At the end of glycolysis, the 6 carbons that
were present in glucose have been converted to 2 molecules of pyruvate, or
pyruvic acid, they're the same thing, and so we have two 3-carbon molecules of
pyruvate, so two of these for every glucose, and that accounts for all 6 of the
carbons that were in the glucose molecule. The first thing that has to happen in the
presence of oxygen is to convert pyruvate to a molecule called acetyl-CoA, and I tend
to call this the bridge step because it isn't
part of glycolysis, and it isn't
part of the Krebs cycle. It's actually a step that has to occur
in between them, so pyruvate is the end of glycolysis, acetyl-CoA is the beginning
of Krebs, but pyruvate isn't part of Krebs, and acetyl-CoA isn't the result of
glycolysis, so it's sort of a bridge between those 2 pathways,
and our 3-carbon pyruvate -- remember again that for every glucose,
this is going to happen 2 times -- so for every pyruvate, what's going
to happen in this bridge step is that pyruvate is going to
get converted to acetyl-CoA. Each one of these blue balls is a carbon,
and so I want you to notice how pyruvate has 3 carbons, but acetyl-CoA only has 2, and what happens? Well, we're going to lose our first carbon
completely oxidized to a CO2 molecule. So from every glucose molecule, 2 of the
carbons will become fully oxidized to CO2 by the time we begin the Krebs cycle,
so we have 6, and 2 of them are going to have been fully oxidized in this bridge
step, which means that we have 4 left to fully oxidize to CO2 if we're going to squeeze every drop
of energy out of those carbons that we can. How do we know we're squeezing energy out? Well, we're oxidizing pyruvate to
acetyl-CoA, but look what we're doing to NADH. We're taking NAD+, and we're
reducing it to NADH, so we're making a high-energy
molecule here, so the energy that was in this molecule is being transferred,
and we're making a high-energy NADH, and remember these NADH molecules
are going to be used in the electron transport chain to make ATP. For every NADH, we're going to make 3 ATP,
and again, this step occurs in the presence of oxygen only, and so I know that this NADH
is destined to release its energy and yield 3
ATP because this is, by definition,
an aerobic process if we're converting pyruvic acid to acetyl-CoA. What's the difference between
eukaryotic cells and prokaryotic cells? We almost always talk about the Krebs cycle,
and actually aerobic metabolism in general, we almost always talk about it from the lens
of a eukaryotic cell, and in eukaryotes, the glycolysis processes are taking place
in the cytoplasm of the cell, but in a eukaryotic
cell, acetyl-CoA has to be shuttled across
the membrane of the mitochondria, and the reactions for the Krebs cycle
occur in the matrix of the mitochondria, that's this inner fluid layer, and then the
mitochondria has a double membrane here. Okay, so in a bacterial cell, the Krebs cycle
just continues in the cytoplasm of the bacteria because bacteria don't have mitochondria,
and the electron transport chain enzymes, which are actually located in the
inner membrane of the mitochondria, they are located within the plasma
membrane of the bacterial cell, so just to kind of give you a
frame of reference, for bacteria, our electron transport chain proteins
are located in the plasma membrane, in the mitochondria, they're
located in the inner membrane. In the mitochondria, the Krebs
cycle takes place in this matrix. In a bacterial cell, the Krebs
cycle would continue to take place in the cytoplasm just like the glycolysis
did. So this is a slide that causes
students to feel anxious. I don't want you to feel anxious. We're not going to memorize, you know, all
of these names, but I'm just going to reorient
you to something we've already talked about. This is the conversion of pyruvate to
acetyl-CoA that we saw 2 slides ago, and remember that we're oxidizing pyruvate,
and we're reducing NAD+ to form NADH, so we're taking some electrons,
and we're shuttling them to NADH to make this a high-energy molecule, and
we're fully oxidizing one of the carbons that was originally on our glucose to CO2,
and because we do this 2 times for every glucose, we're going to make 2 carbon
dioxides at this step. Then our acetyl-CoA molecule,
which we said in a eukaryotic cell with mitochondria will get shuttled
across the mitochondrial membrane, this is going to begin the Krebs cycle, and
what happens is this molecule here, oxaloacetate, is going to combine with acetyl-CoA to form
this molecule citrate, so I just want you to count the carbons, and you have 4 carbons
in oxaloacetate, you have 2 carbons in acetyl-CoA, and our citrate has 6 carbons, 1, 2, 3, 4,
5, 6. So 4 plus 2 equals 6. Okay, so we're keeping track
of our carbons here. Then what's going to happen is
we're going to go through a cycle. So notice that we're going
around in a circle with a bunch of different chemical reactions,
and what's going to happen? Well, we're going to come right
back to oxaloacetate again. So we're going to convert -- the Krebs
cycle converts citrate back to oxaloacetate through a series of steps, and once oxaloacetate
has been remade, it can then combine with another molecule of acetyl-CoA, and
this set of chemical reactions, the pathway, can occur many, many, many times. Now what happens during the Krebs cycle? Well, without memorizing all these names, you can certainly learn some
of the big-picture ideas. One of the things that happens is we're going
to continue to oxidize carbons and squeeze energy out of our glucose molecule, what remains
of it. So notice here when we go from isocitrate
to alpha-ketoglutarate, what do we do? Well, we're going to oxidize isocitrate. We're going to oxidize one of
the carbons completely to CO2, and the energy that's released is going
to be used to convert NAD+ to NADH, okay? So we're stripping the carbon of its energy,
and we're putting that energy into NADH so that we can then use it to make ATP. After alpha-ketoglutarate,
what's going to happen? We're going to do it again. All right, we're going to strip another CO2
off. See, here it goes, fully oxidized. When we oxidize this carbon,
we know that we have reduced -- we have to reduce something else --
so NAD+ gets reduced again to NADH, so we have another high-energy
molecule that can generate ATP for us. The resulting molecule is something called
succinyl-CoA, and when it gets converted to succinate, we are going to
end up generating another ATP. Technically it makes a molecule called GTP
here, but that is equivalent in energy to ATP, so we really just record this as
an additional ATP that gets made. When we go from succinate to fumarate,
we are also oxidizing succinate to become a more oxidized molecule, and we are going to then reduce
a molecule called FAD to FADH2. This can also enter the electron
transport chain and generate energy for us. NAD generates 3 ATP per NADH. FADH2 generates 2 ATP per FADH2, and
in the next set of lecture slides, we'll talk about why that's the case,
but that's a topic for the next lecture. All right, then we go from fumarate
to maleate, and then one more time, we're going to oxidize maleate
to form oxaloacetate, and every time we oxidize one
molecule, we have to reduce another, and again we're really just squeezing energy
out of that original glucose molecule, and we're going to make another
high-energy NADH. Once we get back to oxaloacetate, what happens? Well, this molecule can then combine
with another molecule of acetyl-CoA, and this cycle can go around
and around and around, each time generating all these high-energy
intermediates NADH and FADH2, and don't forget the ATP. Now there's an accounting part of this that
we haven't talked about, but I want you to remember that for every glucose, we
have 2 pyruvates, right? There were 3 carbons here, but there
were 6 original carbons in glucose, so each glucose molecule requires
2 turns of the Krebs cycle to completely oxidize all the carbons that
were in glucose to CO2, so let's count one cycle and count all the CO2, and then we're going
to remind ourselves that we do it twice. So for every pyruvate, we have 3 carbons. To completely oxidize these 3 carbons,
all 3 of them would need to be turned into carbon dioxide, so where does that happen? Well, we lose one in the bridge step,
and we lose one here between isocitrate and alpha-ketoglutarate,
and we lose another one here between alpha-ketoglutarate and succinyl-CoA. So 1, 2, 3 molecules of CO2. That's it. That's all 3 carbons that were in pyruvate. If you do that twice, then you're going to
get 6 CO2s, 1, 2, 3, and 3 times 2 is 6. That's all of our carbons that were in glucose
initially, so they're all getting oxidized in 2 turns of the Krebs cycle to CO2. So that takes our glucose molecule, and it completes the conversion
of all those carbons into CO2. Okay? It doesn't complete our ability
to get energy out of the glucose because we still have the electron
transport chain that's going to allow us to suck the energy out of these NADH and FADH2
molecules, but it does complete the processing of glucose to carbon dioxide where
those carbons are fully oxidized. Don't forget that we said that
reduced molecules have more energy, more oxidized molecules have less energy,
so CO2, we said, was basically a waste product. We've stripped all the energy
out of that carbon at that point. All right. So this is an overview of
the Krebs cycle reactions. Basic idea here, acetyl-CoA enters the mitochondria of the eukaryotic cell. If you are into organic chemistry,
the coenzyme A is a leaving group which allows the oxaloacetate to combine
with the 2 carbon acetyl group in acetyl-CoA, so basically that CoA helps the oxaloacetate
combine with acetyl-CoA to form citric acid. And then here's a summary. So we have 2 decarboxylation reactions. A decarboxylation reaction is when
we remove a carbon as CO2, so, for example, this here is a decarboxylation. We're decarboxylating pyruvate to form CO2,
and then there are 2 more decarboxylation reactions in the Krebs cycle itself, and we also
in the Krebs cycle produce NADH, FADH2. We're going to make 3 NADHs. Oh, it just says 3 here, this is a
different picture of the same cycle. So we're going to make 3 NADHs, 2 FADH2s,
and an ATP, so here we have our 1 ATP, 3 NADH, 1
FADH2, and then our 2 CO2s in the Krebs cycle,
but don't forget that we also lost a CO2 in the bridge step, so ultimately
we lost 3 for every pyruvate, which means we lost 6 for every glucose. So I've got one more short set of slides here
to kind of summarize what we've been talking about and think about the big picture.