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Inositol phosphate

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 Phosphate group
Phosphate group

Inositol phosphates are a group of mono- to polyphosphorylated inositols. They play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation. The group comprises:

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  • #38 Biochemistry Fat/Fatty Acid Metabolism II Lecture for Kevin Ahern's BB 451/551
  • Mod-05 Lec-17 Regulation of gene expression by second messengers other than cAMP

Transcription

Captioning provided by Disability Access Services at Oregon State University. Kevin Ahern: Okay folks, let's get started. So as you can see, I've got grades posted for the exam. It was a very interesting exam grade-wise. Average 75.2. I think combined with the high average that you guys had last year, this class actually has two of the three highest averages I've ever had. So more to your credit. That's very good. The low was about twenty-six. The high was one hundred. I think there were four people who got one hundred. So that was very impressive. I was quite impressed with what I saw looking through things. I thought that you really did a very good job on this. One of the things that probably was a factor on this exam was because of the rain day, we had a little bit less material on this exam. And so consequently on the next exam, we're gonna have a little bit more material. So if you guys does this again on the next exam, I will be delighted. I really will. So that would be very cool. So keep up the good work. If you're finding that you're having difficulties, and you need assistance, or a tutor, or anything; please let me know. I have some very good students who are tutoring, and I can connect you with them if that would be of assistance to you. Or if I can be of assistance to you, of course, let me know as well. I'm gonna finish up, and we're actually gonna get caught up, might even get a little bit ahead today with respect to fatty acid metabolism. And that will lead us into prostaglandin synthesis and metabolism, and then I may actually get into talking a little bit about nucleotide metabolism if I finish early today, which I think I will. You've seen how fatty acid oxidation occurs, and you saw how fatty acid oxidation actually related to the synthesis of ketone bodies. If you recall, the synthesis of ketone bodies was the reverse of the very last step of beta oxidation because thiolase was putting together two acetyl CoAs to make that acetoacetyl CoA and ultimately ketone bodies that were useful for keeping the brain alive and the rest of us alive as we're very low on glucose. Fatty acid synthesis, as I've noted before and I'll go through it again here with you today, also is very closely related to fatty acid oxidation in the sense that it is chemically very much like the reverse of that of oxidation with a few differences as I have noted. So I want to spend just a little bit of time summarizing those reactions one more time for you. And then I will talk about the regulation of fatty acid biosynthesis which is interesting and important. So looking at fatty acid synthesis, that's not what I wanted, we basically saw, that's not what I wanted either. There we go. We basically saw a chemical reversal of the oxidation reactions starting with a condensation, whereas before in the corresponding reactions in the oxidation, we had thiolytic cleavage; a reduction where previously we had an oxidation; a dehydration where we previously had a hydration; and last, a reduction where previously we had an oxidation. Now you notice on this scheme some of the differences compared to fatty acid oxidation. One is that the electron carrier is NADPH. And I haven't mentioned it before I don't think. If I have, I'll repeat myself then. And that is that NADPH is commonly used as an electron carrier for biosynthetic reactions. Very commonly a carrier for biosynthetic reactions. It's not absolute for biosynthesis. For example, you saw NADPH being used in the oxidation of unsaturated fatty acids. But in general, NADPH is used for biosynthetic reactions, much more than NADH itself is. Well, the product of this reaction as I noted gave us, in this case a four carbon intermediate. And that four carbon intermediate becomes then, in essence, this acetyl-ACP except for now it has four carbons instead of two carbons. You'll notice then that the incoming new carbons come with this malonyl-ACP. And so the previous ACP gets displaced, and what it was attached to gets attached right there. So the newest carbons will always be on the end linked to ACP. And that means that the ACP itself will always be the newest one on the molecule as well. So I remind you that fatty acid biosynthesis occurs in the cytoplasm. Not in the mitochondrion. And it turns out that the cells have to get acetyl CoA out into the cytoplasm. I'm gonna talk a little bit about that relative to respiratory control in just a little bit. But suffice it to say that there is a very useful and simple mechanism that cells have for getting that acetyl CoA out into the cytoplasm where the synthesis of fatty acids occurs. And that actually is my good lead-in for this right here. Before I say that, fatty acid synthase, again, I'm not expecting you to know this figure so don't sweat it, but fatty acid synthase, you'll recall, is the complex that makes the fatty acids. It has multiple catalytic activities on it. These are schematically shown by these various letters or two letter scheme that's up here. And literally this fatty acid, as it's being synthesized, goes around the clock. Each time adding two carbons, getting reduced, getting dehydrated, etc., all the way through until finally, we end up with a fatty acid that is 16 carbons long. So the final product of fatty acid synthase is a 16 carbon fatty acid known as palmitate. It's a 16 carbon fatty acid known as palmitate. Well, that isn't the complete end of the story because palmitate, first of all, has 16 carbons. It is full of saturated bonds. There is no unsaturated bonds in palmitate. So we have to account for two things. We have to account for the longer fatty acids, and we also have to account for how unsaturation gets into the molecules. So let me account for those before I come back and talk about how we get acetyl CoA out there. I don't have any great figures for this, unfortunately, but it turns out that these are relatively simple. The first that I will talk about is the unsaturation or the desaturation of fatty acids. This is the act of incorporating double bonds into the fatty acids as they're being synthesized. And there is a fairly elaborate scheme that we used to teach. I'm not gonna go through that scheme, and I'm gonna keep it very simple with you. There's an enzyme, the class of enzymes that catalyze the formation of double bonds in fatty acids are known as desaturases. And desaturases are found in the endoplasmic reticulum. So that means the fatty acid will have to get to the endoplasmic reticulum in order to have double bonds put into it. The desaturases put in cis bonds only. That's one thing about the desaturases. They put in cis bonds only. And if you're an animal, it puts in cis bonds only up to position delta nine. So delta numbers from the carboxyl carbon towards the methyl. If you start with carboxyl as number one, the desaturases in animals will put it in carbon number nine, but it will not go further than carbon number nine. As a consequence of that, and we need fatty acids with double bonds beyond carbon number nine, it means that we can't make fatty acids that have multiple double bonds or have bonds beyond carbon number nine. Those fatty acids are what we call essential, meaning that they have to be in our diet. And of the ones that you see on the screen here, these would include. These are omega designations; so omega designations are not good for our purposes because they're counting from the methyl, and the methyl will depend on how long the carbon is; so we can't really count there and get what we want. But of the ones on the screen, palmitoleate is a nonessential fatty acid. Oleic acid is a nonessential fatty acid. But the two above it are both essential fatty acids. I'm sparing you some structures here, but suffice it to say that both linolenate and linoleate are both polyunsaturated. Linoleate has two double bonds. Linolenate has three double bonds. Yes? Female student: Which one was it again that had [inaudible]? Kevin Ahern: So linoleate has the omega six here; it has two double bonds. Linolenate has three. Yes, Lin? Lin: [Inaudible] Kevin Ahern: Yeah, that's a good question. I said animals, and actually what I really mean is mammals. Mammals are the ones that have this limitation. So replace what I said animals by mammals. So for mammals, we've gotta have these fatty acids in our diet. They're abundant in plant tissue, and so one of the reasons we should get some good plant consumption in our diet is to get essential fatty acids that are in there. Or we get them out of animals that we eat that have eaten it themselves from a plant, etc. So those are also important. So desaturation is fairly straightforward. There's also something I want to talk about. Your book used to talk about it in the old scheme, and it's not even there in the new scheme, and that's elongation. So elongation of fatty acids is also important for us to recognize. And elongation turns out to be kind of interesting. So elongation occurs as a result of action of enzymes known as, and hold onto your seats for this name, elongases. [class laughing] Kind of a surprise, huh? And elongases catalyze the very same types of reactions that you've already seen for the general fatty acid synthesis. They'll go through that condensation. They'll go through that reduction. They'll go through that dehydration. They'll go through the reduction again. These desaturases are located in two places. And the second place will surprise you. The first place we see the desaturases is in the endoplasmic reticulum. Yes, Anicia? Anicia: Don't you mean elongases? Kevin Ahern: Elongase, I'm sorry, yes. Your brain latches onto a word, and it won't let go of that word. Elongases, yes. The two places we find elongases are in the endoplasmic reticulum, and we also find them in the mitochondrial matrix. What the heck is that all about? "I thought you said Kevin that the mitochondrial matrix "was where fatty acid oxidation occurs." And I said, "Yeah, that's right. "Fatty acid oxidation occurs there, "and we've got elongases there." So how does that work? I'll ask you. How does that work? Female student: [Inaudible] Kevin Ahern: A nice thought. They also catalyze the reverse reaction, that is to help break it down. Well, really, no. They're making fatty acids in the mitochondrial matrix. Anicia? Anicia: [Inaudible] Kevin Ahern: Well they do go to the other things your body needs. Definitely, that's for sure. But there's a reason why this is possible. Jarrod? Jarrod: Is it energy use? Kevin Ahern: Not because of energy use. Male student: Does it have to do with the odd number of carbons? Kevin Ahern: Not to do with the odd number of carbons. No, keep going. Female student: Is it for the mitochondrial membrane? Kevin Ahern: Is it for the mitochondrial membrane? There may be some truth to that. That's why. But I'm sort of asking you how. How come this doesn't get all mucked up? We've got synthesis and we've got oxidation going on in the same place. Jodi? Jodi: Can the oxidative enzymes not attack something that large? Kevin Ahern: Ah! Jodi says, "Can the oxidative enzymes not attack "something that large?" You actually know the answer to that question, don't you? Where did we have the first enzymes involved in oxidizing long fatty acids? Were they in the mitochondrial matrix? Nope. They were in the peroxisome, right? So it turns out that once you get these big fatty acids in there, the mitochondrion can't do anything with them. So what does it do? It makes bigger ones. It's an odd scheme. But that's what happens in our cells. So knowing where the acyl CoA dehydrogenases are located allows us really to answer this question. You can see that there's no enzyme there that will start that oxidation process in the mitochondrial matrix on a fatty acid that's 16 or longer. Yes, sir? Male student: What's the mechanism for transporting something that large back out to be used? Kevin Ahern: What's the mechanism for transporting something that large out to be used? It's a good question. I don't have an answer for it. They do obviously have to be transported out. I don't know exactly how that's done. And keep in mind that they're made in two places. So the person who said that they're made and used in the mitochondrion, probably that is why the mitochondrion is making some of its own is for itself; it doesn't have to move them back out. The endoplasmic reticulum, on the other hand, does have to have the mechanism. And it's probably the same mechanism that the endoplasmic reticulum is using to export the unsaturated ones as well. So probably both are handled by the same export system, but I don't know what the export system is. Good thoughts. So that's what's happening with fatty acid synthesis for long fatty acids and for unsaturated fatty acids. So we look at those in a little simpler way than we did before. Well, I mentioned that we had to get acetyl CoA out into the cytoplasm where synthesis occurs. And this schematic shows us how that process occurs. So it turns out that acetyl CoA itself cannot be moved across the inner mitochondrial membrane. Instead, the cell uses the molecule citrate as a shuttle, that is to carry the two carbon piece across. So here's the mitochondrial matrix on the left. In the mitochondrial matrix, we have the reactions of the citric acid cycle up to citrate. Citrate can then be moved with an antiport that will move citrate out, and at the same time it moves pyruvate in. That turns out to be important for our purposes for metabolic control. Citrate gets out in the cytoplasm, and it gets broken down into oxaloacetate and acetyl CoA. Acetyl CoA can then be joined to acyl carrier protein, and fatty acid synthesis ensues. Jodi? Jodi: Is it using the same enzymes that were in the citric acid cycle, like citric synthase [inaudible]. Good question. Is it using the same enzymes as the citric acid cycle, and the answer is no, it's not. Because the citric acid cycle enzymes are specific to the citric acid cycle. The enzyme it takes to break this guy here is called citrate lyase. And that sounds like that glyoxylate enzyme that I talked about earlier which was isocitrate lyase. It's not the same enzyme obviously. And citrate lyase cleaves citrate into acetyl CoA and oxaloacetate. So there's a special enzyme out in the cytoplasm that does that. Now I want to spend a minute talking about what you see on the screen here, because it really relates again to this business of energy and obesity. Very important for us to understand what's happening here. Well, when is this process going to be kicking into place? Well, the most obvious time when we will see this process kicking into place is when citrate concentrations start increasing. Citrate concentrations start increasing. Well, how will citrate concentrations be increasing? Well, let's imagine the following scenario. Let's imagine that I am eating more than I'm burning. Let's imagine that I'm eating or drinking high fructose corn syrup that we talked about last term. If we talk about and think about what happens with high fructose corn syrup, I said that what happens is we bypass the PFK reaction in glycolysis and we start forcing production of pyruvate. This is Kevin Ahern's pet theory about why people are becoming obese. We're coming back to it again. High fructose corn syrup is forcing production of pyruvate that non-high fructose corn syrup will not, at least to the same extent. It means we have an abundance of pyruvate. An abundance of pyruvate coming in, comes in right here. It doesn't have to go through this circle as you see it here. If I got a lot of pyruvate floating around out here in the cell from glycolysis, bang, it's in. If I'm eating and/or drinking more sugar than I am burning, what's going to happen? Is my energy state going to be high or is it going to be low? High. I have an abundance of ATP, right? Because I'm not exercising enough. My ATP levels are high. I'm not burning that ATP off. What happens to my ADP levels? Low. Right? ADP levels are low. What happens to the oxidative phosphorylation? It slows down. There is no ADP to convert to ATP. What happens to the proton gradient? It goes up, right? Proton gradient goes up because the protons aren't coming back in. Proton gradient goes up, what happens to concentration of NAD? It goes down, right? Because there is no place to put the electrons. The electron transport is stopping. If NAD concentration goes down, what happens to the citric acid cycle? It stops. And where are those electrons needed in the citric acid cycle? Oh boy, now you're gonna stretch your memory. I'll tell you. The first place they're needed is isocitrate dehydrogenase. After citrate. So what's gonna accumulate when you're doing all these things? Citrate. And when citrate accumulates, what happens to it? It goes out in the cytoplasm. And what happens in the cytoplasm? We make acetyl CoA, and we make fatty acids. Now Kevin Ahern's pet theory about why Americans are becoming obese is complete. [class laughing] Quit eating all this crap. [laughing] I say this as one who does that. So that's what's happening here. If we force production of pyruvate, we're gonna force this process; and the results of forcing this process are to move acetyl CoA out into the cytoplasm with nothing to do but be made into fatty acids. And guess what? Remember our ATP concentrations are high. And what does it take to make fatty acids? All this stuff that we've been talking about. All this stuff that we've been talking about. Bang! We're in trouble. We break the cycle by breaking the amount of pyruvate that we start feeding into the system. We reduce our intake of sugars. People scoff at low carb diets; but in fact, low carb diets are the easiest way for you to reduce your pyruvate concentration. That's the way to do it. That's the way to reduce it. That's what's happening with obesity or one of the ways that we can become obese. Fatty acids of course lead to fat. The last thing I want to talk about with respect to fatty acid metabolism is to talk about regulation. And I briefly mentioned it before. Now I'll talk about it in a little bit more depth. Acetyl CoA carboxylase is the only enzyme in fatty acid biosynthesis that's regulated. That's the very first enzyme, and that was the enzyme that put that carbon dioxide onto acetyl CoA and made malonyl CoA. That's a necessary step in making fatty acids. That enzyme is regulated in our cells. That enzyme is found of course in the cytoplasm where all the enzymes of general fatty acid synthesis are found. And we see one regulatory scheme up here. The enzyme is partly regulated by phosphorylation-dephosphorylation. This is an AMP-activated protein kinase. An AMP-activated protein kinase. Why would an AMP-activated protein kinase be useful here? What does AMP tell us in the cell? Low energy state, right? Low energy. Do we want to be wasting energy on synthesizing fatty acids? No, we don't. So we phosphorylate the carboxylase to at least partly inactivate it. If we want to activate it, we need a phosphatase. And phosphatase brings it this way. How do we activate phosphatases in the cell based on what we learned last term? Insulin. Insulin. Insulin is going to favor activation of acetyl CoA carboxylase. Insulin is going to favor the synthesis of fatty acids. And when do we make plenty of insulin? After a big carbohydrate consumption. So again, all the wheels are turning in favor of making fatty acids the more carbs we take. The more carbs we take, the more we're favoring insulin and the more we're favoring the activation of acetyl CoA carboxylase. Now I said that phosphorylation is one way of partly inactivating it. There is another way of partly inactivating it, and that is by the byproduct of fatty acid synthesis, palmitate. Palmitate will inhibit acetyl CoA carboxylase. Oh good, we're in the good right? Well, maybe not. We're also in the bad. Because there is also another allosteric effector that activates the enzyme. And that allosteric effector is citrate. Where do we get the citrate? Well, you saw it in the last scheme. It's coming out from the mitochondrion. The citrate starts accumulating. What's going to happen? We're going to activate this enzyme. Now we have different degrees of activation. We see the most inactive enzyme is going to be phosphorylated with plenty of palmitate around. The most active form of the enzyme is going to be dephosphorylated with plenty of citrate around. And some were in between with the other two states. Now this enzyme is also of interest in another perspective in that the enzyme exists in the cells as long polymers when it's dephosphorylated. So the active state of the enzyme is a long polymer. You can actually see it in a microscope. Really long polymers that go one to the other, to the other, to the other, very active in the polymer state. Putting the phosphates onto it causes the polymer to fall apart, and it becomes monomers at that point. The monomers can be somewhat active but not nearly as active as the polymer. Here are the filaments right here. Those are actually acetyl CoA carboxylases that you can see. Pretty amazing stuff. There's a lot of enzyme to make polymers like that. Phosphorylated-dephosphorylated, that's just demonstrating to you graphically what I told you in words, that is the dephosphorylated, the most active, the highly phosphorylated, the least active, and citrate concentration affecting those activities. I think that is basically what I want to say about fatty acid oxidation. I won't go through that. Questions or comments before I talk about prostaglandins? Should we sum it up in a song? So I've got a song, and by now you guys should know this tune because it is the third time in a row we're using the same tune. I can promise this is the last time we'll use this tune this term. It's "When Johnny Comes Marching Home." ["When Acids Are Synthesized" by Kevin Ahern] The 16 carbon fatty acid, palmitate Gets all the carbons that it needs from acetate Which citric acid helps release From mitochondri – matrices Oh a shuttle's great When acids are synthesized Carboxylase takes substrate and it puts within Dioxy carbon carried on a biotin CoA's all gain a quick release Replaced by larger ACPs And it all begins when acids are synthesized A malonate contributes to the growing chain Two carbons seven times around again, again For saturated acyl-ates There's lots of N-A-DPH That you must obtain When acids are synthesized Palmitic acid made this way all gets released Desaturases act to make omega-threes The finished products big and small Form esters with a glycerol So you get obese when acids are synthesized That's the bad news, right? Female student: Bad news right at the end. Kevin Ahern: What's that? Female student: Bad news right at the end. Kevin Ahern: Bad news at the end. So the last topic I'll talk about relative to fatty acid biosynthesis is that of the synthesis of arachidonic acid and prostaglandins. And these are really interesting and odd compounds. They're interesting in that they cause many different phenomena or are linked to many different phenomena in the body. And they do arise from fatty acid biosynthesis. So let's take a brief look at what happens with these guys. So I haven't talked about arachidonate. I need to do that. Arachidonate is a 20 carbon fatty acid. It's a 20 carbon fatty acid. It has four double bonds in it. It's very polyunsaturated. Normally, we don't keep arachidonate floating around in our cells freely. And the reason that we don't is it's very, very readily converted into leukotrienes going above or prostaglandins going below. These guys actually cause some similar things to happen. The simplest and most common things that we associate with prostaglandins is pain. Well, if we don't have arachidonate floating around free in the cell, where does it come from? As soon as the cell gets some arachidonate, what it does is it bundles it up into glycerophospholipids. It doesn't want it floating around free, so it puts it onto a glycerophospholipid, and you know where glycerophospholipids end up. They end up in your cell's membranes. So the arachidonates are sitting there waiting to be released. They can come either directly from phospholipids, which are the glycerophospholipids that I'm talking about, or if we had diacylglycerol. How would we have diacylglycerol in our membrane? Anybody remember? Anybody remember IP3? PIP2, IP3? So when we clipped off that inositol phosphate, we're left with a diacylglycerol in the membrane. In either case, we've got something that's got two fatty acids on it, and one of those fatty acids in our scheme here has arachidonic acid on it. The arachidonic acid can be clipped off by either a lipase cutting from one side, that is by cutting diacylglycerol, we need a lipase; or, if it is cutting off of a glycerophospholipid, it is something called phospholipase A2. You can call it PLA2 if you want. I'll come back to PLA2 in a minute because it turns out to be one of the ways that we can control the synthesis of prostaglandins. Well once we have arachidonate, I'm going to focus our attention going down into prostaglandins. Going down. There's an enzyme that converts arachidonate into prostaglandin H2, and I'll show you a structure very briefly just to give you an idea about what kinds of compounds we're talking about. Prostaglandins generally look like this. If you count, they'll have 20 carbons. They'll have 20 carbons. And they will always have a sort of a ring structure at the end, like this guy. So there's only one prostaglandin. There's actually many prostaglandins, but they all have a general structure that looks like what you see here. This is what I call a cyclic structure, this little ring that's here. If we compare them to leukotrienes, we don't see that ring. So this is a linear structure. This is what I call a cyclic structure. So all prostaglandins will have that cyclic structure in them. Now they also gain some oxygens. Remember we're starting out with fatty acids. We started out with a 20 carbon fatty acid, and you haven't seen fatty acids that have oxygens in them. That meant that something had to put those oxygens in there and make that ring. So now let me come back to the scheme and show you what happens. Go back to the scheme that I showed you before. Prostaglandin synthase is the enzyme that does both of those things. Prostaglandin synthase isn't usually called that. It's usually called cyclooxygenase. C-y-c-l-o-o-x-y-g-e-n-a-s-e. Cyclooxygenase, again now the name tells you what it does, it makes that cyclic ring, and it puts oxygens on there. Cyclooxygenase. People frequently abbreviate cyclooxygenase as COX, and they call this a COX enzyme. Well, why do I tell you that? COX enzymes turn out to be of incredible interest scientifically. And they're of incredible interest because we have a lot of interest in inhibiting the action of cyclooxygenases under certain conditions. So they're very much a target for drugs to inhibit the action of the enzyme. Why? Well, there's many times we want to inhibit the production of prostaglandins. You have a headache? You're producing prostaglandins. What do you take for a headache? You take a prostaglandin inhibitor. Aspirin is a prostaglandin synthase or a cyclooxygenase inhibitor. It inhibits the production of prostaglandins. Ibuprofen is in fact a prostaglandin synthase inhibitor or a cyclooxygenase inhibitor. Most people commonly say it's a COX inhibitor, because that's what it is. Now, aspirin in particular inhibits the enzyme by making a covalent bond with the enzyme. It makes a covalent bond with the enzyme. That stops the enzyme from functioning right in its tracks. Now, aspirin is an example and ibuprofen. Any of the inhibitors that inhibit this enzyme, this COX enzyme, any of the inhibitors of this COX enzyme are known as non-steroidal anti-inflammatory drugs. NSAIDs, N-S-A-I-D-s. You've heard of NSAIDs before. NSAIDs inhibit this enzyme. Non-steroidal anti-inflammatory drugs. That name tells you, "Oh, I bet prostaglandins "are involved in the inflammation response as well." And the answer is yes, they are. If you get a bee sting, and it's hurting, and it's swelling up, the doctor says, "Take some aspirin." It will relieve the pain. It will also relieve the inflammation that happens as a result. You have knee joint problems or something, the doctor's gonna say, "Take some aspirin." And it will reduce the inflammation and hopefully reduce the pain in the process. Prostaglandins are involved in both of those processes. Well, why do we say that they're non-steroidal anti-inflammatory drugs? If we say there's non-steroidal anti-inflammatory drugs, that must mean there are some steroidal anti-inflammatory drugs, and the answer is yes, there are. They inhibit phospholipase A2. Corticosteroids are commonly used to inhibit PLA2. Now while these guys give some reasonable relief, the steroidal anti-inflammatories give great relief. So I always tell this story. When I first came to Oregon many years ago before all of you were all born, I decided that my very first week here, I'm going to go out. And there's blackberries everywhere, and I've never been anyplace where blackberries grow wild, so I'm gonna go out and pick blackberries in my shorts. [class laughing] Oh, I was so young and foolish. And I got this biggest batch of blackberries that you've ever seen. And I said, "What the hell was that?" Well I got into poison oak like you'd never seen. And I literally had my leg twice the size of normal. I mean I was a little scared shall we say plus in extreme discomfort. I went to the doctor, and the doctor looks at that, and he goes, "Whoa, we're doing something with that!" And put me on steroidal anti-inflammatories, stopping as much as possible the synthesis of arachidonic acid. This pathway coming from right into here is very minor. The vast majority of arachidonic comes from this pathway, and by stopping the production of arachidonic acid completely, the swelling was brought down. So when you have people who have a big problem with inflammation, a big problem with swelling, they'll usually get put on to a steroid to help reduce that because the steroids are very effective at working right here. Steroids are not good in general to take, so most of the time we try to inhibit this guy. But in the severe case, we'll use a steroid to inhibit that. Prostaglandins, I will tell you there are many prostaglandins. Some prostaglandins involved in pain. Some prostaglandins involved in inflammation. Some prostaglandins are involved in uterine contraction during the birth process. Some prostaglandins are involved in making your blood platelets sticky. They help the clotting process. So we talked last term a little bit about blood thinners, and I said there were other blood thinners. It turns out that NSAIDs are very good blood thinners as well because they inhibit the production of prostaglandins that will favor the stickiness of platelets. Thromboxanes, in particular, can be very important in this process. They can really help in that clotting process by making the platelets become sticky. There was a lot of interest. Gesundheit! That was emphatic! I like that. There was a lot of interest among drug companies a few years ago to find some very specific prostaglandin synthase or COX enzyme synthase inhibitors. And the reason was as follows. It turns out that we have at least three different sets of COX enzymes in our body. And there's probably more. The COX-1 enzyme is pretty ubiquitous through our body. And it is inhibited by aspirin, as are the other COX enzymes. And so one of the places that problems arise in the taking of aspirin is due partly to the fact that the COX enzyme, COX-1, makes a prostaglandin that stimulates the development of intestinal cells. So some people who take aspirin over a long period of time because they've got chronic pain, find, "Oh aspirin, man, it really nails my stomach." Well, why is it nailing your stomach? They're inhibiting the synthesis of prostaglandins that favor the development of intestinal tissue. And if they don't have that tissue developing as rapidly, what happens is you get ulcerated sores and so forth, problems where that tissue that turns over very rapidly is not being replaced as rapidly. So that's the root of problems associated with aspirin intake in some people. It doesn't happen in everybody. In some people with intestinal issues. Yes, Karen? Karen: What about I think its called enteric-coated aspirin? Kevin Ahern: Enteric-coated aspirin? Yeah, trying to get it past that point where it's... I don't know. Obviously the strategy is they're trying to get that past the point where those prostaglandins are being made and needed. I don't know that. I don't know how effective that is to be honest with you. The whole business of Bufferin. Everybody's heard Bufferin? Many people used to run around and actually think that there was enough acid in aspirin. That's what caused the problem. I mean it's one of the stupider notions that you can have because if you think about the HCl that's in your stomach, there's a heck of a lot more of that than there is in a little tiny aspirin that you're taking. Right? Did you have a question or comment? [professor laughing] You're shaking your head. You like the silly voices that... a little helium. Jodi: That was pretty nice. My question was do prostaglandins of the GI tract that are affected that lead to these stomach discomforts, do they have something to do with controlling the production of new cells in the [inaudible], inside the... Kevin Ahern: Yeah, I don't know. There may be other cells. I don't know exactly the location of the cells, Jodi. I don't know. Now, I said that there was interest in developing specific inhibitors, and the specific inhibitors that people were trying to develop were to inhibit a different class of cyclooxygenases. These were known as COX-2 enzymes. And it turns out that COX-2 enzymes were discovered because they appeared to be produced mainly in joints. People take aspirin for arthritic joints, for problems associated with that. And for the most part, the idea was if I can make a COX inhibitor that inhibits COX-2 enzymes but not COX-1 enzymes, I can have my cake and eat it, too. I don't have to worry about what is going to happen to my digestive system, and I can still relieve the pain associated with these. Billions of dollars went into the development of COX-2 enzymes. And they were released on the market. And it was a disaster. And you probably know some of the disaster. The disaster was that it turned out that people taking many of the COX-2 enzymes found that there were heart problems resulting from that. And it turns out that the heart is another tissue where the COX-2 enzyme is being made. So most of the COX-2 enzymes got pulled off of the market, and that was a big debacle as it were. Celebrex, I think Celebrex is still on the market. Anybody know about that? Yeah, Celebrex is one of the COX inhibitors. I think it is the only one that is still left on the market. Aleve, and things like that, many of them got pulled because of concern over damage to heart tissue that were happening. And I don't know why Celebrex is still there. Maybe it actually doesn't have as much of an effect on the heart enzyme, I don't know. The last thing I'll say about this... oh, yeah, question. Male student: Do you know if there are migraines [inaudible]? Kevin Ahern: Oh, that's a very good question. Do I know if prostaglandins are produced in migraines? If I were guessing, I would say that's not the major pain associated with migraines, but I would only be guessing at that. The pain in migraines is usually very intense and very different from the pains associated with regular headaches, and so I would wager that migraine headaches are more tied to neurons than it is to production of prostaglandins. But I don't know. That's a very good question. Oh yeah, two questions over here. Danielle: [inaudible] Kevin Ahern: Aspirin what? Danielle: [inaudible] Kevin Ahern: I'm not aware of aspirin being linked to blindness, so that's news to me. Do you know what the study was? Danielle: [inaudible] Kevin Ahern: I haven't heard that. I haven't seen that. If you've seen that, I'd be curious to see the article. Lawrence? Lawrence: [inaudible] Kevin Ahern: So his question is, "Is prostaglandin synthase "a type of cyclooxygenase, or is a cyclooxygenase "a type of prostaglandin synthase" and they're synonymous terms. So they're equal. Yeah? Male student: [inaudible] Kevin Ahern: So do prostaglandins trigger nerve cells to tell the brain there is pain in that area. Probably not. Probably the pain that arises, arises partly from the inflammation that they cause. So you feel pressure and so forth associated with those, and that's probably what is happening with it. Yes? Female student: [inaudible] Kevin Ahern: How does prednisone do what? Female student: [inaudible] Kevin Ahern: How does prednisone have so many effects on so many types of illnesses? That's a very good question. They're not all through this enzyme. That would take more than I have time to answer here. Obviously there are other effects that steroids will have on us, which is why we want to avoid steroids in general. We're almost done. And I'm not going to finish early. But I will say one last thing here, and that is the pathway going up, the linear pathway. The linear pathway is important, and we're realizing increasingly the importance of the linear pathway going up because leukotrienes have been implicated in asthmatic attacks. Gesundheit! A little asthma attack right back there. There's a very active research process going on where people are trying to identify the role of leukotrienes and related compounds in triggering asthma attacks. And the idea being that if you can inhibit the production of leukotrienes, specifically by perhaps inhibiting cyclooxygenases, you may have a very new and interesting effective treatment to prevent or reduce the severity of asthma attacks. So that's an important consideration as well. Alright, I think that is a good place to stop. Let's stop there, and I will see you guys on Friday. [END]

Contents

Functions

Inositol triphosphate

Inositol trisphosphates act on the inositol triphosphate receptor to release calcium into the cytoplasm. Further reading: Function of calcium in humans

Other

Inositol tetra-, penta-, and hexa-phosphates have been implicated in gene expression[1] and Steger[2] (both in Science Magazine).

References

  1. ^ Shen, X; Xiao, H; Ranallo, R; Wu, WH; Wu, C (2003). "Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates". Science. 299 (5603): 112–4. PMID 12434013. doi:10.1126/science.1078068. 
  2. ^ Steger, DJ; Haswell, ES; Miller, AL; Wente, SR; O'Shea, EK (2003). "Regulation of chromatin remodeling by inositol polyphosphates". Science. 299 (5603): 114–6. PMC 1458531Freely accessible. PMID 12434012. doi:10.1126/science.1078062. 

External links


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