Biochemistry Fatty Acid Catabolism III

Hello and welcome back to Educator.com, and welcome back to Biochemistry.0000

The last couple of lessons, we have been discussing the catabolism of fatty acids.0004

We talked about fatty acids with an even number of carbon atoms that are saturated, and then, we discussed the few extra reactions that are involved in metabolizing these fatty acids that have points of saturation.0010

Today, we are going to round up our discussion, and we are going to talk about the few reactions that are necessary to deal with fatty acids that actually have an odd number of carbon atoms, instead of an even number; so it does happen sometimes.0025

We will discuss those reactions, and then, we will close it out by talking about ketone bodies; so let's just jump right on in.0038

OK, now, let's go ahead and do this; I think I will stick with blue, so oxidation of fatty acids with an odd number of carbon atoms/carbons.0045

Let's use as our example the following fatty acid.0070

We will do C, C.0075

Let's see if I want to do this; I think I would like to do this all on 1 page.0080

You know what, I think I am going to go ahead and do the molecule in blue.0083

Let me go 1, 2, 3, 4, 5, 6, 3, 4, 5, 6 and 7.0088

OK, we have our 7-carbon S-CoA.0096

Again, I am not doing any of the Hs here.0100

In 2 cycles, this is fine up to a certain point.0105

You remember, we are cutting 2 carbons at a time, so we are going to cut right here; and we are going to cut right here.0110

Two cycles is not a problem.0116

Two cycles, we end up releasing 2 acetyl-CoAs.0120

Up to that point, it is not a problem, 2 acetyl-CoAs, and we will say 2 cycles of our normal beta-oxidation.0125

What you are left with is the following; what you are left with is this 3-carbon so propionyl-CoA.0135

You are left with C, C, C and S-CoA.0141

Now, how does the body handle this; what does it do with this 3-carbon fragment?0148

Well, here is what happens; the reaction that takes place is the following: HCO₃^- and ATP releasing ADP, and let me go ahead and draw the molecule 2, 3, S-CoA, and I will put this there, and I will go ahead and write the enzyme.0155

The enzyme is called propionyl-CoA carboxylase, and the coenzyme for this is biotin.0188

OK, in this particular case, what we have done is the following; we have taken this 3-carbon - this propionyl-CoA - and we have actually carboxylated it.0205

We have added a carboxyl group; we have added CO₂ to this thing.0212

The CO₂ comes in the form of the HCO₃^-.0217

Notice, here is where the carbonyl is; here is where the carboxy is added.0221

It is added to the alpha-carbon - OK - the first carbon next to it.0225

That is the first step of handling this 3-carbon fragment that comes at the end of normal beta-oxidation.0230

You are left with this odd number; OK, the next thing that happens is the following.0238

Let's go ahead and go back to blue.0243

In a reversible reaction, we end up with the following.0247

We are going to actually switch.0252

It is fine; I will go ahead and leave that carbon there.0256

I will go C, O^- and then, C, O, S-CoA.0260

This enzyme is called a methylmalonyl epimerase.0271

This is methylmalonyl-CoA epimerase.0275

This carbon, right here, is a chiral carbon, right?0287

It has a hydrogen; it has 4 different things attached to it.0292

It has a CH₃ group; it has this.0296

It has the hydrogen, and it has this; what this particular enzyme does is it switches places here.0299

It changes; this, right here, this molecule, this is D-methylmalonyl-CoA.0305

This is D-methylmalonyl-CoA.0314

What it does is it switches the chirality here; it changes it into L-methylmalonyl-CoA.0320

We have described it as when you draw these structures horizontally, vertically, if you change any 2 substituents, you actually switch the chirality at that carbon.0326

That is what we have done; notice, we have moved this carboxyl over to the right.0335

This carbon is this carbon; we have moved this up here, and we have taken this and brought it down here.0340

We switched these 2 places; in other words, this bond and this bond, we have just reversed them.0345

Now, I have the C, O, O, S-CoA down here and the COO^- up here.0351

Everything else is still the same; this is L-methylmalonyl-CoA.0356

I have just switched the chirality.0362

Now, the final reaction - let's go ahead and go back to blue - takes place over here.0370

This is called...well, let me go ahead and draw the molecule, actually, first.0378

We have C, C, and we have C.0383

Let me see; I am missing a carbon here, 1, 2, 3, 1, 2, 3.0390

I just want to make sure that this is drawn appropriately.0399

It goes here, COO^-.0405

Let's see, 1, 2, 3.0410

OK, I just want to make sure that all of these carbons are correct here because it is very, very easy to lose your way, and I actually prefer to draw them out, instead of doing it this way.0415

We are going to move that 1 carbon over.0428

OK, now, we have the C; we have the OO.0433

We have the S, the CoA, and we have our carbonyl here.0437

Let's go ahead and just put in some Hs for the hell of it, since this is our last stopping point.0443

OK, now, our enzyme is going to be methylmalonyl-CoA mutase, and the coenzyme is going to be coenzyme B-12.0451

Notice what we have done.0472

We have added a carboxyl group here to this carbon, and then, we have switched this and this.0476

We have moved those, so this stays the same.0484

Now, we have the carboxyl over here, and then, we have this thing over here.0488

Now, what we have done is we have taken this thing, and we have actually moved it over to this carbon; so that is all we have done.0494

We have 1; we have 2.0502

This is 1, 2; all we have done is we switched it, and then, we have moved it over 1 carbon.0505

We end up with the succinyl-CoA, and now, the succinyl-CoA can go and do whatever it does, enter the citric acid cycle or go ahead and go be involved in any number of other biosynthetic processes that it happens to be involved in.0512

This is how the body handles an odd number of carbons; it pretty much does normal beta-oxidation until you end up with a 3-carbon fragment.0527

It carboxylates it, switches it, and then, moves this over to form succinyl-CoA- absolutely extraordinary, absolutely extraordinary.0537

OK, now, let's go ahead and continue here.0545

Now, beta-oxidation - which is what we have been talking about - in the mitochondrion, it is the primary pathway for fatty acid catabolism.0551

OK, it is the primary pathway for fatty acid catabolism in animal cells.0571

OK, there are 2 other pathways.0590

One of them is called omega-oxidation, and the other is called alpha-oxidation.0597

We are going to discuss omega-oxidation; I will talk really briefly about alpha-oxidation.0608

I am not actually going to go through the particular reactions; it is available in your book, online, wherever you want to see it, but I do want to talk about the omega-oxidation, so let's talk about that.0612

This is not W; it is omega, the Greek letter omega, and omega refers to the end of the molecule, not where the functional group it, over at the end, the back end, the last carbon, the CH₃ group.0622

That is where the oxidation is going to take place; let's go ahead and now, we will just stick with the red- not a problem.0635

Omega-oxidation, now, it is a minor pathway, but it becomes more major if there are problems with beta-oxidation.0641

It is a minor pathway when that happens in the endoplasmic reticulum of liver and kidney cells, but becomes more important if there are problems with beta-oxidation.0655

OK, let's just go ahead and run through the process.0716

Let's actually go ahead and go to black here.0720

We have CH₃, CH₂, CH₂, CH₂, 1, 2, 3, 4, 5, 6.0727

Now, let's go ahead and do a couple more: CH₂, COO.0735

OK, we have 1, 2, 3, 4, 5, 6.0745

We have this 6-carbon fatty acid, carboxylic acid.0749

Alright, the first step is this.0755

We have NADPH + O₂ goes to NADP⁺, and the enzyme that is going to catalyze this is something called a mixed function oxidase.0760

I will not get into details of mechanism here or catalytic properties and things like that.0779

I am just going to run through the reactions; let me go back to black here.0788

Basically, what this does is it adds an alcohol group to the omega side, right?0793

This is the alpha; this is the alpha.0797

This is the omega; that is why it is called omega-oxidation, so what you end up with is the following: CH₂, OH, 1, 2, 3, 4, 5.0800

And then, you have this: NADPH, oxygen, NADP⁺, right?0815

OK, now, the next transformation is going to be the following.0825

Let me go to the next page and rewrite this.0831

We have 1, 2, 3, 4, 5, 6.0835

We have that, and let me go ahead and actually write my H₂ because it is going to be important that you see what is happening.0846

We have that that we just made, and now, the next reaction is going to involve NAD⁺, NADH + H⁺; and this is going to be an alcohol dehydrogenase.0855

This enzyme, this is an alcohol group that we have formed in the first step, and now, we are going to oxidize it, so alcohol dehydrogenase.0875

We are going to pull away a couple of hydrogens, right?0886

We are going to pull away that and that, a couple of hydrogens to turn this into an aldehyde.0890

Let me go back to black, and now, I have got C, H, 2, 3, 4, 5, 6.0897

OK, we have turned it into an aldehyde, and now, we are going to do the same thing again, NAD⁺, NADH + H⁺.0910

We are going to pull away a little bit more, and we are actually going to...this is called...let me go ahead and write the enzyme.0923

This is going to be an aldehyde dehydrogenase- that is it.0930

We are very, very familiar with what dehydrogenases do.0936

They oxidize, that is what they do, and let's go back to black; and what we are left with is COO^-, 2, 3, 4, 5 and 6, and we are left with that.0942

This is our final molecule; notice what we have.0959

Now, we have a fatty acid that has carboxyl groups at both ends.0962

Now, either end, both ends can be involved in normal beta-oxidation.0966

OK, let's go to red.0973

Now, both ends can form the acetyl-CoA or the coenzyme A.0980

Well, let's put it this way.0991

Both ends have this COO^-.0995

So, either end can form that - the coenzyme A end of it - and enter normal beta-oxidation- that is it.1003

OK, 1, 2, yes, acetyl-CoA, 1, 2, 3.1031

OK, now, let's talk about alpha-oxidation just very, very briefly.1043

Fatty acids containing a methyl group on the beta-carbon, they cannot be beta-oxidized.1052

They undergo alpha-oxidation in paroxysms, and we are not going to go through the particular reactions.1092

Basically, what it is is the following, so if you have C, C, C, C - let's do 1 one more - if you have something like this - this is the carbonyl, this is the alpha, this is the beta - if there happens to be a methyl group - a CH₃ - on the beta-carbon, there is no way that this thing can actually undergo beta-oxidation.1107

This methyl group, it presents some problems, so if you would like to go ahead and take a look, there is something else, something called alpha-oxidation, that takes place in paroxysms.1130

It is what the body uses to actually deal with molecules of this sort.1140

That is all that is going on there; OK, let's go ahead and close off this discussion of fatty acid catabolism by a discussion of ketone bodies.1146

Let me go back to black.1155

Now, the 2 fates of acetyl-CoA formed by the beta-oxidation - OK - in liver cells, the first thing it can do is enter the citric acid cycle.1161

We have seen that; it is what acetyl-CoA does.1198

One of the thing it does is enter the citric acid cycle; OK, another thing that it does or it can undergo, another one of its fates, is conversion to something called ketone bodies - and this does happen - and exported by the liver to other tissues to be used as possible fuel if there is something going on.1201

OK, there are 3 ketone bodies of importance.1236

One of them is acetone and its structure is COO, CH₃, CH₃.1245

OK, there is acetoacetate, which is CH₃, OO, CH₂, COO, O^-.1262

That is acetoacetate, and there is something called beta-hydroxybutyrate or D-beta-hydroxybutyrate.1282

That is CH₃, C, OH.1299

I will go ahead and put the H there.1306

This is CH₂, and this is COO, 1, 2, 3, 4.1310

Yes, there we go; these are the 3 ketone bodies that the body makes and exports to other tissues.1316

OK, let's go ahead and take a look at how this is done.1324

Let me go ahead and go to blue; I am going to start off with 2 molecules of acetyl-CoA: S-CoA + C, C, S-CoA.1330

Two molecules of acetyl-CoA are combined, and they form the following.1345

They form acetoacetyl-CoA.1355

Actually, let me draw these arrows.1359

Let me draw this one here and this one here, so that I can show this CoA.1364

SH is what leaves, and what we end up with is the following.1369

We end up with C, C, C, C.1374

This goes there; this goes there.1380

This is S-CoA; these molecules are put together, and they form something called acetoacetyl-CoA, and the enzyme that catalyzes this is something called thiolase.1383

We are left with acetoacetyl-CoA.1397

OK, now, the next reaction, what we have is something that comes in, something that goes out.1407

What comes in is C, C, a molecule of S-CoA and some water, and what is released is enzyme CoA; and the enzyme that takes care of this is something called HMG-CoA synthase hydroxymethylglutaryl-CoA synthase, just HMG, and the molecule looks like this.1420

1, 2, 3, 4, 5, we have 1, 2, 3, 4 and 5.1455

We have our S-CoA on that side.1463

We have that; oops, sorry.1470

Let's see, this is a beta-hydroxy, alpha-beta-hydroxymethyl.1474

We have a methyl group, and then, we have 2; and then, we have this.1482

There we go; this is our HMG-CoA.1488

This is HMG-CoA.1494

It is beta-hydroxy, beta-methylglutaryl-coenzyme A.1501

That is what the HMG, hydroxymethyl, they are both on the beta-carbon.1509

If you want, it is beta-HMG-CoA, but that is fine; HMG-CoA, you can just call it that- not a problem.1513

OK, now, from here, the following reaction takes place.1520

We end up forming...what ends up leaving is acetyl-CoA, C, C, O, S-CoA.1526

That is that one, and we are left with that.1542

OK, the enzyme is going to be HMG-CoA liaise, and what you end up with is acetoacetate.1549

Let's go ahead and see if we can draw this out.1562

Let me make it 1, 2, 3.1567

I will go ahead and put the CH₃ group there; I will go ahead and put that there, that there and that there.1574

Basically, what has happened is this.1581

This thing has gone away as that thing, and this carbon skeleton right here, 1, 2, 3, 4, that is the 1, 2, 3, 4.1586

This OH has turned into a carbonyl, and this carboxyl group, of course, stays.1600

What we are left with is the acetoacetate.1605

Yes, it is acetoacetate.1610

OK, now that you have your acetoacetate, let me go to the next page here, and let me redraw this; and then, we have...let me go back to blue.1615

We have 1, 2, 3, 4.1625

This is there, and this...actually, you know what, let me put it over here, and that is that; and this is CH₃, and let me put it that way.1630

That is the acetoacetate, and it undergoes 2 reactions.1645

Again, this is one of the ketone bodies.1652

One of the things that happens is if this loses CO₂, what you end up with is your acetone.1656

OK, and this will normally happen...let's go ahead and just say non-enzymatic decarboxylation, again, decarboxylation, non-enzymatic.1672

CO₂ is a very, very stable molecule, and if it can form, it will do so naturally.1690

It does not necessarily need an enzyme for this process to happen.1697

There is an enzyme that actually does make this happen also, so it can happen either way; but I am just going to call it non-enzymatic decarboxylation here.1701

What is important is that this acetoacetate ends up losing CO₂, this CO₂ group right here, and then, what you are left with is the acetone backbone.1709

Add a couple of hydrogens to this, and you are left with acetone.1718

Now, here is where it is interesting, so let's go ahead and...this is going to be NADH + H⁺, and released NAD⁺; and this is going to be catalyzed by beta-hydroxybutyrate dehydrogenase - OK - right?1728

Dehydrogenases, they can go backward of forward; they can oxidize, and they can reduce, and what you are going to end up with is the beta-hydroxybutyrate.1768

Notice how we have named this; what you are forming is beta-hydroxybutyrate.1777

We have named it, in this particular case, for the molecule that you are forming because normally, dehydrogenase are named for the molecule that you are oxidizing.1782

In this direction, it would be an oxidation.1791

In this direction, it is a reduction; that is why it is called the beta-hydroxybutyrate dehydrogenase for the product, and what you end up with is...let me go ahead and go back to blue.1795

We have C, C, C.1807

We have CH₃; we have OH.1812

We have H; we have that, and we have that, and this is beta-hydroxybutyrate, alpha - I am sorry - carbonyl carbon, alpha, beta, beta-hydroxybutyrate, 1, 2, 3, 4, 4 carbons, beta-hydroxybutyrate dehydrogenase.1816

Acetoacetate breaks down and reacts this way to form beta-hydroxybutyrate.1842

It can go this way to form acetone.1848

OK, now, the acetone is exhaled.1854

Yes, you are occasionally exhaling acetone.1860

Now, the acetoacetate - excuse me - and the beta-hydroxybutyrate are exported by the liver to other tissues, where they are reconverted to 2 molecules of acetyl-CoA, where they are reconverted to 2 acetyl-CoAs, thus entering the citric acid cycle and producing energy.1865

It is used as fuel- reconverted to 2 acetyl-CoAs, thus entering the citric acid cycle for fuel- that is it.1926

That is the formation of ketone bodies, acetoacetate, beta-hydroxybutyrate, acetone.1944

Two acetyl-CoAs are converted to acetoacetate; acetoacetate breaks down into this.1952

These are the 3 ketone bodies; the acetone is exhaled.1956

The acetoacetate, the beta-hydroxybutyrate, are transported out of the liver, out to tissues that need them.1960

They are reconverted back to acetyl-CoA; acetyl-CoA enters the citric acid cycle, electrons, electron transport chain, fuel oxidation-all the normal stuff.1966

That is that; this concludes our discussion of fatty acid catabolism.1977

Next time, we will start on a discussion of protein metabolism, amino acid metabolism, actually.1983

We are not going to be discussing the actual protein breakdown; we are going to be discussing amino acid breakdown and conversion.1990

Thank you for joining us here at Educator.com; we will see you next time, bye-bye.1995