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Unformatted text preview: MCB 102 Professor Fyodor Urnov
08/05/10 Lecture 27
ASUC Lecture Notes Online is the only authorized note-taking service at UC Berkeley. Do not share, copy, or illegally distribute (electronically or otherwise) these notes. Our student-run program depends on your individual subscription for its continued existence. These notes are copyrighted by the University of California and are for your personal use only. ANNOUNCEMENTS I have good news about the midterm. You all did very well and the average is 103. The material on DNA that we go over on Monday, Tuesday, and Wednesday will be separated from the rest of the final. I will also give you some study guides for those specific lectures before class. That way, you can write down notes while we go along. LECTURE I had a really good question e-mailed to me recently. A student who worked in a lab asked about why she was creating p53 Ras knockouts in lab to induce cancer? She was wondering shouldn't it do the opposite? Well she mixed up the 2 most important genes in cancer, something I'm sure may of you are doing so let me go over it again. p53 is a tumor suppressor gene that is a transcription factor. The most common form of cancer from smoking works by inactivating p53. So the loss of p53, a suppressor, causes cancer. Ras, on the other hand, is a G protein. It is not a transcription factor and, in its active form, it's bound to GTP. Ras belongs to family of genes known as oncogene which have evolved to regulate cell division; a mutation in an oncogene causes cancer. Notice, therefore, a deep dichotomy between oncogenes and tumor suppressors. Cancers are caused by either an inactivation of a tumor suppressor or by changing an oncogene so it gets a new function. Student: Do you need a mutation in both to get cancer? Yes you do. All cancers need an inactivation of tumor suppressors and a mutation in an oncogene. This is a very general description of the causes of cancer, but it is important to know for anyone who plans to do anything in biology. Regulation of Glycolysis Alright ladies and gentlemen. I spent a good amount of time yesterday talking about the Calvin's-dad-ism that your textbook goes through when it comes to fructose 2,6-bisphosphate. I told you all to look it up in your textbook, but I'm going to just explain it to you right now. Despite what your textbook says in another portion of the book, the PFK-1 reaction does not control the flux of glycolysis. You might be wondering then why does your textbook say that insulin and glucagon control glycolysis? It's an artifact of history. Figure 15-7 illustrates a very simple experiment where glycolysis rates were measured depending on the concentration of 3 enzymes, phosphohexose isomerase, PFK-1, and hexokinase IV. It turns out that glycolysis's rate is dependent on hexokinase IV's concentration. PFK-1, on the other hand, only provides a very moderate increase in rate. It turns out that both biological and genetic increases in PFK-1 does not induce a change in flux for glycolysis. This does not mean you shouldn't study fructose 2,6-bisphosphate because I will ask about it on the final. Why? It's very well studied process DO NOT COPY Sharing or copying these notes is illegal and could end note taking for this course. MCB 102 ASUC Lecture Notes Online: Approved by the UC Board of Regents 08/05/10 and it provides good conceptual information about regulation as a whole. because you want to take in more glucose. If insulin signaling tells your body to absorb more glucose, then activating hexokinase will allow you to absorb that sugar. Figure 15-7 is absolutely crucial for understanding why we treat Type II diabetes by targeting hexokinase. Since hexokinase is responsible for controlling glycolysis's flux, we need to target it rather than other enzymes like PFK-1. Student: It looks like in the graph dealing with F26BP's concentration, a lack of the molecule could lead to PFK-1 not working. But doesn't that mean that the experiment in figure 15-7 is a bad experiment since F26BP isn't present? The key to that question stems from hexokinase's presence upstream of PFK-1. That means that even if there isn't F26BP, hexokinase's correlates with glycolytic flux so hexokinase must be the master regulator. It's ok if none of you can understand that form the data at this point because you'll learn how to read data in grad school. This experiment provides proof that hexokinase IV controls glycolytic flux Ok let's go on to talking about diabetes. Both Type I and Type II diabetes represents the body's inability to handle sugar. Why would this be a problem? Well if you can't use sugar, then your body can't make ATP correctly. Insulin is a hormone secreted by the pancreas which mediates your body's correct response to sugar. However, there can be two major issues that stems from improper insulin use. The first problem comes when you stop making insulin which results in Type I diabetes. It comes from the destruction of the beta-islet cells in the pancreas. It's treatment is the lifelong infusion of insulin, if you can afford it. The other major problem is a failure to sense that insulin is made, also known as insulin resistance. Insulin resistance, which is the cause of Type II diabetes, is usually preceded by obesity. Currently, our greatest treatment is exercise and diet though there are some drugs affect it as well. One of the tragic public health issues in America today is that Type II diabetes is increasing greatly in children, a problem unseen 30 years ago. And this is obviously bad. Final Question: Activators of hexokinase are major targets of drugs to treat Type II diabetes. Why would you want an activator and not a repressor? Explain how would you expect an activator to be useful in treating hexokinase. You use an activator The problematic graph Student: Why don't you just have 3 different samples, one without hexokinase, one with hexokinase but without PFK-1, and one with both? Because you want to do the simplest experiment. It's due to Occam's Razor really. And keeping everything the same besides 1 variable is the simplest experiment to perform so it makes more sense performing it all within the same environment. DO NOT 2 COPY Sharing or copying these notes is illegal and could end note taking for this course. MCB 102 ASUC Lecture Notes Online: Approved by the UC Board of Regents 08/05/10 We've successfully debunked the idea that PFK-1 is the master regulator of glycolysis, but where do we go from here? Well regulation starts becoming tissue specific. A good example of this can be seen on figure 15-19. This picture shows how the liver and muscle pyruvate kinases are regulated by different factors. There are a few questions from glycolysis you should be asking yourself. Final Question: What is the goal of the Krebs Cycle compared to the other processes we go through? Final Question: What does the Krebs Cycle need to work? What molecules are mandatory for it to function? There are 5 things that I can think of. Final Question: After reading 16-18, ask yourself how is the metabolic regulation of the Krebs Cycle derived from the answers to the past 2 questions? Tissues are regulated differently Final Question: How do small molecules like acetyl-CoA, ATP, etc. affect the regulation of pyruvate kinase? Final Question: How do you want glucagon and insulin to react with the enzyme? Final Question: What regulation does the liver pyruvate kinase have to go through that the muscle doesn't need to? Why is the liver more highly regulated? There's a deeply cool reason for this and all 4 questions will appear on your final. Regulation of the Krebs Cycle, Glycogen Breakdown and Beta Oxidation Let's discuss briefly now how the Krebs Cycle is regulated. I hope you remember that figure 16-13 was on your midterm, but it didn't show NADH or FADH2. You were asked how was the figure different from the complete Krebs Cycle and what is the importance of the missing elements. The answer was that the electron carriers are the limiting factors so they help regulate the Krebs Cycle. But there are other regulators which Figure 16-18 shows and you need to study. Krebs Cycle Regulation We have been talking these past few classes about glycogen and its relation to several hormones. You should be able to go through and talk about the importance of insulin, glucagon, and epinephrine. I want you to memorize the pathways for all 3 of the molecules. Final Question: How do insulin and glucagon/epinephrine signal to the synthesis and breakdown of glycogen? You need to know them all because you will see signal cascades like this for the rest of your life. It's just part of what you need to be able to do for any career in biology. DO NOT 3 COPY Sharing or copying these notes is illegal and could end note taking for this course. MCB 102 ASUC Lecture Notes Online: Approved by the UC Board of Regents 08/05/10 You must also read about the regulation of betaoxidation which depends on a molecule known as malonyl-CoA. Malonyl-CoA is the primer for the creation of triacylglycerols. The mechanism goes through the process seen in figure 21-2, which I don't have time to go through, and will eventually form palmonyl-CoA. Why am I going over this? Because I'm giving you some more homework. Read up on all the information surrounding figure 17-12. I'm expecting you to study how are the body's energy-storing needs manifest in fatty acid synthesis versus breakdown. along with everything else we've learned about insulin and glucagon. The Obesity Epidemic Don't worry about what we will talk about now for your final. It will be on there, but I want you to focus on everything else we've talked about. We all came from Africa and our hormone signaling adapted to that environment. The obesity issue comes from the fact that we have not evolved to deal with a lifestyle where we get have food around us at all times. As a result, we are starting to have to deal with the horrible disease known as Type II diabetes. I talked early in the class about leptin and grelin and these two molecules will appear on the final. When it comes to grelin, you should understand everything you see in figure 23-43. Why do grelin and insulin have the correlation that they have? We know what grelin does so make sure to read up on it if you haven't. On the other hand, we're not actually sure what leptin does. We know that a deficiency in it causes obesity, but we're not sure about the specifics. However, it is being research currently and you will have a question on your final that comes from the article that I put up about a leptin-deficient family. To make it easier for you, you don't need have to read anything except the abstract. What's interesting is that the family doesn't have a problem with leptin itself but rather with a mutation in the leptin receptor. Final Question: How can you explain the fact that a mutation in the leptin gene and the leptin receptor gene cause the same condition, obesity? It's because leptin's problems comes from the body being able to identify leptin. Regardless of whether it can't sense leptin because of the protein itself or because of the receptor, your body is unable to detect the hormone and you will have the same issues. So great, we have discovered the way to treat obesity. Let's just give them more leptin. The TAG synthesis Final Question: How does the body use fatty acids? How does the body use fat storage? Final Question: What would you expect the body to do with respect to regulating when fats are broken down and when fats are synthesized? The answer to this is that when the diet provides a ready source of carbohydrates as fuel, beta oxidation of fatty acids is unnecessary and the process down regulated. The problem is that your book contradicts this in other places because it says that fatty acids are the primary source of energy. Learn about it and figure out why your book seems to contradict itself. For the final, you need to know about the regulation of glycolysis, the Krebs Cycle, and beta oxidation DO NOT 4 COPY Sharing or copying these notes is illegal and could end note taking for this course. MCB 102 ASUC Lecture Notes Online: Approved by the UC Board of Regents 08/05/10 problem is that very few cases of obesity come from leptin issues and that obesity is most likely not a genetic problem. Unfortunately, we can't even treat obesity by giving more leptin because those suffering from obesity are resistant or tolerant to leptin. Something else is going on, but we don't know what it is. I want to leave you with a brief discussion of table 23-7. Let's look at adiponectin, which is the most abundant mRNA in adipose tissue. What does it do? Despite having 3000 publications about it, we still don't know its role. However, we think it might have something to do with how we evolved. You have a 20,000-year-old body that has evolved to live in a calorie-poor environment and it seems that adiponectin has been selected evolutionarily to promote leanness, large amounts of exercise, and food deprivation on occasion. Obesity, in the end, is an artifact of the fact that we used to live on the plains and don't anymore. End of lecture. Notes prepared by Adnan Haque. Edited by Luis J. Diaz. DO NOT 5 COPY Sharing or copying these notes is illegal and could end note taking for this course. ...
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This note was uploaded on 10/31/2010 for the course MCB 70456 taught by Professor Urnov during the Summer '10 term at University of California, Berkeley.
- Summer '10