I leave WordPress for a week, and suddenly it looks like the Tumblr designers were let loose on it?
(I’m sorry, I shouldn’t have said that… I love Tumblr with a good portion of my heart. It’s just…)
But anyway! It’s Thanksgiving break for we UNP students, which means that we’re coming up on the end of the semester real quick-like. In fact, the end of the semester is coming so fast that I almost didn’t see it coming—I’ve been spending this whole weekend drawing and babbling aloud in really bad Chinese.
Today, in following with the theme of Thanksgiving, we’re going to study a critical aspect of metabolism that we haven’t touched yet: fatty acid catabolism.
We’re all painfully aware that our bodies love to store fat. It’s something we become increasingly sensitive to around holiday season, where we try in vain to limit our caloric intake in order to prevent our body from doing it. Still, if you’re anything like me, there’s no point in even trying to pass up on that turkey gravy…
However, as we also know, at least on some level, our bodies break down fats, as well. As hard as it may be to believe, it is, in fact, true—when our bodies are low on energy, we release glucagon, which triggers us to break down fatty acids in our mitochondria into energy that we can use. When we look more at the details of this metabolism, called beta-oxidation, we’ll see why our body is so keen to hang onto all of those fats that we think are the bane of our existence.
However, before we can metabolize anything, we have to get fatty acids from our cytosol into our mitochondrial matrix. This is a bit trickier than you’d think, and it follows this general reaction:
1 Fatty Acid (cytosol) + CoASH + ATP —> 1 Acyl-CoA (Matrix) + AMP + 2 Pi
There are a couple of things to note here: firstly, the fatty acid that we transport doesn’t appear in the matrix as a fatty acid, but rather as an acyl-CoA. Also, we consume not one, but two phosphoanhydride bonds in transporting this little sucker from the cytosol to the matrix.
To look at it in a little more detail, this whole process takes place in four steps:
- Activation of the Fatty Acid
- Acyl Transfer
- Acyl Transfer
In Step 1, CoASH and ATP are reacted with the free FA to produce Acyl-CoA, AMP and PPi using an enzyme called Acyl-CoA Synthetase. (As you may remember, PPi is immediately cleaved in half in the cytosol, becoming 2 Pi.) This step transfers the CoA group from CoASH to the fatty acid, producing that all-too-familiar thioester bond and using energy in the process.
In Step 2, the acyl group on acyl-CoA is transferred to a molecule called carnitine using Carnitine Acyl Transferase I. This regenerates CoASH, for the time being.
In Step 3, a Translocase exchanges this acyl-carnitine (which is in the inner space) with a carnitine in the matrix.
In Step 4, Carnitine Acyl Transferase II transfers acyl groups, this time from acyl-carnitine to CoA, regenerating acyl-CoA and carnitine in the matrix.
All right, now that we’ve gotten our fatty acids into the mitochondrial matrix, it’s time to actually break them down. This is where beta oxidation comes in.
Let’s use the example of the metabolism of palmityl-CoA, the acyl-CoA version of palmitate. For one round of beta oxidation, we have this net reaction:
Palmityl-CoA + 1 FAD + 1 NAD+ + 1 H2O + 1 CoASH —> Myristyl-CoA + 1 FADH2 + 1 NADH + 1 H+ + 1 Acetyl-CoA
Now, looking at the net reaction, we notice a couple of things. Firstly, we’re using doing a lot of redox (getting a total of four electrons with FADH2 and NADH). Secondly, we’re using another CoASH to make another thioester bond, meaning that we have two CoA products. Thirdly, our palmityl-CoA (FA = palmitate, 16 C) has been reduced by two carbons into myristyl-CoA (FA = myrsitate, 14 C). This reaction proceeds by four steps, which are each mediated by an enzyme:
- Dehydrogenase (FAD —> FADH2)
- Dehydrogenase (NAD+ —> NADH)
Now, let’s look at each of those steps in a little more detail, shall we?
First, an FAD-dependent dehydrogenase mediates the oxidation of Palmityl-CoA into an α,β-Enoyl-CoA. It does this by abstracting a proton and a hydride from the alpha and beta carbons of the acyl-CoA, reducing FAD to FADH2 in the process. As we know, FADH2 reduces CoQ, contributing reduced CoQH2 to the Q-Pool.
Second, a hydrase adds water across the double bond created in the first step, hydroxylating the beta carbon (hmmm…) and turning the enoyl-CoA into a L-hydroxyacyl-CoA.
Third, an NAD-dependent dehydrogenase oxidizes the beta carbon of the hydroxyacyl-CoA, making it into a ketoacyl-CoA in a reaction that’s quite familiar. This makes NADH, meaning that that beta carbon is now oxidized by a total of four electrons.
Fourth, CoASH is used to cleave the ketoacyl-CoA into an acetyl-CoA and an acyl-CoA that’s two carbons shorter than it was originally. (In this case, palmityl-CoA becomes myristyl-CoA). This is accomplished using Thiolase, which is an acetyltransferase.
Here’s a Thanksgiving Break-tier image that summarizes the whole mess. (The intermediates have proper names, I’m sure, but as I can’t get any reliable confirmation that the ones I chose were correct, I just used generalizations. Also, the internet calls my professor’s “palmityl-CoA” “palmitoyl-CoA.”):
Now, probably you’re looking suspiciously at that Myristyl-CoA and thinking, “You’re going to do the thing, aren’t you.”
You’re right! Myristyl-CoA goes through this cycle again, losing two more carbons. That acyl product goes through it again, and then again and again and again and…), until you end up completely oxidizing palmityl-CoA into eight Acetyl-CoAs.
Overall, this takes seven steps (think cutting a sixteen-carbon chain into eight pieces—you have to cut it seven times), and it produces quite a lot of FADH2 and NADH. Don’t believe me? Look at the net reaction:
Palmityl-CoA + 7 FAD + 7 NAD+ + 7 H2O + 7 CoASH —> 7 FADH2 + 7 NADH + 7 H+ + 8 Acetyl-CoA
As you can see, we make seven FADH2 and seven NADH for each molecule of Palmityl-CoA. If you think back to aerobic production of ATP, you’ll remember that that’s a heck of a lot of energy.
In fact, let’s just break it down, shall we? Let’s pretend we have a six-carbon fatty acid and a molecule of glucose, and we run them each through their respective metabolisms. Glucose produces two pyruvate, which are collectively worth 25 ATP (eight NADH*2.5 + two FADH2*1.5 + 2 GTP), two NADH (*2.5 ATP) through glycolysis, and two ATP through glycolysis. For one glucose, we use that nice, round number of thirty ATP, which we thought was pretty impressive.
Meanwhile, pushing our six-carbon fatty acid through beta oxidation produces two NADH, two FADH2, and three acetyl-CoA. Each acetyl-CoA is worth ten ATP when it’s pushed through the citric acid cycle (3 NADH*2.5 + 1 FADH2*1.5 + 1 GTP), each NADH is worth 2.5 ATP, and each FADH2 is worth 1.5 ATP. Overall, we end up with 3o + 5 + 3 = 38 ATP for a single six-carbon fatty acid. That’s twenty percent more energy than we get from a glucose molecule.
It gets even better when you evaluate this energy content based on weight: one gram of a carbohydrate contains 4 Cal, whereas one gram of a TAG contains 9 Cal. That’s over twice the energy of a carbohydrate.
Now you get why our bodies love these suckers so much, eh? They’re beautifully energy-efficient, and relatively compact, to boot. Just think about that, when you’re staring in resentment at that gravy that you’ll probably be eating this week. 😉
All right, there’s a lot more to say on this subject (what about unsaturated fats?), but since our professor is pressed for time, we’re skipping it. Instead, we’re going to move on to something that makes us feel a little twitchy—fatty acid biosynthesis.
Questions? Comments? Recipes for gravy? Put them down there! (I have to learn these things at some point, you know.)