Glycolysis

Here it is! The long-awaited! The foreshadowed! The promised! The awful!

[ahem]

Yep, today I’m finally going to talk about glycolysis.

[cue cheesy YouTube opening music]


We all know that, when we eat something, we’re taking in energy for our body to use to keep us going. However, not everybody knows exactly how we go about that.

“You break it down for ATP!” is the general answer. If you’re my sister, you’re rolling your eyes and going, “Stoppit. I know that cellular respiration exists. Let me name for thee the stages.”

(Shh! I have to do an intro bit, okay?)

Well, our bodies love to break glucose down into little bits and suck the energy out of it in the process. We have, in fact, numerous ways of doing this. The most efficient way uses oxygen, which is why we belong to an itty bitty class of organisms known as aerobic organisms. However, if you’re an anaerobic organism, a red blood cell, or a plain ole plain Jane cell without some pyruvate to work with, you’ve got to do things the old fashion way.

That’s right, today we’re going to be looking at glycolysis, a form of anaerobic respiration that unites us all. All of us. All living organisms.

(All of us.)

Glycolysis can generally be referred to as the oxidation of glucose to pyruvate. While we’re doing that, we put some electrons (the ones glucose loses) into NADH and get some ATP. The net reaction looks a little like this:

1 Glucose + 2 ADP + 2 Pi + 2 NAD+ —> 2 Pyruvate + 2 ATP + 2 NADH + 2 H2O + 2 H+

Oh, that’s not too terribly bad, you might be tempted to say. Well, unfortunately, the actual process of glycolysis is one wild ride that you might want to get off of now.

Still with me? Okay! Don’t say I didn’t warn you!

Glycolysis is divided up into ten distinct steps, and those steps can be split up into three stages. We’ll take things nice and slow by looking at things step-by-step, so don’t worry too much, okay?

Stage 1: Conversion of Glucose to Fructose-1,6-Bisphosphate

This is the first stage of glycolysis, and probably the last time you’ll see something recognizable unless you’re someone who enjoys doing chemistry in their spare time. In this stage, we’re going to kick things off by introducing flux with a lil’ bit of ATP.

Step 1: Glucose to Glucose-6-Phosphate

In this first step, a transferase called hexokinase irreversibly transfers a phosphate group from ATP to a molecule of glucose, producing glucose-6-Pi and ADP. This is a flux step, meaning it is not in equilibrium. Here’s a picture:

step 1 glycolysis

(I can’t get the little curvy arrows to go in, but imagine that, at the same time, ATP is going to ADP.)

Step 2: Glucose-6-Phosphate to Fructose-6-Phosphate

Now that we’ve got our phosphorylated glucose, an isomerase called glucose-6-phosphate isomerase will interchange glucose-6-phosphate (aldohexose-Pi) with fructose-6-phosphate (ketohexose-Pi). This reaction requires no energy in either direction, and is in equilibrium.

If you’re having a bit of trouble seeing these two molecules as isomers, here’s a little picture I made. (Keep in mind that, in cells, these are both present as their cyclic forms, not their linear forms. It’s just easier to see this way.)

glucose fructoseStep 3: Fructose-6-Phosphate to Fructose-1,6-Bisphosphate

In the last step of stage 1, a transferase called phosphofructokinase 1 irreversibly transfers another phosphate from ATP to fructose-6-phosphate. This is another flux step, and it’s not in equilibrium. Here’s another image, again, without the curly arrows (:/):

step 3 glycSo, in all of stage one, we’ve used 2 ATP (1, 3), facilitated two flux reactions (1, 3) and made 1 fructose-1,6-bisphosphate.

Stage 2: Conversion of Fructose-1,6-Bisphosphate to 1,3-Bisphosphoglycerate

Now that we’ve spent all of the ATP that we’re going to spend in this reaction, it’s time to start getting something out of it. In stage 2, we use three equilibrium reactions to make NADH, a reduced form of NAD+ that we can pull electrons out of.

Step 4:  Fructose-1,6-Bisphosphate to Glyceraldehyde-3-Phosphate and Dihydroxyacetone-Phosphate

In this step, a lyase (bond-breaking) enzyme called aldolase cuts fructose-1,6-bisphosphate into two pieces: glyceraldehyde-3-Pi and dihydroxyacetone-Pi. This is how we’ll eventually get our 2 pyruvate. Here’s an image of the overall reaction, which is at equilibrium.

step 4 glycStep 5: Dihydroxyacetone-Phosphate to Glyceraldehyde-3-Phosphate

In this step, an enzyme called triose phosphate isomerase converts dihydroxyacetone-Pi (ketotriose-Pi) into glyceraldehyde-3-Pi (aldotriose-Pi). This is also in equilibrium. At the end of this step, we have two glyceraldehyde-3-Pi to work with:

step 5 glycStep 6: Glyceraldehyde-3-Pi to 1,3-Bisphosphoglycerate

Now we’re going to do something interesting again. In this reaction, each molecule of glyceraldehyde-3-Pi is oxidized by an oxidoreductase into 1,3-bisphosphoglycerate using Pi and NAD+. This produces a reduced form of NAD+ known as NADH. This reaction is at equilibrium, too. Here’s an image:

step 6 glycPhew! That’s quite a lot of ground we’ve covered, eh? In step 2, we’ve used three reactions that are at equilibrium to turn fructose-1,6-bisphosphate into two molecules of 1,3-bisphosphoglycerate, and we’ve gotten 2 NADH in the process. We’re finally in the homestretch! Now, let’s make some ATP!

Stage 3: Conversion of 1,3-Bisphosphoglycerate to Pyruvate

Now that we’ve split our phosphorylated fructose into two pieces and pulled electrons out using NADH, it’s time to use the chemical energy stored in these bonds to make some ATP. That is, after all, the whole purpose of this, right? Thankfully, these last four reactions do exactly that.

Step 7: 1,3-Bisphosphoglycerate to 3-Phosphoglycerate

In our first effort to make ATP, an enzyme called phosphoglycerate kinase takes a phosphate from each of the two 1,3-bisphosphoglycerate molecules and puts them on two ADP molecules. Because the energy to break the mixed phosphoanhydride bond in the 1,3-bisphosphoglycerate is pretty similar to the energy it takes to make the phosphoanhydride bond in ATP, this is a reversible reaction. Observe:

step 7 glyc

Step 8: 3-Phosphoglycerate to 2-Phosphoglycerate

Reaction eight is a pretty standard isomerization reaction which converts 3-phosphoglycerate to 2-phosphoglycerate using an enzyme called phosphoglycerate mutase. This is also at equilibrium:

step 8 glycStep 9: 2-Phosphoglycerate to Phosphoenolpyruvate

Now things get a little interesting. A lyase enzyme called enolase (because it makes an enol) pulls water out of 2-phosphoglycerate, generating a double bond and, with it, a hugely energetic molecule. You might recognize this one, in fact: it was one of the ones I said was more energetic than ATP! Dun dun dun dun…

step 9 glyc

All right, ladies and gentlemen! Now, what you’ve all been waiting for! It’s time for us to generate some net ATP!

Step 10: Phosphoenolpyruvate to Pyruvate

Here’s the step where we finally generate some net ATP. (We made some in step 7, but we also had to use ATP to start the whole thing, so really, we were just breaking even.) An enzyme called pyruvate kinase transfers a phosphate group from phosphoenolpyruvate to ADP, making 2 ATP and 2 pyruvate. This reaction is really favorable, since phosphoenolpyruvate is so high in energy. Remember why we said that is? Yup! It’s because it really wants to become its keto form (instead of its higher-energy enol form)! Don’t believe me? Just watch!

step 10 glycDang! That was a lot of work for two measly ATP, wasn’t it? Let’s recap, just to see what we did overall. Again.

Through these ten reactions, we used 2 ATP (Steps 1 and 3), made 4 ATP (2 each in Step 7 and Step 10), made 2 NADH (Step 6) and 2 water (Step 9). Now we have the context for the net reaction:

1 Glucose + 2 ADP + 2 Pi + 2 NAD+ —> 2 Pyruvate + 2 ATP + 2 NADH + 2 H2O + 2 H+

In addition to what we see above, we now know that there are three flux (far from equilibrium) reactions in this pathway (Steps 1, 3 and 10) and that we’ve released a total of -70 kJ/mol by running the whole pathway. That means the whole setup has a negative free energy change, and it’s spontaneous.

Well, heck. I’ve built up to this for a while, and it’s ended up being a fairly straightforward post. What’s a gal to do? Well, I could talk about gluconeogenesis…


I now can’t get Uptown Funk out of my head. Thanks, Obama.

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