ahern's BB 450/550)

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[Ahern laughing]
Student: Do it.
Ahern: Do it.
[laughing]
I'm guessing if I gave everybody who came to class
an A today then they'd never come to class again.
That's just my hunch.
Which would kind of be a self-defeating thing, right?
So...
Student: Not necessarily.
Ahern: Maybe we would, right?
What she should say is, "Ahern, you're a scientist,
"let's do the experiment and fight out," right?
Student: Exactly.
Ahern: Well, we can't do that.
Student: You can give us extra credit.
Ahern: I could give you extra credit.
There's a lot of things I could do.
I could give you money.
[class laughing]
We could go have beer.
We could have pizza.
Student: How many of us would not get in
trouble for you buying beer.
Some of us are still under age, so...
Student: Yeah, you could get in a lot of trouble.
Ahern: No, actually the way I do that is I go to a place
where they can serve people underage
and you have to show an ID so it's not my responsibility.
A lot of energy.
I hope everybody's got a big Thanksgiving planned.
Wild plans?
Student: Family.
Ahern: Oh.
Family, huh?
Like I said, if any of you are in town
and would like to come over, give us a holler
and I'll let you know where we're going to live and everything,
but if you'd like to come over,
we've got plenty of turkey and other things.
And no, I won't get you drunk.
But we'll have a good time.
Today we're going to have a good time
because we're going to be thinking of the making of glucose.
I know that for many of you,
that's been something you've dreamed of doing
and you're going to get that dream today.
Happy days are here again.
Glucose synthesis is an interesting process.
The phenomena of course is known as gluconeogenesis
and it is a pathway that is very similar,
very similar to glycolysis.
Very similar.
It's very similar to the reverse of glycolysis.
However, there are important differences and specifically,
there are two reactions.
I'm sorry, specifically that there are 3 reactions.
There are 3 reactions in gluconeogenesis,
in glycolysis that are replaced
by 4 reactions in gluconeogenesis.
So gluconeogenesis has 11 steps, glycolysis had 10.
One of the steps takes two steps to get around.
So it's 2 step.
If you learned glycolysis, gluconeogenesis for 8 of the steps,
Let's get that right for 7 of the steps.
I can't get my head right today.
for 7 of the steps is identical to glycolysis
except for in the reverse.
Same enzymes, same intermediates going to the opposite direction.
Three of the steps that are in glycolysis
as I said are replaced by 4 steps.
So let's take a quick look at that.
Before I take a look at that, I'll show you something
your book is distracted by and that is this process here,
which is the making of glucose from glycerol.
Why do we care about the making of glucose from glycerol.
One of the reasons we care about the making of glucose
from glycerol is glycerol is a byproduct
of fat metabolism and so it turns out
that the only portion of the fat molecule
that can be converted directly into glucose is the glycerol.
We don't convert fat into glucose for the most part,
with the exception of the glycerol.
I just show you this, I'm not going to go through
and expect you to memorize these are anything,
but just show you that glycerol is a 3-carbon molecule.
It gets made in a couple of reactions
into an intermediate in glycolysis,
dihydroxyacetone phosphate.
And of course, once it's dihydroxyacetone phosphate,
we can now do the upwards pathway,
going into making glucose via gluconeogenesis.
And we see this, this is a phenomena you've seen before.
We saw how other sugars entered glycolysis
and gotten broken down by being converted
into glycolysis intermediates.
We saw, for example, fructose got converted
into fructose-6-phosphate and then got metabolized
as an intermediate in glycolysis.
In this case, we see glycerol being converted
into an intermediate in glycolysis or gluconeogenesis,
it can actually go either way,
and be made into either glucose or ultimately into pyruvate.
Let's focus on gluconeogenesis
since that's our main topic of the day.
You'll notice in looking at the screen
that we oriented very much like we oriented glycolysis
except that we're going upwards in gluconeogenesis
where as we were going downwards in glycolysis.
So we start at the bottom and the place where we will
start gluconeogenesis is actually pyruvate.
But again, we remember that all these designations
about where something starts and stops is really arbitrary.
We could just as easily start it at lactate
for some types of metabolism.
We can start at amino acids as well,
but we're going to start right here at pyruvate.
So starting at pyruvate, and that's a good place to start
because that's where we finished glycolysis,
starting with pyruvate, cells can convert pyruvate into glucose.
Well, not surprisingly, if pyruvate is a 3-carbon molecule
and we want to make a 6-carbon glucose,
we need to have two pyruvates to start everything.
We're going to start with 2 of everything
and eventually they're going to combine
into 1 as we get higher up in the pathway.
What we discover in gluconeogenesis is the first
instance that we see of a phenomenon I call
sequestration meaning we're sequestering something.
All of glycolysis occurs in the cytoplasm of the cell.
All of the enzymes of glycolysis are found
in the cytoplasm of the cell.
In the case of gluconeogenesis, we see 2 enzymes
that are not found in the cytoplasm of the cell.
These are sequestered into other organelles
in the cell and I'll show you those.
They actually end up being the first
and the last enzyme in the pathway.
All the other enzymes between the first and the last
are all found in the cytoplasm.
Let's look at what's happening in making glucose from pyruvate.
If we recall in glycolysis, in going from PEP to pyruvate,
I said that was the big bang.
I said that was a reaction that was extraordinarily energetic.
It had a large delta-G-zero prime.
And as a consequence, that,
you might imagine going in the reverse direction,
would be an enormous energy barrier to overcome.
And in fact, that's exactly what it is.
It's because of this enormous energy barrier
that cells can't go directly back from making
pyruvate to PEP in one step.
They have to do a two step around it.
And the two steps around it are these two enzymes here.
Pyruvate carboxylase and phosphoenolpyruvate carboxykinase,
which you are more than welcome to abbreviate as PEPCK.
Let's talk about the first one first,
pyruvate carboxylase is an enzyme that is found
in the mitochondrion of cells.
It's not found in the cytoplasm.
The very first reaction of gluconeogenesis
occurs in the mitochondrion, not the cytoplasm.
In this reaction, as you can see on the screen,
carbon dioxide in the form of bicarbonate and ATP
are used to convert pyruvate into oxaloacetate.
You can see the structure here.
Here's a 3-carbon, here's a 4-carbon over here.
We've put an additional carboxyl group onto the end of pyruvate.
The carboxyl group going right here.
We can see the new carboxyl group on the right side.
Here it was what pyruvate looked like over here.
So what we did is we took this methyl group
and we added a carboxyl group to it.
That takes energy to put that on there.
It makes a 4-carbon intermediate
and that 4-carbon intermediate you're going to hear
a lot about next term because oxaloacetate is one
of those molecules that appears in so many metabolic pathways.
It's a very, very important molecule.
It's important in amino acid metabolism.
It's important in the citric acid cycle.
And it's also important as you can see here
in the synthesis of glucose.
This is an energy requiring reaction
so if we started with 2 molecules of pyruvate,
it's going to take 2 molecules of ATP
and 2 molecules of bicarbonate to make
2 molecules of oxaloacetate.
We haven't gotten to PEP yet because even with all
that energy that we've put in, we've made a 4-carbon
intermediate and we have to convert
that 4-carbon intermediate into phosphoenolpyruvate or PEP.
To do that, the oxaloacetate which was made
in the mitochondrion has to be moved
out of the mitochondrion and into the cytoplasm.
Next term we'll talk about how molecules
move across an organelle.
But it turns out there are specific proteins
that will shuttle a molecule across a membrane.
There are specific proteins that will transport
oxaloacetate out into the cytoplasm.
When it's out in the cytoplasm,
oxaloacetate can be acted upon by this
second enzyme that's unique.
By the way, all the unique enzymes are shown in red on here.
By the unique enzyme phosphoenolpyruvate carboxykinase, or PEPCK.
Notice that it also takes energy
and that energy in this case comes from GTP.
So GTP is just like ATP, a high energy source.
GTP is used in some places in the cell for energy.
The most common place we actually see GTP used
is in the synthesis of proteins because all proteins
are made using GTP, not ATP.
We'll talk about that next term.
If we have 2 molecules of oxaloacetate
and we want to make 2 molecules of PEP,
it takes us 2 molecules of GTP and
this enzyme to accomplish that.
In the process, a CO2 is released.
Look what we did.
We put a CO2 on the form of bicarbonate
and we've released the CO2 up here,
so no net gain of carbons have occurred.
We've done a molecular rearrangement and in the process
of doing that molecular rearrangement,
we've also put a phosphate onto the molecule,
creating that very high energy PEP molecule.
As I said, this reaction occurs out in the cytoplasm.
To go from pyruvate to PEP in terms of synthesizing glucose,
we had to use 2 high energy phosphates for each
molecule for a total of 4.
So in order to go from here 2 pyruvates to 2 PEPs,
we need 4 triphosphates.
2 ATPs and 2 GTPs.
From an energy perspective, GTP is exactly equivalent to ATP.
There's no difference.
Going down, if you recall, when we went from PEP to pyruvate,
we only got a total of 1 ATP for each one,
or a total of 2 ATPs.
So we can see that building molecules in anabolic pathways
takes more energy than we get out in catabolic pathways.
That's not surprising.
We're thinking okay, well we're going.
Yes?
Student: So how does this prevent PEP from immediately
switching back to pyruvate?
Professor: She's reading my mind.
My next point is, her question was
how does the cell keep PEP from just going back to pyruvate?
Well, that's a very, very important consideration
because we know that if that molecule has the opportunity
to go back to pyruvate in the presence of pyruvate kinase,
it's going to do it.
That's the big bang reaction, right?
We see now why we have to regulate that pyruvate kinase,
because if we want this thing to go upwards,
we darn sure don't want to be turning this right back
around and making pyruvate because we will have destroyed
our purpose and we will have wasted energy
and we would have gotten nowhere.
This business of wasting energy and getting nowhere,
where we're making something and breaking it down,
going in sort of a circle is something
that we'll talk about later.
But it is a non-productive metabolic process
that can occur in cells.
We don't want that to happen.
So for that reason, we want to turn off pyruvate kinase
when we're turning on this process.
Similarly, we want to turn these off when we are turning
on the pyruvate kinase.
Everybody follow?
Student: Can you say that again?
Ahern: Okay, well, to kind of go through that again,
so basically we want to turn off the enzymes
of gluconeogenesis when we have on the enzymes
that's catalyzing those big reactions of glycolysis.
In this case, pyruvate kinase.
Conversely, we want to turn off pyruvate kinase,
or turn on pyruvate kinase when we turn these guys off.
So we want to have on one vs. the other.
There's a name for what occurs if we put both of these
on at the same time.
Let's imagine we have a situation in a cell
where these enzymes were active and so was pyruvate kinase.
The cell would turn pyruvate into PEP,
pyruvate kinase would turn it back into pyruvate
and we would go around, and around, and around, and around.
That phenomenon is known as a futile cycle.
F-U-T-I-L-E cycle.
It's futile because the cell is getting nothing out of it.
It's burning 4 triphosphates going up
and only getting 2 back on the way down.
So each time it turns the cycle, it's losing 2 triphosphates.
It's also producing one thing.
What's the one thing it's producing?
No, there's no net carbon dioxide because
it goes in and it goes out. It's heat.
Just like we talked about exercising, heat's generated.
This process will generate heat
and it's going to be totally wasted.
Totally wasted.
So we don't want to be running these
two processes at the same time.
For the moment, we will say yes,
we've got the pyruvate kinase turned off,
so PEP starts to accumulate.
When PEP starts to accumulate,
now the reverse reaction of glycolysis is favored,
catalyzed enolase and we convert PEP into 2-phosphoglycerate.
Next, we convert 2-phosphoglycerate into 3-phosphoglycerate.
And next we convert 3-phosphoglycerate
into 1,3-bisphosphoglycerate and we remember now
that in going from here upwards, we have to use ATP again.
So now we've got to put 2 more ATPs into the process.
We get to 1,3-bisphosphoglycerate
and we want to go back to glyceraldehyde 3-phosphate,
now we have to reduce that molecule.
We have to use electrons from NADH to convert
the 1,3-bisphosphoglycerate into glycoaldehyde 3-phosphate.
That involves loss of a phosphate as well.
Now we've got a two molecules of glycolaldehyde 3-phosphate.
Our triosephosphate isomerase converts one of them to DHAP,
leaves the other one alone,
they combine together to make fructose 1,6-bisphosphate.
We're climbing the ladder.
You see in each case all that we're doing
is we're reversing every blue enzyme reaction.
We're just reversing.
We're going upwards instead of downwards.
How do we do that?
We do it by increasing the concentration
of these from the bottom filling upwards.
When we get to fructose 1,6-bisphosphate,
we have another consideration.
The other consideration is that if you recall
during the discussion of the glycolysis pathway,
I said that PFK catalyzed a reaction
that released a lot of energy.
Why did it release a lot of energy?
I said if we did a reaction with just phosphate,
it wasn't very favorable.
But we used something to make this reaction favorable.
What was it?
ATP.
This reaction became energetically favorable
in the glycolysis direction going down
because we put ATP energy in.
One thing that we could do is we could say okay,
well let's reverse that reaction and we'll remake that ATP.
That would be tough for us to do because A,
the reaction is very favorable energetically going down.
That doesn't make sense to try to do
so instead we do a different reaction.
So instead of trying to remake that ATP,
we use a different reaction,
and we use consequently a different enzyme.
The enzyme that we use to catalyze the conversion
of fructose 1,6-bisphosphate into fructose 6-phosphate
is this enzyme known as fructose 1,6-bisphosphatase.
Now you see these names start sounding like the intermediates.
I'm going to help you on this one.
We're going to call this guy FBPase-1.
FBPase-1.
Alright, that name will sound different
than fructose 1,6-bisphosphatase.
We're going to call the enzyme by a different name
and you'll see why later why I want to call
that enzyme FBPase-1.
And now what we're doing is instead of remaking ATP
by a reversal of the reaction,
we're simply clipping off a phosphate.
It turns out that's energetically favorable
to clip off a phosphate.
Why?
Remember phosphate bonds a higher energy
and if we just simply clip it off,
we make that upwards reaction become favorable.
It's a very cool trick that the cell is doing
to make fructose 6-phosphate from fructose 1,6-bisphosphate.
Questions about that?
Yes, sir?
Student: Is there a time when the body chooses
to run futile cycles to make heat?
Ahern: Very good question.
His question is are there times the body runs
futile cycles to make heat.
As a matter of fact it turns out there are.
Not this reaction, but other reactions
I'll talk about next term.
And one's a very important consideration
in something in our body called brown fat.
It is a way of helping to up the temperature.
It's not this reaction, but another reaction
that's done in a futile sense.
Very good question, yeah.
Other questions?
We're getting near the end.
We're at fructose 6-phosphate.
We need to convert that back to glucose 6-phosphate.
That's simply a reversal of the reaction of glycolysis.
Again, we use the phosphoglucose isomerase
to make that isomerasation and we're at glucose 6-phosphate.
At glucose 6-phosphate, we have exactly the same problem
that we had with converting fructose 1,6-bisphosphate
into fructose 6-phosphate.
If we try to simply reverse the glycolysis reaction,
we would have to make ATP.
That would be an energetically unfavorable reaction.
It wouldn't make much sense for us to do.
Instead, cells use a different enzyme
to catalyze a different reaction.
The reaction that they catalyze is again parallel
to the one catalyzed by FBPase-1 and that is we simply
clip the phosphate off of this guy to make 3-glucose.
This last enzyme is found only
in the endoplasmic reticulum of cells.
It's only found in the endoplasmic reticulum of cells.
Now if we look at this, what we see is,
here's the glucose 6-phosphatase.
This is what it looks like in the membrane
of the endoplasmic reticulum.
This glucose 6-phosphatase, you can see,
is embedded in the membrane of the endoplasmic reticulum
and in order for a glucose 6-phosphate to be converted,
it must be moved first into the endoplasmic reticulum
and here is another one of those proteins
that does the transport of specific molecules.
In this case, it's moving glucose 6-phosphate
into the endoplasmic reticulum.
There it interacts with the enzyme,
gets its phosphate clipped off,
and then both of them are kicked out into the cytoplasm.
So as a result of that, cells now have made
a functional glucose molecule starting with 2 pyruvates
and they're left with one glucose.
In the process of making this glucose,
they have required six triphosphates,
four ATPs, and two GTPs.
They've also required two NADHs.
And obviously two pyruvates to start the process.
It takes more energy to make a glucose
than we get out of glucose when we burn it.
That's why we have to eat.
If we relied only on our energy from that which we made
and then broke down and made and then broken down,
we would run out of energy.
We have to eat to make up that deficit of energy.
Connie?
Student: So you need 2 NADHs, 4 GTPs, 2 ATPs, and 2 pyruvates?
Ahern: No, you need 2 NADHs, 2 GTPs, 4 ATPs, and 2 pyruvates.
So there's only 2 GTPs, that's the reaction of PEPCK.
We have made that.
I want to tell you a little something
about gluconeogenesis that's important.
That is gluconeogenesis is not found in every cell of our body.
In fact, it's fairly carefully sequestered again as it were.
Not now where in the cell, but actually where in the body.
So the primary organs that we have in our body
that make glucose are our liver, part of our kidney.
That's the 2 primary places that we make glucose.
So muscle cells for example do not make glucose.
Muscle cells are really good at burning glucose.
They're not designed to make glucose.
That means that when we're running
and we're exercising very heavily,
we have to have a way of getting that glucose
that's made in the kidney and more importantly
in the liver into our muscles.
That's where our blood stream is very important.
That's why our heart starts beating faster
when we start exercising more heavily
is to carry more nutrients in the form of oxygen,
in the form of glucose, and in the form
of carrying away carbon dioxide.
So all those things are important when we're exercising.
That's one of the reason our blood flow
increases as a result of that.
Glucose turns out to be a wonderful compound
for this purpose because glucose is very soluble in water.
It can move in the bloodstream
very easily because it's an aqueous environment.
The liver dumps it into the bloodstream and poof,
it's off to its target tissues in seconds.
It gets there very, very quickly.
So glucose is very, very useful for that.
As we will see next term, fat is not so good
for that quick energy because A, fat is not water soluble,
B, fat has to be packaged up into lipoprotein complexes
that have to made to be able to be soluble
in a water aqueous environment.
That's a broad view of gluconeogenesis.
Now gluconeogenesis as I said, if you know glycolysis,
you basically know gluconeogenesis because gluconeogenesis
uses 7 of the enzymes that are the reversal
of those in glycolysis and yes,
you should know the 4 enzymes of gluconeogenesis
that are different from those other enzymes in glycolysis.
I'm not asking you to know additional structures though.
I'm not asking you to know additional structures.
Student: Does glucose 6 - phosphatase have an acronym?
Ahern: Does glucose 6 - phosphatase have an acronym?
If you want to call it G6Pase, you may.
The other thing I noticed I didn't mention here
and I'll mention it very briefly
is the enzyme pyruvate carboxylase.
That was the first enzyme that I talked about.
That was found in the mitochondrion.
We'll see next term why that's kind of an important thing.
It catalyzes the reaction that you see on the screen.
There's the oxaloacetate molecule, there's the ATP,
the carbon dioxide, actually in the form of bicarbonate,
carbon dioxide, that's all the same thing.
The enzyme is one that uses a coenzyme.
I haven't really talked about coenzymes yet
and I want to say just a brief thing about them.
Coenzymes are molecules that enzymes
use to help catalyze a reaction.
They're a non-amino acid that an enzyme uses
to help it catalyze a reaction.
That's what a coenzyme is.
The coenzyme that pyruvate carboxylase
uses is one you'll see commonly for reactions
that involve an addition of a carbon dioxide to something.
The coenzyme it uses it known as biotin.
And biotin is really great at grabbing onto carbon dioxide
and getting it to the enzyme to do something with.
That's what biotin does.
Whenever you see the name carboxylase in an enzyme name,
it tells you A, that it's putting
carbon dioxide onto something, and as a consequence of that,
it almost always uses biotin to help it do that.
It turns out that the carbon dioxide is carried
at this end of the molecule out here.
The lysine is the place where it attaches to the protein.
So the protein has a lysine side chain,
the biotin gets attached and out here
there's a carbon dioxide that this biotin
will carry to the active site to the enzyme
so the enzyme can use that carbon dioxide.
PEPCK, just a brief word about that,
there's the reaction that it catalyzes.
PEPCK is one of those enzymes,
although your book shows some allosteric effectors,
it's really not very regulated allosterically.
A much more important regulation of this enzyme
is control of where it's synthesized.
So for example, my muscle cells are not going to make PEPCK
because they're not going to go through gluconeogenesis.
There's no reason for them to have and use that enzyme.
My liver cells on the other hand,
which do go through the reactions of gluconeogenesis, uh oh.
[laughing]
My liver cells, which do have the reactions
of gluconeogenesis will in fact make PEPCK.
What I just introduced for you, you probably didn't realize,
was a third mechanism of controlling enzyme.
We talked about 3 earlier in the term.
One was allosteric control.
2nd was covalent modification.
Now the third is whether or not an enzyme is made.
If the enzyme is not made, that's the ultimate control.
So PEPCK is regulated primarily by whether
or not a cell makes it.
That of course involves control of transcription
and/or translation, and we'll talk about that next term.
Questions about that?
You guys look like you're asleep today.
Why is everybody smirking?
Yes, sir.
Student: So when you eat like a meal that's really full
of fat and you feel super lethargic,
is it just your body trying to put all the energy
into breaking it down?
Ahern: So when you eat a meal that's super high
in fat and you feel how did you say?
Student: Lethargic.
Ahern: Lethargic.
Is that because your body is putting all its attention into
breaking down that fat?
Partly.
One of the things that happens with eating a meal of anything,
even if it's not a big meal of fat,
is that your digestive system diverts
a lot of blood supply to it to help carry things away.
So instead of more blood being available to your muscles
and brain and so on and so forth,
your digestive system is kind of taking over.
As a consequence, there's less oxygen for you to think
and there's less oxygen
for your muscles and so forth to do things.
So it's a natural response of your body with that lower supply
that you're just not going to feel like
going out and doing stuff.
Student: Tomorrow, when we all eat ungodly amounts of food...
Ahern: When we eat I believe you said ungodly amounts tomorrow,
is that going to be a factor?
It is going to be a factor.
One of the things some people say is a factor
with Thanksgiving, if you eat a lot of turkey,
the claim is that turkey is full of tryptophan
and tryptophan can be converted into molecules
that help you to sleep.
That's a little controversial
so whether that is true or not I don't know.
But I'm willing to take the risk.
[class laughing]
Other questions?
Would you guys like to sing a song?
Alright, let's sing a song.
I've got two songs.
Maybe we should sing,
let's sing the short one first.
To do this one, I have to get you
in the right frame of mind, okay?
The right frame of mind goes as follows.
There was a song that was written back in the 1930s.
The 1930s was the Depression.
And everybody was very upset,
kind of like you guys will be after the lecture is over.
Oh damn, I don't get to hear anymore biochemistry.
They're very upset, they're very depressed.
They needed something to build them up, right?
They needed something to make them feel better.
America's songwriters created some really
amazing songs at that time.
I'm going to get you started on one of them.
You'll see why I get you started
on this song in just a second.
The song is called "Happy Days Are Here Again."
Does anybody know this song?
We're going to start to sing this song together.
Lyrics: Happy days are here again
The skies above are clear again.
Let us sing a song of cheer again.
Happy days are here again.
Aren't you happier now?
Happy days are here again.
The skies above are clear again.
Let us sing a song of cheer again.
Happy days are here again.
One more time!
Happy days are here again.
The skies above are clear again.
Let us sing a song of cheer again.
Happy days are here again.
Next verse.
Crappy days are here again.
The sky above's not clear again
And the sun has disappeared again.
Crappy days are here again.
Rain is falling from the sky.
I wish I knew the reason why.
Guess I'll have to wait until July
For the weather to be dry.
I do not mean to harangue.
Since rain provides yin and yang.
Because the flowers every one
Love moisture followed by the sun.
Let's stay happy til the rain is done.
In Corvallis, Oregon.
Ahern: Now don't you feel better?
[class laughs]
I know you do.
Pretty much, yeah.
This time of year it is kind of relevant i think.
I have another one but we'll save it until
I tell you about a couple other things.
I'm actually going to go easy on you guys today
because you came here on a tough day.
Thanksgiving's tomorrow and everybody else
is leaving down and why didn't he give a pop quiz
so that we got extra credit?
You know, and why didn't he give us those As
that he talked about and so forth?
I'm not going to go off the deep end,
I'm going to save that for Monday.
Going off the deep end is something I can do.
And I figure why should we do that now?
Let's do it Monday.
I'm going to tell you about a cycle that you'll find
very interesting and very easy to understand.
It's called the Cori cycle.
I'm going to skip this and come back
and talk about this on Monday.
But the Cori cycle is what I want to finish with
and then we'll sing one more song.
So the Cori cycle is an important cycle
that was discovered by a husband and wife team named Cori.
It turns out to be of critical importance in our body.
The Cori cycle is a way for our body to handle
very diverse sets of exercise situations.
So let's imagine, forget the screen for a moment,
let's just imagine that I am out on my morning jog
which I haven't be able to do all week
because it's been raining and I've been sick.
But I'm out for my morning jog,
which I'll be out tomorrow morning.
Anybody who wants to run, come with me.
And out running, and I will take off from
my house and go for a ways.
My body will fairly quickly recognize
that my muscles really want glucose
because my muscles burn glucose to get pyruvate,
ultimately get ATP and all kinds of things from that.
My muscles don't have a tremendous amount of glucose in them
so my liver wakes up and starts producing glucose.
That epinephrine hormone that we talked about,
one of the things it does is it stimulates
the release of glucose by the liver.
So my liver takes that glucose
and it dumps it into the bloodstream
because the liver doesn't need the glucose.
The muscle cells need the glucose.
The glucose travels to my muscle cells,
it gets to the muscle cells,
the muscle cells go thank you very much.
Student: So it's doing more of the releasing
previously stored glucose, not running gluconeogenesis...
Ahern: Her question is "is it releasing previously stored
"glucose or doing gluconeogenesis,"
the answer is it's doing both.
So the liver releases the glucose, the muscle cells grab it.
And I keep running and running and I'm an old guy
so I have a pretty good heart, but my heart probably
isn't delivering as much blood and as much oxygen
as fast as my muscles can use it.
That's especially true the longer that I run.
So the longer I run, the less oxygen
my muscle cells are going to have.
My muscle cells are going to take this glucose
and as long as they've got oxygen
and they can make pyruvate and acetyl-CoA, they're happy.
But what happens when they start running out of oxygen?
Well, we remember that the only thing that they can do
to keep glycolysis going at that point
is convert pyruvate into lactate.
And they do that.
Lactate, as I said in class at the time I mentioned it,
is a biological dead end.
It doesn't go to anything else.
All we can do is convert it back to pyruvate.
And to do that, we need oxygen.
The muscle cell doesn't have oxygen, lactate's sitting there,
it's not doing the muscle cell any good.
Moreover, lactate is an acid,
so it's starting to drop the pH of the muscle cell
and that's a problem.
The muscle cell says hell with that,
and it dumps lactate into the bloodstream.
The bloodstream goes right back to the liver
which has plenty of oxygen because the liver
is close to your lungs.
It converts that lactate to pyruvate and then boingo!
It does gluconeogenesis.
What we see is a cycle that's occurring in the body
and it's known as the Cori cycle.
The liver is making glucose, dumping it in the bloodstream.
The muscles are using the glucose,
making ultimately lactate when they run out of oxygen.
Lactate's going back into the blood stream
and back up into the liver.
It's a beautiful system and it works amazingly well.
Make sense?
One last thing.
This cycle is needed because, again,
muscle cells can't make their own glucose.
They're depending on the liver.
It makes sense for the liver to do it
because the liver has plenty of oxygen.
The muscle cells don't have plenty of oxygen.
Yes, sir?
Student: Eventually, the liver will run low on oxygen.
The oxygen demand will eventually out stretch
your lung and hearts' ability to put out, right?
That's like hitting the wall in a marathon run or something?
Ahern: So his question is, is hitting the wall
in marathon running the equivalent of the liver's
basically losing the ability to maintain oxygen and so forth
and people argue about what hitting the wall
in marathon running actually means.
A lot of thinking is it actually is resulting
from the depletion of your stores
of glycogen which liver is storing.
So in addition to making glucose by gluconeogenesis,
the liver can also release glucose
as she was referring to up here, by breaking down glycogen.
It's thought that hitting the wall occurs when you really
don't have hardly any glycogen left.
Again, that's argued.
Other questions about that?
Connie: Speaking of hitting the wall,
I heard that after you hit the wall, you start burning fat.
What is that about?
Ahern: She says she heard that after you hit the wall,
you start burning fat.
Yes, you will be burning fat.
You'll be burning fat to some extent as you're running as well.
It's just that it's not as readily available
source of energy for quick things at that time.
But yeah, if you didn't have some back up energy
source at that point, you'd be in pretty deep trouble.
Burning up fat's important.
Turns out burning up fat is very important for your heart.
Your heart uses fat as a big energy source.
Though I don't talk about it much here,
another thing that your heart can actually use
as an energy source is lactate.
The heart can pull lactate out, convert it to pyruvate,
but then instead of making glucose,
it will convert pyruvate to acetyl-CoA again
because the heart has plenty of oxygen
and acetyl-CoA is a source of ATP.
Lactate can be used by the heart as a way
of keeping the heart going.
That's an important thing to do, too.
Other comments, questions?
Student: Is it generally?
Ahern: Generally, that's considered an important thing.
Depends on how well you like your relative, I guess.
Did you have a question?
Student: If the heart muscle has developed the ability
to use lactate, why haven't regular muscles
developed that ability?
Ahern: Why haven't regular muscles developed that ability?
Well, they would, but remember the regular muscles
are away from the lungs.
So they run out of oxygen.
They could, if they have oxygen,
but they don't have that.
If they had oxygen, they wouldn't be making
lactate in the first place.
They're only making lactate because they have
to when they're out of oxygen.
It's the oxygen that's determining that.
It's not any limitation that's there of theirs.
Make sense?
How about a last song?
The last song I always get out of breath.
That's why I didn't sing it after the last one.
because the last one is a long song.
It's my favorite song I've ever written.
I hope you guys like it.
It's to the tune of "Supercalifragilisticexpialidocious."
[class laughing]
You know what it is.
Here we go.
It's called gluconeogenesis.
Lyrics: When cells have lots of ATP and NADH too
They strive to store this energy as sugar, yes they do.
Inside the mitochondria they start with pyruvate.
Carboxylating it to make oxaloacetate
Oh gluconeogenesis is so exhilarating
Memorizing it can really be exasperating
Liver cells require it so there's no need for debating
Gluconeogenesis is so exhilarating
Glucose, glucose come to be
glucose, glucose come to be
Oxaloacetate has got to turn to PEP
Employing energy that comes from making GTP
From there it goes to make a couple phosphoglycerates
Exploiting ee-nolase and mutase catalytic traits
Oh gluconeogenesis is liver's specialty
Producing sugar for the body most admirably
Six ATPs per glucose is the needed energy
Gluconeogenesis is liver's specialty
Oh glucose, glucose, joy to me
Glucose, glucose, joy to me.
Converting phosphoglycerate to 1,3BPG
equires phosphate that includes ATP energy
Reduction with electrons gives us all NAD
And G3P's isomerized to make DHAP
Oh gluconeogenesis is anabolic bliss
Reversing seven mechanisms of glycolysis
To do well on the final students have to learn all this
Gluconeogenesis is anabolic bliss
Oh glucose, glucose factory
Galactus, glucose facotry
The aldolase reaction puts together pieces so
A fructose molecule is made with two phosphates in tow
And one of these gets cleaved off by a fructose phosphatase
Unless F2,6BP's acting blocking pathways
Oh glucogenesis a pathway to revere
That makes a ton of glucose when it kicks into high gear
A cell's a masterminding metabolic engineer
Glucogenesis a pathway to revere
Oh glucose, glucose jubilee
Glucose, glucose jubilee
From F6P to G6P that is the final phase
The enzyme catalyzing it is an isomerase
Then G6P drops phosphate and a glucose it becomes
Inside a tiny endoplasmic-al reticulums
Oh glucogenesis is not so very hard
I know that on our final we will not be caught off guard
Because our professor lets us use a filled out index card
Gluconeogenesis is not so very hard.
Yeah!
Thank you.
Happy Turkey Day.

#第24回 ケビン・アハーンのBB450/550のための生化学グルコネジェネシス講義 (#24 Biochemistry Gluconeogenesis Lecture for Kevin Ahern's BB 450/550)

#第24回ケビン・アハーンのBB450/550のための生化学グルコネジェネシス講義 (#24 Biochemistry Gluconeogenesis Lecture for Kevin Ahern's BB 450/550)