#16 Biochemistry Blood Clotting/carbohydrates I Lecture for Kevin Ahern's Bb 450/550

Ahern: How's everybody doing? Student: Amazing. Ahern: Amazing. Everybody's doing amazing. You're speaking of everybody here, alright. Okay, so we're not too far from finishing up regulation of enzyme activity. When I finished last time, I had started, at least introduced the topic of blood clotting and as we will see, blood clotting is another system that uses zymogens. It is a system that, in addition to using zymogens, uses an interesting scheme or an interesting strategy that we will see later and it's what I call a cascade and the cascade system is used in other enzyme control systems and the beauty of a cascade system is that you can mobilize an effect very, very rapidly. Okay, what does that mean? So if I think about the Cascades, the Cascade maintain range and I go climbing the Cascades and I get up to a high point, the higher I get up, the more I see that the cascading waterfalls get smaller because I've got a smaller source of water. As I go down the mountain, the further I go down the mountains, the waterfalls and everything get bigger because the streams start coalescing together. That cascading system, one stimulating another, stimulating another, stimulating another, is a very, very effective way to make things happen very rapidly, okay? As I said, we'll see another example of it, but this shows a very involved system for blood clotting. I'm not going to take you all the way through, in fact I'm only going to emphasize a couple major points in it. But sufficed to say that a cascading system, if we think about a signal, let's say it's a damaged tissue or a damaged blood vessel in some way. That signal has to be amplified and the reason it has to be amplified is because as I said at the end of the lecture last time, we really need to stop that blood flow before we lose too much blood. If we don't, then the person will bleed to death. So we have to have a system that works very rapidly and is very effective, alright? So a small signal here, if this is an enzyme, this enzyme activities another enzyme and this enzyme in turn activities a bunch more enzymes, and this bunch of enzymes activates an even bigger bunch of enzymes, and at every step along the cascade, the signal gets bigger and bigger and bigger. The beauty of this is it happens very rapidly, it's happening in our blood stream. And so the main thing that we have to do in order to protect ourselves via a clotting mechanism is to make sure that we have plenty of zymogens in our blood stream. Things that are not yet clottable but can be very quickly be turned into a clot. Now, that's the good side. The bad side is the same thing. We have a blood stream that's full of things that can form a clot. And so if the system screws up, then we can very rapidly form a clot and kill ourselves if we have the clot forming in the wrong place, alright? So there's a Ying and a yang to blood clotting. We're going to focus mostly on the good side, I guess the Yin. I wasn't going to say good, but on the positive side of the blood clotting, which is the forming of the clot, and I'll also talk about how we dissolve a clot. So just like I said before, if the body has a way of turning a system on, it's also going to have a way of turning a system off. If it makes blood clots, it's got to be able to dissolve those blood clots as well. We'll talk about both of those. Okay, so like I said, I'm not going to go through this pathway in detail and no I'm not going to ask you to regurgitate this pathway to me, alright? The important aspects of this pathway are actually down here for our purposes, okay? We don't really care much of up here. For our purposes, we're going to focus on what's happening down here, okay? Now as we start with things on the left, or things, I should say on things on the left, but things that are coated in this sort of pinkish color, these are inactive zymogens, or inactive factors. So when I see for example, prothrombin, prothrombin is a zymogen. It is inactive, it is incapable of acting. By the way, most of these guys on here are proteases. One protease activating another protease, activating another protease, activating another protease and that last protease is going, which happens to be thrombin, is going to convert the clotting material from an inactive form to an active form, meaning that the clotting material will start to make a polymer. So once this guy right here gets converted to fibrin, fibrin is a self-assembling polymer. That's very important. It's a self-assembling polymer. In the absence of this activation, fibrin is floating through your blood stream all the time. Or fibrinogen is floating through your blood stream all the time doing nothing. That's what you want it to do. You don't want it to clot unless you got an issue. Well, this raises a couple of concerns. One is we want plotting to occur in a specific place, we don't want it occurring randomly in our body. And our body, I'll show you one way, has a way of knowing where to put that clot. There are several things in place that help to do that but I'm going to tell you about one of them at the molecular level. So our focus for right in is going to be on the prothrombin to thrombin and the thrombin catalyzing the conversion of fibrinogen to fibrin, okay? Alright, so let's consider that. Where was I at here, there we go. First of all, we have to consider the structure of fibrinogen. So fibrinogen is the inactive polymerizing material. When it gets activated, then it will form polymers. Well it's kept inactive by the action of these two things here. This label with its capital B and this guy down here with its capital A. These we can think of as knobs that basically stop the polymerization process. During the polymerization of fibrin, what we will see is these knobs get clipped off and they yield ends that can link into these things that we see here, okay? You see this little hole? The B will fit into that little hole, so I can take one fibrin molecule that's got a B and stick it into the hole of another one that's got this. The As will stick into the gammas, okay? So what thrombin is doing is it's clipping off the knobs. It clips this guy off, it clips these guys off and now we've got some ends that the pieces can start sticking together. The tinker toys, as it were, can start building themselves into a bigger structure. Alright, so that actually occurs in this mechanism that you see here, okay? In this case, the alphas are linked up with the gammas as we can see here, okay? The alphas and the gammas have been stuck together. We don't see the betas going into the Bs, into the beta structures and the reason is because that goes in the 3rd dimension. We could imagine that this polymer is going to stick back out towards us, right? So we have this guy sticking in here, this guy sticking in here, this guy sticking let's say in here, and now we get a three dimensional structure. So coming back out at us, we got all these things tied together. Now that's, what's amazing is A, that happens very rapidly, okay? It happens very, very rapidly, and second, it is a pretty good structure, but it's not a perfect structure. What does that mean? Well, what you see on the screen is a sort of a two dimensional display of what we call a soft clot. A soft clot, why do we call it a soft clot? Well, it's the very first thing that forms when there's been damage, there's been a cut and you're losing blood. The very first thing that happens is what's called a soft clot. And the reason we call it a soft clot is that these interactions are not, underline not, covalent. These are hydrogen bonds. It's soft because, yes, it helps to put all the pieces together, but it's not very sturdy. It doesn't hold things real well. We can imagine we get a few hundred or a few thousand of these hydrogen bonds, it's really going to start to add up to a reasonable structure, but for a good protection, we want to have what's called a hard clot, okay? To get a hard clot, we have to make covalent bonds, alright? So what you see in terms of that initial polymerization reaction only makes hydrogen bonds, it does not make covalent bonds. The covalent bonds require action of another enzyme, okay? The other enzyme is known as a transglutaminase and it catalyzes a reaction like this. The side chain of a glutamine and the side chain of a lysine can be joined together to make a cross link. This is a covalent bond. Now this is not happening in those little *** structures. This is happening just between the strands when they get adjacent to each other, if there is a lysine next to a glutamine, this transglutaminase will join these bonds together. When we make these covalent bonds, we've converted a soft clot into a hard clot, okay? We've converted a soft clot into a hard clot. If you watch a scab on your hand, you'll notice that when it first forms, it's different than what it looks like a couple of a hours later, okay? It goes from being literally soft feeling to being hard. The scab does that. Now as I said, the remarkable thing is this happens in the order of minutes and this happens and the place you wanted. It's rare that you're forming clots at places in your body where you don't want to have it, okay? And it's water tight. Those are really remarkable features of blood clotting. Well how do we know, how does the body know where to make that? How does the body know where to do it, okay? One of the ways in which the body uses information about how to do it is by a modification to prothrombin. Prothrombin. Remember prothrombin is the zymogen form of thrombin. It's the inactive form of thrombin. But the body has a way of collecting prothrombin at the site of the wound. As a way of collecting prothrombin at the site of the wound, I need to tell you about that, okay? So that happens as a result of action. Of prothrombin, let's see, let's go here. Here's what I want to show you. In order for prothrombin to get gathered at the site of the wound, it has to be modified. So prothrombin gets modified by vitamin K. Vitamin K is known as the clotting vitamin, all right? Vitamin K is required by an enzyme that puts an extra carboxyl group on the side chain of glutamate. So prothrombin has several glutamates. This enzyme that uses vitamin K, grabs a hold of prothrombin, grabs a hold of vitamin K and it puts additional carboxyl group on the side chain of glutamate, okay? Here's a regular glutamate side chain, here's the addition of a new carboxyl group on it, okay? So in black, you see the regular, I'm sorry going up here, the regular side chain of glutamate, all right? And now this guy's had an extra carboxyl group added to it. Why is that important? Well it turns out that when that extra carboxyl group gets added, prothrombin can all of a sudden bind calcium very, very well. It can bind calcium very, very well. With only one carboxyl group, prothrombin doesn't grab calcium worth a darn, all right? But with two carboxyl groups, they sort of gang up on calcium and hang onto it, okay? One doesn't do it, two are positioned perfectly to bind calcium, calcium is charge plus 2, each carboxyl group is charge minus 1, they form a very nice bond. Why is that important? Well at the site of the wound, we've got cutting, we've ruptured open cells and we've exposed a bunch of calcium, okay? So right at that site of the wound, we're going to have an abundance of calcium there and that calcium is going to attract prothrombin. Prothrombin will be concentrated at the site of the wound. Now, prothrombin sits there and waits for all of the other zymogens to get activated to get activated and finally it gets activated, making thrombin. And what's thrombin going to do? Well thrombin is gonna convert fibrinogen into fibrin and right in the site of the wound, that polymer is going to form. So there's other systems the body uses but one is this one. It's vitamin K dependent, it's why we have to have vitamin K to have efficient blood clotting, okay? Yes? Student: So when...[inaudible question] Ahern: Okay, so there's many causes of stroke, but one of the most common causes of stroke can be the formation of a clot in a place that would stop blood flow to a vital organ like the heart or the brain, okay? And yes, those do happen and those are a problem and to prevent the formation of clots in places where you don't want them, people are given what are called blood thinners and I'm going to talk about that in just a second, okay? Yeah, please. Student: So if you're a hemophiliac, what goes wrong? Ahern: If you're a homophilic, what goes wrong? There's several places in the scheme where you can be lacking an enzyme genetically. So if you're lacking a critical enzyme, and there's several places where this can happen, if you're lacking a critical enzyme in that activation pathway, you may not be able to convert zymogens and that's going to stop the whole cascade and you're literally going to bleed to death if you don't have that factor. But there's several places where that can happen. Okay, so a very interesting phenomenon, a very important phenomenon, it has a molecular basis, when I talk about vitamin K, this is what vitamin K looks like, okay? Vitamin K is needed by that enzyme that puts the carboxyl groups in the side chains of glutamate of a prothrombin, all right? Blood thinners, okay, the things that people refer to as blood thinners, resemble vitamin K. And the enzyme binds those molecules and when it binds those molecules, it cannot put a carboxyl group on the side chain of prothrombins. Would you describe these guys or competitive or non-competitive? These are competitive. They resemble in some way vitamin K. They're competing for the same site. Warfarin is also known as rat poison. That was the original use of warfarin. Oh my God, if I poison rats, am I going to get blood all over my house? No, do you know why? Internal bleeding, yeah. So when you really thin the blood a lot, what happens is the most common thing that happens is the slightest bruise can kill you. So people that get put on blood thinners, okay, are, they have to do what we call titrate the thinner. We don't want to give them too much thinner because we will kill them if we thin their blood too much. They will bleed to death internally. So a physician who's giving a person thinners will measure what's the clotting ability of this person. You're trying to lower it but not stop it because you don't want to completely stop it or you're going to kill the person, okay? Warfarin and dicumarol both are very effective in this respect. They both do reduce the clotting ability and people, for example, who had a stroke or have other problems. I have relatives who have phlebitis. Phlebitis is a clotting disorder in the legs and they get put on blood thinners to keep them from forming these clots in their legs and again, they have to balance the right amount so they don't give them too much. At the same time, they want to stop the clotting as much as they can. Student: A DVP? Ahern: I'm sorry? Student: A deep vein thrombosis. Ahern: A deep vein thrombosis, uh huh, yeah. Okay, all right, let's see here. What was I going to say? All right, so that's how we form clots and that's a fairly cursory look of how we form clots. I also want to say a word about how we get rid of clots because as I said, the body has to not only make things, it has, if it has something, a switch, to turn something on, it has to have a switch to turn something off, and so how does it get rid of clots that it forms? Well it turns out our body has an enzyme that does this very, very well. The enzyme that dissolves blood clots is also a protease. And it's known as plasmin. PLASMIN. Plasmin. And plasmin is present in the blood stream, not as plasmin, but as plasminogen because we want to have that available so that we can activate it when we want to dissolve the clot and make that, alright? Now how do we activate plasminogen? Well that's activated by another enzyme known as TPA, which also stands for tissue plasminogen activator. Tissue plasminogen activator is also a protease. We see a lot of proteases involved here. And the effect of this protein is remarkable. Now TPA has the historical note that it was the first genetically engineered protein that was made available for human use, okay? It was actually the first protein that Genentech, you've heard of Genentech, that was the first protein, they were the first one to get that approved. TPA is a very powerful molecule. It needs some activation as well and we're not going to talk about how all that occurs, but TPA basically, if you give TPA at the site of a blood clot, it will activate plasminogen at that site and effectively break down the clot. Now it's not given routinely because as you can imagine you could have some problem turning this on like giving people too much blood thinner. But at the site of a clot, this guy can convert a plugged artery in the heart to complete flow through in a matter of minutes. So for a person who has a blocked artery because of a clot, TPA can be a life saver. In some cases, TPA is actually given to people after they've had a stroke in hopes that if there are small clots in the brain or something, that they can be dissolved very quickly and readily. That they can actually alleviate the effects of a stroke and in many cases, that actually can have a very positive effect. As I said, it's used very carefully because again, it's a very, very powerful substance and we don't want to be indiscriminately breaking down clots that might otherwise be protecting us. Yes, sir? Student: I know that in situations like you're describing, they describe that as a clot buster. What portion of that is TPA, or are there other components that we use? Ahern: His question is, when you hear the term clot buster, does that refer to TPA or other things? And there are other things that can be used as well, but TPA, the term clot buster is just a generic term. TPA is definitely a clot buster, yes. Yeah, back there? Student: How long does TPA remain active in the bloodstream? Ahern: That's a very good question. How long does TPA remain in the blood stream? And I don't honestly know the answer to that question. So that's the activation. The inactivation of blood clotting, it's a pretty phenomenal process I think. If there are no other questions, I'll move forward to carbohydrates. One other question back here. Elliot? Student: What was the enzyme that catalyzes the vitamin K? Ahern: Yeah, his question is what enzyme catalyzes the carboxylation of prothrombin. I didn't give you the name of that so you're not responsible for that. Vitamin K is a cofactor for that enzyme, though. all right, we turn our attention now to a subject that most students tend to like because this subject is something I've covered before in organic chemistry. This structure of carbohydrates and it's almost all focused on structure. So we'll say a lot about the structure of carbohydrate, there are a lot of terms that are here, and it's very straight forward kind of stuff. So I'm going to go through it sort of quickly but also hopefully not too fast to run over you with that. We talked about carbohydrates. Carbohydrates are obviously important molecules for us. Carbohydrates are one of our main sources of energy. They are in fact our primary source of quick energy. Carbohydrates include sugars, they include polymers of sugars, and they also include modified forms of those sugars. The term carbohydrate actually tells us what the structure of the molecule is. Carbo referring to carbon, hydrate referring to water. Carbo-hydrate is basically the structure of these molecules. For example, look at the structure of glucose, the structure of glucose is C6H12O6. You don't have to write that down but I could easily write that CX H20X. In its case, the X is 6. That's a 6 carbon sugar. Well it would be C4H8O4. So it's a hydrate of carbon, that's what a carbohydrate is. Water to carbon. Probably never thought of that before. Well the first term I want to introduce you to with respect to carbohydrate, and by the way, we also use the term carbohydrate, we use the term saccharides. Saccharides are the same as carbohydrates. SACCHARIDE. Saccharide. A saccharide literally means and I think it's Latin, sweet taste. Sweet taste. So carbohydrate, saccharide, same thing. Well let's look at a couple of structures of very simple carbohydrates or saccharides. These are three carbon molecules. In this case, we would have C3H6O3. We notice that they are similar in structure but not identical. We see first of all that this guy is a ketone and these guys over here are aldehydes. Ketones vs. aldehydes, right? And if you look at the two on the right, they are both aldehydes but they are slightly different in their three dimensional configuration. We remember that a carbon that has 4 different groups attached to it can have those groups attach in three dimensional space in two different ways. And here's where you're going to like biochemistry because biochemistry, very simple people, we like to think of the terms D and L to describe those. And you'll see this is a great simplification in terms of describing their overall structure. The ketone doesn't have, in this case, doesn't have a symmetric carbon. There is no carbon that has 4 different groups attached to it, so there's only one form of this three carbon ketone. A carbohydrate that has a ketone bond in it is called a ketose. KETOSE. Whenever you see the letters "ose" at the end of a name, we're talking about a carbohydrate. A ketose is a general name for a carbohydrate that has ketones. Fructose is a specific ketose. And I'll show you the structure of that. On the other hand, if instead of having a ketone bond in it, that the carbohydrate has an aldehyde bond in it that structure is known as an aldose. ALDOSE. And again, that's a general term for a carbohydrate that has an aldehyde bond in it. We can further delineate the names of these guys by describing the numbers of carbons that they contain. The guys I just showed you are three carbon molecules. They're known as trioses. I could describe them as an aldotriose, or a ketotriose, depending upon whether they had an aldehyde or ketone bond in them. If they have four carbons, they're known as a tetrose, five a pentose, 6 a hexose, 7 a heptose, 8 an octose. We don't generally see carbohydrates with single units containing more than 8 carbons. But we will see polymers of some of them that have 6. Now when we look at the different structures of carbohydrates, we see that there are a variety of names that can be used to describe these. Let's start down here. This guy down here shows those two aldoses that I showed you before. One is known as D-glyceraldehyde, the other is known as L-glyceraldehyde. You'll notice the structure. C3H6O3. They are mirror images of each other because again, that relates to the three dimensional arrangement of those structure, those substituents on the asymmetric carbon. We draw them in simple terms. We're going to then draw them three dimensional. We can draw them like this where we take the asymmetric carbon and we put the hydroxyl on the right side vs. putting the hydroxyl on the left side. In general, when we look at the structure of carbohydrates, and we decide if it's D or L, we look at the next to last carbon. If the OH is on the left side of the next to last carbon, it's an L sugar. If it's on the right side of the next to last carbon, it is from the bottom, it's a D sugar. If we orient the OH on the left side of the next to the last carbon from the bottom, it's an L sugar. If we orient it on the right side of the next to the least carbon from the bottom, it's a D sugar. Two carbohydrates that are mirror images of each other are called enantiomers. Yes? Student: Are there biases in proteins? Ahern: Are there biases? Do we see carbohydrates being in one vs. the other? We do tend to see many more in the D form than in the L form. Yes, we do. But it's not as strong as we see with amino acids and other things. But D is very strongly favored. Two molecules are enantiomers if they're mirror images of each other. These guys are mirror images of each other. Now, [inaudible] uses this term "constitutional isomers." I don't like that term, so we're not even going to hold you responsible for that. What is a stereoisomer? Stereoisomers are molecules that have the same general structure, that is they're both C6H12O6. They're both aldoses. But they're not mirror images. Look at this. This guy is not a mirror image of this one. They are stereoisomers of each other. And another term is used, it's not on here, actually it is right here, they are called diastereisomers. DIASTEREOISOMERS. So stereoisomers will include enantiomers. They will also include diastereoisomers. Now notice what I said had to be for a diastereoisomer. They had to be the same kind of sugar. In this case, they had to both be aldoses. They had to have the same number of carbons but they're not mirror images of each other. Yes, sir? Student: [inaudible] Ahern: I'm sorry? Student: There are 7 oxygens instead of 6. Ahern: Oh, that's a very good question. That's actually incorrect. I didn't even notice that. Obviously the book didn't either. That should only be an H, yeah. Good eyes, wow. I've stared at this I never noticed that before. When I was working on a textbook, I was an author, a co-author on a textbook about 10 years ago and I was on the third edition of the textbook and so they, you know, I was reading all the things that the other authors were writing and so forth and we use a lot of the same figures in our textbook that have been used in the previous edition of this textbook. And so I look at this one and this one figure and I said, "this is ridiculous, "it's a carbon that's got 5 bonds." [class laughing] And so I go to my co-authors and I said, "this carbon has 5 bonds." And they said, "oh my God, it's been in the past "2 editions and nobody's ever noticed it." So you found 5 bonds, so you found an extra oxygen. Good. We should contact, we've seen other errors in this edition of the textbook, so that's kind of bad. This is the first time this figure has been used in this edition of the textbook, so we didn't used to have this figure. I kind of like this figure and there's my little... Now, two other terms. Stereoisomers include enantiomers and they include diastereomers. Diastereomers include epimers. And epimers are two sugars that again have the same kind, they're both in this case aldoses. They have the same number of carbons. They only differ in configuration by one hydroxyl. So if we look at this guy on the left, on the left. On the right, on the right. On the right, on the right. The only place they differ is right here. These two guys are epimers of each other. They're not mirror images. They're not mirror images of each other. They're epimers. They're only different in the configuration of carbon number 2. Last, anomers are also diastereomers. And anomers arise from the different configuration that comes upon cyclization. I haven't said anything about cyclization so I'm going to show you that in a minute. I'm going to introduce the term to you right now and then I'm going to come back and show you more detail in a minute. You should know what an enantiomer is, you should know diastereomer is, you should know what an epimer is, you should know what an anomer is, you should know what a stereoisomer is. Just some basic terms of carbohydrates. Here are some common monosaccharides that we see. We call them monosaccharides because they're not polymerized. They're only existing as a single unit. Glucose is a monosaccharide. Fructose is a monosaccharide. Galactose is a monosaccharide. Ribose is a monosaccharide. Deoxyribose is actually an oddball because it's lacking an oxygen. That's why we have the deoxy part. We show it to you here because obviously this an important constituent of DNA. It's what gives DNA the D part of its name. When we start looking at sugars, carbohydrates here, you started thinking, "okay, is Kevin going to make us "know all these structures?" Well there are hundreds of possible carbohydrate structure, that pained look that says, "I really don't want to know that, right?" I'm not going to make you know all those. But I will make you know the structures of the important ones. And the reason I make you do that is you're going to need to know them in other classes. So you should know the straight chain and the ringed structure forms of glucose, galactose, fructose, and ribose. Ring and straight chain, glucose, galactose, fructose, ribose. Now these actually are quite common. They're quite similar to each other. Let's look at glucose and fructose for example. The only difference between them is glucose is an aldose and fructose is a ketose. Because if we look at the configuration of the OH groups, this one is lacking an OH in position 2, so we go to position 3, it's on the left. Position 4 on the right, position 4 on the right. Glucose and fructose are identical except for whether they're ketose or aldose. Galactose is an epimer of glucose. It's an epimer of glucose. The only place that galactose differs in configuration from glucose is right here. These are very easy to learn in terms of structure. I learned glucose is right, left, right, right. Right, left, right, right. I can always draw glucose and then remember that this guy's going to be identical. I remember that galactose is going to differ at carbon number 4. 1, 2, 3, 4. There's the difference. So you can put these to memory pretty easily. Now, you learn in organic chemistry, I trust that these 6 carbon or 5 carbon rings have a geometry such that they can actually come back around and interact with each other to make ring structures. The ring structures are named according to their resemblance to a couple of molecules. Pyran is a molecule that looks like what you see on the top. It has 6 carbons, I'm sorry it has 5 carbons and it contains an oxygen. Furan has 4 carbons and contains an oxygen. This is a 6 membered ring, this is a 5 membered ring. We use these names as our way of describing sugars. Sugars that form six-membered rings we refer to as pyranoses. Notice I said 6-membered rings. 6-membered rings have 5 carbons in them. Sugars that form 5-member rings are known as furanoses. 4 of those are in there. Can a 6 carbon sugar form a pyranose? Can a 6 carbon sugar form a furanose? Yes. We're only counting them with carbons in the ring. Other carbons can be sticking off as we will see. Okay, so how do these form? Well, aldoses form a structure known as a hemiacetal. A hemiacetal arises by reacting an aldehyde with an alcohol. An example would be glucose can make a hemiacetal structure because glucose is an aldose. A hemiketal arises from taking a ketone and reacting it with an alcohol to make a hemiketal. And fructose is a ketose. So it can form a hemiketal. Let's watch this cyclization process happen. The cyclization process happens as you can see right here. Here's the 6-member glucose. The 6-membered glucose has a geometry such that this hydroxyl group on carbon number 5 right here can get very close to that aldehyde group on carbon number 1. When it does, it can make a ring structure. And it turns out it can make 2 rain structures because what's happening is this guy, which only had 3 members on it, now is going to have 4 members on it. We don't have the double bonded oxygen anymore. If it forms in this configuration such that the OH is down, we refer to that configuration as the alpha configuration. If it forms such that the hydroxyl is up, we refer to it as the beta. Now, at this point, I can tell you these two guys we see here on the right are anomers. Their only difference is whether they are alpha or beta. Everything else is the same. So we can have alpha-D-glucopyranose, we can have beta-D-glucopyranose. Those two will be anomers. But if I had alpha-D-galactopyranose and beta-D-glucopyranose, they would not be anomers because they would have other differences. So anomers can only differ in the configuration of the anomeric carbon. And by the way, the anomeric carbon will always be the carbon that had the double bonded oxygen. I'll repeat that. The anomeric carbon will always be the carbon that had the double bonded oxygen. That's true whether it's an aldose, or whether it's a ketose. So we have a glucopyranose here, we have a glucopyranose here. Alpha vs. beta. Yes, Shannon? Student: So is an anomer also an epimer? Ahern: Is an anomer also an epimer? Technically it is, but we don't tend to use that term for that. We use epimers for other than the anomeric carbon. all right, when we have a ketose like fructose, what happens? Well, looky here. Here is our anomeric carbon. There is a double bonded oxygen. Here is carbon number 5. We see this same sort of intermediate structure forming here and voila. We have in this case alpha-D-fructofuranose. Alpha meaning the hydroxyl is down. Notice it's the hydroxyl that determines the position of alpha or beta, not the carbon that's there. Can we have a beta-D-fructofuranose? Yes, we can. They just have, your book has gotten lazy and they haven't drawn it. If we had the beta, we would have the same structures we have the hydroxyl of and we would have the CH2OH down. Now, notice this is a 5-membered ring. It has 6 carbons. Carbon #1, 2, 4, 5, 6. If you want to spare yourself grief on the exam, always number your carbons. You'll always bail yourself out. Don't forget to number your carbons because the most common things I'll say, "what's the structure of fructose?" A five-membered ring, 1, 2, 3,4, 5, I've got it. Well you know that fructose is a 6-membered, has a 6 carbon molecule. It's a hexose, right? So don't forget to number your carbons. That will always bail you out. An important thing about these structures is that they are reversible. They are reversible. In solution, which is the most common way that we have glucose, these molecules can go back and forth from one structure to the other structure quite readily. They can go from one structure to the other structure quite readily and it turns out that there's a little bit of steric hindrance for the beta form. I'll show you that in just a little bit. And so we tend not to see as many of these in the beta form as we see in the alpha form. But nonetheless, we do see some in the beta form. In solution it's going back here, over here. Back here, over here. One of the criteria for the reverse ability of this process. Okay, is the ability of these guys to go back to the straight chain. If they can't go back to the straight chain, they can't flip. These guys can flip. Well what stops it from going back to the straight chain? If I modify the hydroxyl. If I modify the hydroxyl, that process is not reversible and it will be stuck in that configuration. It will stay. So let's say I put a methyl group in place of that hydrogen right there. If I put a methyl group right there, it can't go back. It will stay stuck in the alpha configuration in this case. Let's say I put a nitrate right there. Same problem. It's not going to go back, it's going to stay in this case in the beta configuration. So if I do anything to that anomeric hydroxyl, and notice it's the anomeric hydroxyl, I will lock it in whatever configuration it happens to be in. Student: So they switch between alpha and beta, they don't switch between straight and ring... Ahern: Well they can make straight, yes. They can make straight, yeah. They have to be able to go back to straight and back to here. Don't waste your time on this slide. [laughing] Since I've shown it, I'll tell you. I'm going to show it to you, you're not responsible for it. This is to be showing you that yes, these guys can make 6 membered rings just like glucose can make 6 membered rings. It's not the most common form we find fructose in and I think it just adds another level of memorization that you don't really need. So we're not going to worry about the 6-membered rings of fructose, okay? These are the ring structures of sugars that we find very commonly. Yes, you're responsible for ribose, yes you're responsible for glucose, yes you're responsible for fructose, and yes you're responsible for galactose, alphas and betas. And again, these are very, very similar to each other, but don't forget to number your carbons or you'll get lost. Look at fructose. "Whoa, those aren't identical!" Yes they are. There's carbon 1, 2, 3. There's carbon 1, 2, 3. Hydroxyl up on 3, hydroxyl up on 3. If you don't number your carbons, you will get lost. Yes? Student: So the ribose ring doesn't have an alpha or beta indication which [inaudible]. Ahern: It actually should have that. If I were to say, "what configuration would that be?" What would you say? Student: Alpha. Ahern: That's beta, that's beta. They do have alpha and beta. What we see in nucleotides is it's always in the beta. I think that's why they haven't drawn it or given that designation but you're right, it should have that designation on there. So this would be the beta-D-ribose right here. Good, you guys have good eyes today. Let's say a word about steric hindrance, I had mentioned it. We talked about steric hindrance earlier in the term and steric hindrance relates to nuclei or electron clouds that get too close to each other. And we saw that there's a tremendous amount of energy that opposed putting things too close together. This is a schematic way of looking at a sugar that has a couple of groups that are kinda butting heads with each other. And we can imagine that if there was a way for the sugar to avoid butting heads, it probably would do that. And in the case of an animatic carbon, it's actually fairly readily able to change that. This shows glucose in the beta configuration. The beta configuration, we can see that this guy over here has a hydroxyl that is sort of interacting with this CH20H in carbon number 6. They're too close to each other. We describe the structure this guy has as a boat. Because if we trace the path of the carbons, the carbons look like this. There and then down and then across like this. It looks like a boat, all right? The same beta, this is beta, this is beta, they're both betas, can twist bonds and rearrange itself so that that interaction does not occur. This is a beta form like this is a beta form, but this is a beta that has a different confirmation and it's flipped itself so that hydroxyl which was in the way up here is flipped down over here. And it should say down equatorially instead of being flipped up. Now that configuration is called the chair because it has a sort of configuration of a chaise lounge. There's the back, there's the butt end part, and there's where you put your feet. You have a question? Student: Yeah, over here, that hydroxyl [inaudible]. Ahern: These two guys do interact actually right here. There is interaction. There's much more interaction here than there is here. And so this is favored of the two structures. The chair form is favored over the boat form because of that. So if you compare this to this, this has much more interaction than this one does. Yes, Connie? Student: When you say the chair form is favored, do you mean in all cases or just... Ahern: In this particular case, but in general, when you can arrange things away from each other, you're going to be better off. I'm just illustrating this as one example to show you how a boat vs. a chair form might be favored for structure. Student: Will we need to put these in chair or boat form on the exam? Ahern: Will we need to draw a chair or boat form on the exam and get all these axiology and so forth and the answer is no, I think that's kinda busy work. But I think you should certainly know what a chair form is. And I think you should know what a boat form and why one vs. the other might be favored. Question back here? Student: So maybe I missed it, but how do you determine whether it's an alpha or beta [inaudible]? Ahern: The alpha has the hydroxyl down as we draw it and the beta has the hydroxyl up. That's a good place to stop, I hear the rustling. I'll see you guys on Friday. Captioning provided by Disability Access Services at Oregon State University. [END]