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L10v02a_-_glycolysis
[00:00:00.00]
[00:00:01.00] SPEAKER 1: Hi there. In this video, we'll discuss central metabolism, which as
we saw is the two processes of glycolysis and the citric acid cycle. Glycolysis converts glucose,
which is six carbons into two molecules of pyruvate which is three carbons each. This occurs in
the cytosol. It's anaerobic and it produces a small amount of ATP. The pyruvate will then be
transported into the inner mitochondrial matrix. It'll get converted to acetyl-CoA.
[00:00:32.19] Acetyl-CoA will enter the citric acid cycle, which is also referred to as the TCA
cycle, tricarboxylic acid cycle and Krebs cycle. All these names mean the same thing. And once
as part of the citric acid cycle you will burn the one carbon of acetyl-CoA at a time. There's only
two so it's going to do it twice. Generate high energy, intermediate molecules, NADH and
FADH2. And these molecules, which we'll see in the next set of lectures and the next class
session, these produce a lot of ATP in an oxygen dependent manner in a process called oxidative
phosphorylation.
[00:01:15.85] This is a reminder of the overall pathway which we'll cover today. Glycolysis is
the conversion of glucose to pyruvate. And the citric acid cycle is pyruvate being converted to
acetyl-CoA and getting integrated to this cycle and producing carbon dioxide and NADH and
FADH2 which goes on to make a lot more ATP.
[00:01:43.43] Now here's a bit more detail on this process of glycolysis in which glucose gets
converted to pyruvate. I need to mention that I've made the decision not to require you to
memorize the structures of the carbohydrate even though I think most similar courses which
cover less material would require. It's also essential if you plan on taking the MCATs because
they will test for the independent structures. But for this course, this slide will just look at the
process at a higher level.
[00:02:16.19] Note that the first thing we do is we're going to invest two molecules of ATP. So if
the goal is to produce ATP, we're already two in the hole right off the bat. These two ATP
molecules end up donating phosphoryl groups to the sugar and we get fructose 1,6-bisphosphate
which is then split into two three carbon sugars initially different but then they are both
converted into two molecules of glyceraldehyde 3-phosphate.
[00:02:47.46] And now from the aldehyde moiety, we're able to make NADH which will provide
dividends down the road. And we'll be able to make two molecules of ATP from each of the
three. And so it's a total of four ATP molecules are made, minus the two we've invested means
we have a net of two ATP during glycolysis.
[00:03:12.45] This is what you get from anaerobic metabolism. And you'll see that oxygen has
not entered into the picture yet here. The process of making ATP without oxygen is referred to as
substrate level phosphorylation. As opposed to oxidative phosphorylation which we'll see occurs
in the mitochondria. In oxidative phosphorylation, each of these two NADH molecules will be
worth about three ATP each so we've made basically 10 molecules of ATP here although six will
be coming later.
[00:03:46.71] And then finally pyruvate is the molecule that will be shuttled into the
mitochondria for the citric acid cycle.
[00:03:53.52] I'd like to look at a detail of step three in glycolysis. As you know, we invested
two molecules of ATP. The first ones produces fructose 6-phosphate. At this point, the cell can
still use this molecule for things other than glycolysis or it can be converted back into
unphosphorylated fructose without significant loss of energy. But now when we invest the
second molecule of ATP and convert using the enzyme phosphofructokinase. Now we're
committed to pursuing glycolysis for this molecule. This is referred to as the committed step of
glycolysis. And that's because we've invested so much energy now into the production of that
molecule that it's too wasteful to do anything else with it.
[00:04:39.86] So here's some detail of step six and seven which are some of the energy
producing steps. See here we're making NADH. And here we're making the first of two ATP
molecules. So these are energy capturing steps. Notice that we have to, the first thing that
happens is we utilize a molecule of NAD+, which we're combining with glycerol 3-phosphate to
form this high energy intermediate.
[00:05:08.48] And normally, from that NAD+, we're going to get the NADH which in the
presence of oxygen is a good thing. If oxygen is not present like in anaerobic situations or when
you're exercising and you can't get enough oxygen to your muscles, the important thing is having
plenty of NAD+ present just so you can proceed, not so that you can get energy out of it.
[00:05:32.93] Now notice that we've taken an aldehyde which is a highly reduced form of the
carbon and converted it into an intermediate of a hydroxyl group. But here it is a thioester which
is an oxidized version of an aldehyde. But this is still a high energy bond and that can later be to
form a high energy phospho intermediate. And this phospho group can be transferred from ADP,
forming ATP in the process which I mentioned is called substrate level phosphorylation.
[00:06:10.46] And on this slide we can see the results of those two steps summarized. We have
an aldehyde converted to a carboxylic acid, which is an oxidized form, more oxidized than
aldehydes. We've gotten high energy electrons in the form of NADH and we've captured some of
the bond energy as a molecule of ATP.
[00:06:34.78] And on this slide, although making NADH and ATP themselves are energetically
costly, we show that steps six and seven overall is energetically favorable. The delta g of minus 3
kilocalories per mole. The oxidation step drives the synthesis of NADH and the formation of this
high energy bond which can then be hydrolyzed to produce ATP.
[00:07:03.16] So this has gone in the cytosol. The sugar has been converted down to pyruvate in
the process of glycolysis. And what we'll see in the next slide is that fats taken out for the
bloodstream, fatty acids imported into the cell, they'll go straight through the cytosol into the
mitochondria and they'll get converted to acetyl-CoA as well, allowing the citric acid cycle to
occur.
[00:07:28.21] Once fats and sugars are converted to acetyl-CoA, the metabolism is the same for
the both, how could be any different?
[00:07:37.13] The conversion of pyruvate to acetyl-CoA is a pretty interesting process. And
pyruvate is the three carbon molecule that's the endpoint of glycolysis. Acetyl-CoA is a two
carbon molecule. So we're going to lose a molecule of carbon dioxide. This represents the first
loss of carbon in the process. And three different enzymes are involved with the production of
NADH.
[00:08:02.11] The formation of another high energy intermediate eventually producing this
molecule called acetyl CoA. What's interesting about it is the structures of the enzyme complex
pyruvate dehydrogenase which has three different sub-units, sub-unit A, B, and C, which are
doing three separate reactions.
[00:08:23.10] Now we normally think of these reactions occurring in solution where one enzyme
would work on a substrate. It would release the substrate into the solution. It would diffuse
around. It would hit another enzyme and it would go ahead and do it's biochemistry. But that
takes a long time to encounter the substrate and the enzyme.
[00:08:47.26] And what actually occurs is more like bucket brigade, where one enzyme, the blue
one, will hand off the molecules directly to the second enzyme and will hand it off directly to the
third enzyme. The substrates are never free in solution. They are not given chance to defuse
away. So this is a very speedy way of performing three successive reactions in a geographically
constrained area.
[00:09:20.29] Now here's a molecule of CoA. The acetyl group would be added right here on the
sulfhydryl group. You do not need to know this structure. I just wanted you see it. You'll
recognize the basic structure here of ATP or ADP. And then a linker section. It's almost never
drawn out. It's always just represented as like this, acetyl-CoA. But I just want you to see it once.
[00:09:53.80] Now to conclude this portion of the video I just want to get ready for the citric acid
cycle. So I want to talk about the breakdown of fatty acids in the cell. Remember the fats are
absorbed from the bloodstream. They are converted to fatty acids. They are transported through
the cytosol right into the mitochondrial matrix. And then this cycle will occur. This is called the
beta oxidation cycle of fats. It is not to be confused with the citric acid cycle.
[00:10:25.91] The reduction of the two carbons occurs in four steps. And we're starting with an
energy rich saturated hydrocarbon which is a single bond. The first thing that is going to happen
is we're going to eliminate two hydrogens forming a double bond, which will then get oxidized
by the addition of hydroxyl group, which will get converted to a carbonyl. Then we'll cleave this
bond, releasing acetyl-CoA.
[00:10:53.22] Now these two carbons are just like the acetyl-CoA produced by glycolysis. And
we'll reattach another molecule of CoA to the now shortened fatty acid. And we're going to
repeat this cycle as many times it takes to cleave the hydrocarbons down by two at a time until
we have cleaved them all, we've captured them all as molecules of acetyl-CoA.
[00:11:24.97] In the process of making acetyl-CoA which will be very useful for oxidative
phosphorylation, we're also making molecules of NADH and FADH2 which will also be able to
be cashed in for molecules of ATP down the road.
[00:11:45.67] And here's where we'll start the next lecture with acetyl-CoA whether it's produced
by glycolysis or by beta oxidation of fatty acids entering into the citric acid cycle.
[00:11:58.68] Thanks.