Peripheral Nerve Gangliosides

Kevin Ahern Wow, what a lucky day, huh A threeday weekend You guys wanna come in on Monday, we can all just feel like we’re all together on Monday No Student Pizza and beer Kevin Ahern What’s that Student Pizza and beer Kevin Ahern I’d come in for that. Pizza and beer. Student Extra credit Kevin Ahern laughs Kevin Ahern Do I get any extra credit No. No I kind of doubt I’ll be here too. If you want to come in you can. I tell you what, if you come in here on Monday,.

Assign yourself some extra credit. How’s that laughter I give myself four extra points for this, you know. It’s good to pat yourself on the back. Well enough of that silliness. Let’s dive into biochemistry because the sooner we dive into it the sooner we can be done with it, right That’s a good thing. We finished talking about the citric acid cycle. We finished talking about the glyoxylate cycle. And I hope you can see the relations between the two. They’re very very similar cycles. But those two enzymes of the glyoxylate cycle.

Make it a very different set of considerations than we have in the citric acid cycle. Moving our attention now to a structural thing, sort of an odd turn to take. We’re not talking metabolism in the lecture today and probably even a little bit into the lecture on Monday, but the reason we stop and make this sort of side turn is it’s important to understand membranes because we’re getting ready to talk about electron transport and oxidative phosphorylation and these processes, first of all, occur in membranes, and second of all, they require membrane integrity.

At least oxidative phosphorylation does. And so it’s important that we understand what is in a membrane. So that’s why we’re doing this little side thing. Membranes, as I’m sure you learn in any basic biology class, are comprised of what we call a lipid bilayer. And this schematically shows you that lipid bilayer. We can imagine this being a cell. Of course it’s not to proportion as this would be the membrane around the cell and this would be the inner portion of that cell in white, which we would think of as the cytoplasm.

The, organizational materials in that membrane are such that there are molecules that have a duel nature about them that comprise that membrane, okay The duel nature is that they are what we refer to as amphiphilic. Last term in the very first lecture we talked about what amphiphilic meant, and amphiphilic means it sort of has characteristics of being hydrophobic and being hydrophilic. Well in the case of these compounds that we see in the lipid bilayer, we see first of all that, they have what we describe as polar heads.

And we’ll see a little bit of the structure of these in just a little bit. This polar head is water soluble. It is hydrophilic. They also have long nonpolar tails. These are typically the sidechains of fatty acids although there are some exceptions to that, but they’re typically the sidechains of fatty acids. And these are very nonpolar. These nonpolar things associate with each other. The polar components associate with the water in which the cell finds itself. So here’s the outer portion of the cell, there’s the inner portion of the cell,.

And of course both of those are watercontaining substances. Well, I said that the hydrophobic portion of the membrane is comprised mostly of fatty acids and so it’s important we spend a little bit of time talking about fatty acids. On the screen you see two fatty acids. They’re probably the two most abundant fatty acids we find in our cells. Palmitate, which is the ionized form of palmitic acid. People always ask me, What’s the difference between acetate and acetic acid I use the terms interchangeably but technically acetate has lost a proton.

Palmitate has lost a proton. If we call it palmitic acid technically it means the proton is on. I don’t make that distinction but that’s the difference between them. Oleate is of course the ionized form of oleic acid. And you can see that there is a chemical difference between these two, and more importantly you can see there’s a structural difference between the two. Because palmitic acid is what we describe as a saturated fatty acid, all of its bonds can rotate. And since they tend to be hydrophobic in nature.

They will extend themselves out as far as they can to make it a fairly linear, substance like so. The oleate, on the other hand, has a single double bond, and that single double bond makes it become an unsaturated fatty acid. So when we hear that term that’s what that means. This is a monounsaturated fatty acid because oleate only has a single double bond. But that single double bond changes the shape of this fatty acid. You can see there’s actually a bend in it, unlike what we saw above.

And this bend that we have in the fatty acid is resulting from the fact that the double bond in there has a cis configuration. The vast majority of cells that weI’m sorry, the vast majority of fatty acids we find in the membrane of our cells have bonds in the cis configuration. When we talk about trans fats, I’ll talk about them later, but trans fats generally arise from the fact that your food has been chemically treated. Trans fats are not made in any significant abundance in most biological systems.

There are some exceptions to that but for the most part trans fatty acids do not occur naturally. Well, when we look at a fatty acid we can see that, there are, various ways we can describe it. We have, a carboxyl end. We have, a methyl end. And these bring up, there’s actually two different ways that we can refer to fatty acids and the first one you see on the screen is called the omega numbering system. The omega numbering system would start numbering, if we put numbers on there,.

Actually it’s not showing you omega it’s showing you the delta even though it has omega out here. The delta numbering system starts with carbon, the carboxyl carbon being number one and moving with greater numbers towards the methyl group. If we were to do the omega numbering system it would be the other way around. We would start with this one being number one and count that way. Well why do I mention that I’m sure most of us have heard about omega3 fatty acids, and omega3 fatty acids arise from the fact.

That they have a double bond three carbons away from that methyl carbon. So the numbering orientation that we use is important. Most designations of fatty acids are actually not according to the omega numbering system but are in fact according to the delta numbering system which is actually the numbering that you see on the screen. I said that wrong the first time. Now this shows an omega3. So after they’ve just shown you a numbering the opposite way here’s the omega system. One, two, three, there’s a double bond.

Omega3 fatty acids are in fact associated with some positive health benefits. We’ll talk about those later. One of the benefits of omega3 fatty acids in a person’s diet is associated with having lowered lateral, I can’t say it, lowered levels of LDLs, which are what people refer to as the bad cholesterol, and higher levels of HDLs, which are what people refer to as the good cholesterol. Well there’s a list to memorize for the first exam and. class chuckling Okay you guys know my jokes by now. So, it’s a list of fatty acids and I just show it.

To you to show you that there’s quite a variety in terms of fatty acids. The most common, we don’t typically see fatty acids as such much shorter than about twelve carbons in length. And we don’t see them much larger in size than about 22, 24, maybe 26 in length, okay Now I’m not going to ask you to memorize any of the configurations here. I think you should know, and we’ll talk about this later when we talk about the metabolism, you should know that palmitate is a saturated fatty acid.

And later I will ask you to know some unsaturated fatty acids. From today’s lecture all I’m going to ask you to know is the fact that oleic acid is an unsaturated fatty acid. Now that bend that arises in the fatty acids that are unsaturated as a result of that double bond causes some interesting structures to arise. Here is linolenate which is a, one, two, three doublebonded fatty acid. It is in fact something we refer to as an essential fatty acid. So essential fatty acids are fatty acids.

That have double bonds beyond position delta 9. I’ll explain what that means in a second but from the delta numbering system we would say we’re doing delta numbering. We’re going to start over here with carboxyl. One, two, three, four, five, six, seven, eight, nine. Okay If they have double bonds out beyond this point, you can see this guy has ten, eleven, twelve, thirteen, fourteen, fifteen, okay We can see that it’s got double bonds out here beyond where position 9 is. Now why do we say that they’re essential.

If they have double bonds beyond position 9 The reason we say that is in animals, of which we are that category, we cannot make in our bodies double bonds beyond this position. This is the last one we can make a double bond with. If we try to make these we can’t do it. We don’t have the enzymes to make that. So because they’re essential, that means they must be in our diets. Question Student Notationwise do we use upper, or lowercase Greek delta Kevin Ahern The triangle. Which I guess is uppercase, yeah.

Let’s look at how these things play into some of those molecules that we have in the lipid membrane. Remember I was talking about fatty acids there. I haven’t described the molecules that are in the membrane. So in terms of, amphiphilic molecules in the membrane, there are two big categories that we find in the membrane of cells. Two big categories of, molecules in the membrane. One category is schematically shown on the screen, and it’s a category I refer to as the glycerophospholipids. Glycerophospholipids. You commonly hear people refer to phosphoglycerides.

And this would also describe these. I tend to like the word phosphoglycerolipid because I think it better describes it. What does the name mean Well phospho means it’s got a phosphate. Look at that phosphate. Glycero means it’s got a glycerol molecule in it. There’s the glycerol, okay And lipid means it’s got a nonpolar component. There’s the fatty acids with the, with the nonpolar tails. Schematically, this guy looks like the following. This portion of the molecule on the right is very polar. That’s that polar head that I talked.

About in the glycerol, in the lipid membrane. These two tails hanging off are very nonpolar and they’re the nonpolar portion of that amphiphilic molecule. Here’s another example. And this one is unfortunately twisted around a little bit but I think you get the idea. This is a common molecule that we’ll talk a lot about. It’s used in the metabolism of making the general glycerophospholipids and it’s also used in the making of fat. And this guy is called phosphatidate, or as we’ll probably more commonly call it, phosphatidic acid.

That’s what I usually refer to it as, phosphatidic acid. And we can see that it too is a glycerophospholipid. There’s the phospho part, there is the glycero part and there is the lipid part out here. In fact this guy is identical to what you saw in the last, slide, except for in the last slide the phosphate was attached to something else. In this case it’s not attached to anything. Cells make this molecule in the process of making those other ones that I showed you. Now, when we take and we attach something.

To that phosphate we create something we call a phosphatide. A phosphatide. Okay there’s yet another name for this same class of molecules. A phosphatide is a general name, it’s not a specific name, for molecules that are glycerophospholipids that have something attached to the phosphate. Phosphatidic acid would not by itself be a phosphatide. But if that phosphate were attached to any of these molecules that you see on the screen we would have a phosphatide. Well that’s actually done to simplify the naming a little bit, alright So if we think of the phosphatidic acid as being.

The phosphatidyl part, we’ve used one word to describe that whole molecule. It’s phosphatidyl. Then we attach something to it. If we attach an ethanolamine to that phosphate we have phosphatidylethanolamine. If we attach an inositol to it we have phosphatidylinositol. If we attach a Kevin Ahern to it we have a phosphatidylKevinAhern, okay laughter You start to get the idea. So there’s a lot of different things that can be attached to that phosphate. As you might imagine they can give that molecule some different properties depending upon their chemistry.

We won’t really go much into that here. But, this is what these guys look like once we’ve made those attachments. Here’s phosphatidylserine. There’s the phosphatidyl part over here on the left, and the red part includes, in every case, the attachment. This guy down here, is a little unusual in that it’s two phosphatidyls that are linked by a middle glycerol. This one is a lipid that we commonly find in the membranes of heart cells. It’s called phosphatidyl, diphosphatidylglycerol. It’s also called cardiolipin. This guy up here we talked about last term, you might recall.

Phosphatidylinositol. Where did we talk about phosphatidylinositol Does anybody remember A derivative of phosphatidylinositol It had a name of IP3. Student PIP Kevin Ahern PIP. Yep, and what was that involved in Student inaudible Kevin Ahern It was in the signaling, right So this was involved in the signaling pathway that we had near the end of the term last term. And so, not surprisingly, when is drew that we showed that that was found in the membrane. And of course all of these compounds are found abundantly in membranes. They make up the lipid bilayer.

So I told you that one category of molecules in the membrane are the glycerophospholipids. The second major category of lipids that we find in the membrane are known as the sphingolipids. Now at first glance they look somewhat different in overall structure compared to the glycerophospholipids, but in fact they’re not as different as they would otherwise seem. Here is an unusual sphingolipid shown on the bottom. It is unusual in that it contains phosphate. This is one thing, most sphingolipids do not contain phosphate. But there’s a phosphate in this guy.

This guy, sphingomyelin, is a very important molecule. It’s found very commonly in the membranes of nerve cells. You’ve heard of the myelin sheath. The myelin sheath is extraordinarily abundant in sphingomyelin. The sphingolipids in general tend to be more abundant in nerve tissue and consequently are more abundant in brain than they are in other tissues of the body. Some of these sphingolipids. Some of these sphingolipids that we find in the brain are actually quite complicated. Here is a schematic representation of a simple one. It has the sphingo part which I’ll come back.

And show you schematically in a second attached to either a glucose or a galactose. Now we didn’t see that with the glycerophospholipids. We did not see attachment there to any of the sugars. Here’s a deference. The sphingolipids are usually linked to a sugar, at least one. This guy is a cerebroside. Again, a cerebroside is a category of molecules. There’s a whole set of classes of these. And cerebroside is distinct from a ganglioside in that a ganglioside has all of this general structure over here, but instead of having.

A simple sugar on the side it has a complex oligosaccharide out there. So remember how the blood groups had those complex oligosaccharides out on the cell surface This guy has a complex oligosaccharide, oligosaccharide meaning it has several sugars. And they’re commonly very intricate in their structure. Yes sir Student Are these guys associated in any way with degenerative neuro plaques as in Alzheimers Kevin Ahern Are these guys associated in any way with degenerative neuro plaques in Alzheimers I’m not aware that they are, no. But I will tell you that one of the things that happens.

With multiple sclerosis is that there is, the myelin sheath for example can be attacked by your own immune system, an autoimmune reaction that can happen. So that’s one place where sphingolipids can play an important role in the health of neural tissue. And we’ll see other examples in a little bit of places where enzymes that break down sphingomyelins or sphingolipids, when they are deficient in the body they can lead to very severe neurological deffects. So yes. But I’m not aware of anything with respect to Alzheimers, no. Oh, I thought I had a schematic.

I guess I don’t have this schematic. Well we’ll leave it be, that’s not a big deal. That’s one less structure for you guys to recognize. You’ll have to take it on my word that the sphingolipids structurally are very similar to those of the glycerophospholipids. Well let’s talk about some more molecules that are found in membranes. And here’s a very common component of membranes. You’ll notice it’s not very amphiphilic. It mostly resides in the nonpolar portion of the lipid bilayer. The only portion of this molecule that has.

Any polarity at all is this OH that’s on the end, alright Cholesterol. Now cholesterol I’ve talked to a couple of you in class about already. Cholesterol’s a really really interesting compound. We’re going to talk more about its metabolism later. We’re also going to talk about its movement in the body later. And I’ll be honest with you, it’s one of the bigger mysterious of biochemistry despite the fact that it’s been studied intensely for over hundred years. There have been something like five Nobel prizes that have been given for the study of cholesterol.

And there still are a lot of things about cholesterol that we don’t know. What we do know is that cholesterol is an important component of membranes. An important component of membranes. And it probably contributes to, at certain temperature ranges, increasing the fluidity of membranes, which is important. It doesn’t change the temperature but it certainly widens the range over which the membrane is fluid, when it’s embedded in it. Now, as I said cholesterol is found inside of the nonpolar portion of the lipid bilayer, and we’ll talk more about that in just a bit.

So what I’ve given you so far are the big, oh, one more thing I wanted to say about cholesterol. Cholesterol is interesting. Again when we look in the brain the brain really is a different kind of an environment than what we see the rest of the body. Cholesterol is extraordinarily abundant in the brain. If you take brain tissue and you dry it down, that is remove the water, 14 of the dry mass of cholesterol, of the brain, is cholesterol. Your brain is full of cholesterol. So you have to have cholesterol.

You have to have cholesterol. The old, Cholesterol, bad, right Well your body’s making cholesterol for a reason. Too much cholesterol, bad. But we have to have some cholesterol for our membranes. Alright, I love this picture. It looks like some, a professor I once had, you know that mouth is out there. class laughing Maybe I look like that sometimes. I don’t know maybe Monday morning that’s the way I look up here. But this depicts an interesting environment. I believe this picture was actually taken at Yellowstone and there are organisms that can live on virtually.

Every niche they can live in on the face of the earth. And the environments in which they find, in which cells typically find themselves in their native environment can be very, very in some cases, chemically nasty. Well this is one of those chemically nasty places. And when we think about places where there’s nasty chemistry, as it were, we have to start thinking well how do cells protect themselves How do they avoid being consumed in reactions or being damaged by the conditions in which they find themselves. And one of the ways in which we find that is.

By modification of the lipids that are found in the membranes of these cells. Now there’s a class of compounds called the archaeons. That was the word that was on the last slide. And the archaeons live in very odd environments. They can live in salt water that’s amazingly salty. They can live in those hot conditions here. They can live in very acidic conditions. They can tolerate things that a lot of other cells can’t tolerate. Well it turns out that, the bonds that we have, between the fatty acids or the compounds.

That are in glycerophospholipids are susceptible to acid breakdown. So if they’re growing in an acidic environment they can be losing their membranes if the pH is too low. Well some of these cells have modifications to the glycerophospholipids that they have. And you’re probably going to be look at them and say, Well what is the difference here The difference is that in the regular glycerophospholipids this bond right here is an ester bond. That is there’s normally a doublebonded oxygen coming off of here and there’s a doublebonded oxygen.

Coming off of right there. In the case of the, archaeons, they make what are called ether linkages. This is an ether linkage. COC with nothing else that’s there. And these ether linkages that are in these glycerophospholipids of these archaeons tend to be more stable and allow them to be more succesful in those environments. And there’s other modifications that we see in some things as well. Now this picture is nice because it does schematically remind us of the fact that the glycerophospholipids, there’s a phosphoglyceride, same thing, resemble very much the sphingolipids.

There’s sphingomyelin. Look at that. We’ve got a long polar tail. We’ve got long, well actually two polar tails. We have two long polar tails here. We have a polar head group. And so overall they don’t appear that different from each other. Here’s an archaeon lipid and although it’s slightly bulkier, slightly different here, the overall structure really isn’t that different. So it tells us again structure and function are related. When we see conservation of structure between different organisms we know that structure must be very important for some purpose.

And there’s a shorthand depiction. There’s the head, polar head. There’s the nonpolar tails. we’ve all heard of micelles. We know what micelles are. And micelles arise as a result of having amphiphilic molecules. These are fairly simple amphiphilic molecules and the most simple example of these would be something like fatty acids in which we have a COOH at one end which is negatively charged, and then a tail sticking out like here. Well if we only have a single tail these guys arrange themselves in a nice tight little sphere.

That doesn’t form a lipid bilayer. It just forms what we call a micelle and that’s the structure you see on the screen. So it tells us that that second tail is important and when we look at that second tail what we see is the addition of a second tail prevents micelle formation. So instead of bending around and making a sphere like we saw on the last example where we had a single tail, the two tails instead will arrange spontaneously into a lipid bilayer. So again structure and function are important.

We have that extra tail on there. It can’t make a micelle. It makes these sorts of things. And these sorts of things are important because they make up our membranes. They can form neutrally in aqueous environments and it’s very easy to make membranes. And as we shall see it’s very easy to artificially make membranes. Blah blah blah. Ooh I like that okay. Memorize that structure, right scattered laughter Well that artificial structure..that I was referring to is called a liposome. LIPOSOME. Why would I want to make a liposome.

Well let’s imagine that, first of all I want to make one. So how would I make a liposome Say I take a lot of glycerophospholipids that I have isolated, I take a bunch of sphingolipids that I’ve isolated, and I put them in an aqueous environment in, let’s say in a beaker. So I dissolve them in some water. I shake them up. Maybe I sonicate it or something and get everybody moving around. When everybody gets moving around what will happen is the membrane will spontaneously form. And so the membrane will arrange itself.

In a bilayer just like a cell. That is, we’ll have an outer portion here where we have the polar thing sticking outwards. On the inner portion we will have the polar thing sticking inwards. The nonpolar tails will arrange in this green region. But the important thing here is we’ve basically encapsulated something inside of this lipid bilayer just like a cell does. We’ve made it artificially. We’ve mixed these things in a beaker and this spontaneously forms something like a cell. Well why do we want, why do we care about that.

It turns out that we can do some cool things with that. So here’s my mixture. Here’s my glycerophospholipids, sphingolipids, and now let’s say that I have a drug that I want to use to treat cells with. Moving drugs across cell membranes is murder. You can create the greatest drug in the world, and if you’re curious come by and I’ll tell you some really depressing stories, you can create the greatest drug in the world that will specifically target and kill specific cells if only you can effectively get it across the membrane.

So there are strategies that people have introduced for getting difficulttomove molecules across membranes and one of them involves making liposomes. It’s easy to make an liposome. Here’s my drug. This drug in red. I take, I sonicate, I shake this up, I do whatever, and what’s going to happen is I’m going to form liposomes as a result of that agitation that I’ve just given. Some of these liposomes will have, of course depending on the concentration of my drug, are going to have encapsulated in them drug. Well so what.

I want to get it into a cell. I don’t want to get it into a liposome. Well it turns out that because this membrane is essentially, has the same chemical structure as the, compounds in the membranes of your cells, you can mix them with the membranes of your cells and they will actually fuse with each other. And when they fuse with each other guess what’s happening The drug is being kicked into the cell. So this is a mechanical way of introducing drugs or other compounds into cells that.

Don’t normally want to go there. It’s useful as a laboratory tool. It’s probably not the most useful thing in your body because you’re not necessarily wanting to fuse every cell in your body with things that you’re going to put into it, but as a laboratory tool it’s a wonderful way of delivering things across the membrane of a cell. Okay I’ll slow down for a second. Questions, yeah Student For the two membranes do they have to use certain proteins because otherwise all our membranes would just fuse Kevin Ahern So her question is does the fusing.

Require certain proteins because otherwise if it didn’t all of our membranes would just fuse. Yeah, you’re correct. Not all of our membranes will automatically just fuse, and I’m simplifying this considerably. You’ll notice when I made the liposome, for example, I had to use some agitation and that is an important component in helping that fusion to happen. But you’re exactly right. If we didn’t have that then we’d just be one great big fused membrane, yeah. Other questions Okay, lipid bilayer permeability. One of the reasons cells have a lipid bilayer.

Is it’s really great at keeping things you don’t want out of cells. The lipid bilayer is fairly impermeable to most substances, and there are some exceptions to that. The biggest exception that you see on the screen is on the top right and that’s water. Water surprisingly moves across the lipid bilayer quite freely. Quite freely. That actually poses a logistical problem for cells which I’ll talk about in a bit. But it moves quite freely. Glucose, on the other hand, which is something you’d say, Hey cells want glucose, they need energy,.

Glucose doesn’t move very well across that lipid bilayer. So does that mean that cells are starving to death most of the time No, it means that cells have to have a way of getting in besides simply letting it move across the membrane. If they sit and wait for this guy to move across the membrane the cell’s going to starve to death. So the membrane is very good at keeping out things that we don’t want. It’s unfortunately also very good at keeping out things that we do want.

But cells aren’t stupid. Cells have evolved mechanisms over the years of integrating inside of them things that they need and they want. And the mechanisms that they have evolved involve proteins that are specific for specific molecules. Last term we talked about insulin signaling. We talked about the GLUTs. Everybody remember the GLUTs Glucose transporter proteins. What was the function of the GLUTs The function was to bring glucose in. These are membrane proteins that are specific for letting glucose in. So we’re going to spend some time talking about proteins that bring specific molecules in.

Small ions, sodiumpotassium, boy they don’t get across there by themselves very well at all and we’ll see they play some very important roles, however, in cell chemistry. Well I’m at the point of talking about membrane proteins. that one really doesn’t tell us anything does it This schematic diagram shows us something about the different nature of proteins that are found in a lipid bilayer, right The membranes of cells contain a considerable amount of protein as she noted up here. They contain a considerable amount of protein. The amount of protein varies form one cell type.

To another cell type, and from one membrane type to another membrane type. For example, if we look at the membranes of the mitochondrion, they have something like 90 of their mass as protein. They’re really abundant in protein. Other, if we look in the plasma membrane of the same cell it won’t have anywhere near that amount of protein. So we have some designations that we give as names to these different classes of proteins, and I will tell you that different books give them different names. So we’re going to use my names for here, for one time, okay.

My names, I have specific names for these proteins. A protein that goes through both layers of the lipid bilayer is called an integral membrane protein. So a and b are integral membrane proteins. A protein that goes partly into one of the layers of the membrane is called a peripheral membrane protein. I couldn’t pull it out there. A peripheral membrane protein. So c is an example of a peripheral membrane protein. Other proteins don’t even really interact with the lipid bilayer but they may interact with something else, like d is interacting with b here,.

We call d proteins associated. That is if we were to look at a membrane we would see some d there but it’s not really interacting with the membrane itself. It’s associated with something that’s in the membrane. Student What is d called again Kevin Ahern d is called an associated membrane protein. The last category of proteins are what you see over here as e and you’ll look at e and you’ll see this little springlike tail hanging off. What that is a fatty acid that is covalently linked to e.

And that fatty acid has buried itself in this nonpolar region. This guy is what I refer to as anchored. We can see a little anchor hanging off e to help hold it in the membrane protein in the lipid bilayer, I’m sorry. Alright, so we have a is integral, b is integral, c is peripheral, d is associated, and e is anchored. Now I want to tell you about a cool protein. And I want to show you this cool protein. And when we talk about electron transport, I think is next week, I’m going to show you guys.

How to make a photosynthetic fish. I’ll show you how to make a photosynthetic fish. It actually involves this protein. This protein is called bacteriorhodopsin. And bacteriorhodopsin is shown schematically. You can see that is a protein that is an integral membrane protein and this integral membrane protein has a very cool function. It’s got a little molecule of vitamin A on the inside of it and that molecule of vitamin A plays a very important role when light hits it. When light hits the vitamin A that’s inside of this bacteriorhodopsin the vitamin A molecule.

Changes its configuration. Vitamin A, of course, is involved in our vision, and the reason we see things is because that vitamin A is changing its configuration in our eyes. This is happening in a bacterium. It’s changing its configuration in the presence of light. The configuration change involves a change of a cis bond to a trans bond. It’s a very simple kind of a mechanism. Now I want to plant that idea in your head as an interesting integral membrane protein and if you want to remind me if I forget when.

I talk about electron transport, we’ll have a photosynthetic fish, okay Cool integral membrane protein. Another interesting protein, we talked about it last term, is porin. Porin was a molec, a protein we described as having its insides out because we said that most, last term we talked about protein structure. We said that most proteins that are dissolved in the cytoplasm, in fact virtually all proteins that are involve, dissolved in the cytoplasm, have an arrangement of amino acids such that the nonpolars are where on the protein On the inside.

And the polars are on the outside. However, when we get to a protein that lives most of its existence in a lipid bilayer we frequently see that’s inverted. This was an example of one that was inverted. It had its nonpolar proteins, nonpolar amino acids, on the outside associating with these nonpolar tails and on the inside there was water moving through it. So we saw the hydrophilics on the inside. So again structure function relationships sort of make sense once we know the chemistry of the cell. This is an enzyme that is a good example of a peripheral.

You can see it’s going through one portion of the lipid bilayer. And this enzyme whose name is very long which I’m not even going to go through here, is given a simpler name of prostaglandin synthase. And for the moment I don’t care that you even know that. I’m just showing you some interesting proteins here. I will talk about this protein later because it catalyzes a very important reaction in the synthesis of compounds called prostaglandins. And, these compounds are involved in pain, swelling, and other problems. And this particular enzyme is interesting because.

It makes these prostaglandins and it’s inhibited by aspirin. It’s inhibited by ibuprofen. So the reason we describe these things as painkillers is they’re stopping this enzyme from making molecules that make us feel pain. So, cool example of a peripheral membrane protein. There’s aspirin. Memorize that structure. So we’re moving rapidly along. Questions before I dive into one more topic here Everybody exhausted You want a song to maybe perk things up a bit You’re going to have sing loud because I’m not, I don’t know how well I’m going to do this.

This is a long song too. class murmuring This song actually is the only song I sing in class that was not written by me. It was written by one of my students a few years ago. So I will encourage you to develop your own songs, bring ’em to me, and if they’re good I’ll steal them from you. laughter That’s what I did with this one. Actually she knew I stole it but it’s very cool. So this one is called Citrate Sonata. It’s about the citric acid cycle which.

We just finished so I thought we’d go through it. It’s to the tune of God Rest Ye Merry Gentlemen. everyone singing Citrate Sonata by Taralyn Tan Lyrics Our fats and carbs get broken down To acetyl CoA Oxaloacetate combines In cycles TCA. The product of reaction one Oh, citrate is its name Isocitrate, the product that ensues Atoms got moved Isocitrate is the product of step two An oxidation soon occurs Reducing NAD An alphaketoglutarate Resulting from step three From here we could make glutamate That is, if there’s a need.

Don’t forget that we lost a CO2 Yes it is true In reaction three we lost a CO2 So what’s the point of all these steps Well let me tell you friend We use electron carriers In working towards our end Of synthesizing ATP A metabolic trend Oxidize, and then oxidize some more Here in step four Ketoglutarate gets oxidized some more The enzymes with cofactors five Including TPP Lipoate, FAD, CoA And also NAD A succinyl that’s on CoA Is what gets made, you see This reaction occurs so fav’rably.

Don’t you agree It’s a good reaction energetically With four more steps, we’re halfway there So let me summarize When CoA’s lost we see that G TP is synthesized The succinate that is produced Will soon get oxidized FAD goes to FADH2 What did we do We made fumarate and FADH2 Add water ‘cross the double bond And malate we create With one last NAD we can Then dehydrogenate To give a final product of Oxaloacetate It’s removed, and this lowers Delta G Oh yes, indeed It’s through pulling that this last step can proceed.

So take a breath you’ve learned it all But what is it You say That’s of such great importance that I need to take away Three NAD’s have been reduced Each now NADH GTP and an FADH2 They were made, too Yes, a GTP and FADH2 We’ve passed electrons eight in all We’ve made two CO2’s Triphosphates like our GTP Give energy to you Electron transport is the chain That certainly ensues But I think this deserves another song This is too long And with that, I end our citrate sing along.

Kevin Ahern Isn’t that cute applause cheers I want to recognize that was written by a former student of mine. Her name’s Tari, actually she goes by the name Tari, Tari Tan, and Tari is presently in the PhD program in neurosciences at Harvard. So very happy, very proud of her also. So very cool. students murmuring loudly Let’s see, where was I Let’s dive in. We’ll spend, just a couple minutes, yeah we’re not going to stop. Otherwise we have to rush next time. So let’s go through and do this.

For the. Kevin Ahern sighs students quiet Alright, the last thing I told you about had to do with the fact that we saw that there’s arrangement of the structure of proteins depending on the environments in which we found themselves. Porin was inside out. We start thinking about proteins that have to cross that lipid bilayer. It’s not surprising that we might be able to look at amino acid sequences and say, Hey, there’s a very nonpolar portion and then there’s a turn, there’s another nonpolar portion, there’s a turn, there’s another nonpolar portion..

We might be able to predict based on amino acid sequence which proteins are found in membranes. And in fact we do this reasonably well. We can’t predict the exact structure but we can predict whether they’re going to be in membranes. There are some rules that people have written and given out and no we’re not going to worry about the rules. But you can look at these and see, going from top to bottom there’s various energy values that have been assigned to these. And these have to do with their tendency.

To associate with water. High positive values they don’t like to associate with water. Low positive values they do like to associate with water. And if we start looking at a sequence of proteins we can say, Hey, here’s a region of the protein that’s got very positive values. Here’s a region of the protein that has very negative values. We can start understanding something about the general shape of that protein, of the general structure of that protein, and the tendency based on where we see these helices will this be a membrane protein.

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