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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.

[Ahern laughing]

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