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Cellular Respiration By Sarah Redd I think that your textbook makes this subject harder than it ought to, so I wrote this to help you focus on the main points. Use this reading to help you with cellular respiration. What is cellular respiration? Cellular respiration is a process that consists of multiple metabolic pathways. If you recall from the previous chapter, ATP is the main energy transferring molecule of the cell. ATP frequently undergoes the hydrolysis reaction ATP + H2O ADP + Pi . Since this reaction is catabolic (breaks something apart) and exergonic, it releases energy. The energy released can be used to power anabolic, endergonic processes such as protein synthesis. Recall that when we use an exergonic process such as the hydrolysis of ATP to power an endergonic process such as protein synthesis, this is called energy coupling. ATP + Energy from catabolism (exergonic, energy-releasing processes) H2O ADP + Pi Energy for cellular work (endergonic, energy-consuming processes) After ATP has been hydrolyzed, we have a bunch of ADP and phosphate floating around the cell. ADP does not contain nearly as much energy as ATP, so we need some way to change it back. However, the reaction ADP + Pi ATP, which would turn our ADP and phosphate molecules back into ATP, is anabolic and endergonic, meaning it requires energy. We know that energy coupling is one way to get energy to power an endergonic process, we just need to find an exergonic process to release the energy necessary to power our endergonic ADP + Pi ATP. It turns out that the exergonic process that we will use here is the breakdown of food molecules, such as carbohydrates and fatty acids. Breaking down these food molecules releases the energy necessary to rebuild ATP out of ADP and phosphate groups. Cellular respiration is the name we give to the major metabolic pathways that break down food, thereby releasing energy that is used to turn ADP + Pi into ATP. You may also know this process as “burning calories;” breaking down food to get energy to regenerate ATP. What are the different types of respiration? The major pathway that we are usually talking about when we refer to cellular respiration is more specifically known as aerobic respiration (“aerobic” meaning that it uses oxygen; think of aerobic exercise, which makes you breathe hard). Some organisms, especially bacteria, use another method called anaerobic respiration that is very similar to aerobic respiration except that it does not use oxygen. A third method of breaking down food molecules to get energy for making ATP is called fermentation. Fermentation uses the first pathway from cellular respiration (glycolysis), but does not fully break down food molecules and thus generates less ATP than either aerobic or anaerobic respiration. There are many types of fermentation; we will look at both alcohol and lactic acid fermentation in this reading. Details of Aerobic Respiration We will follow the pathways of aerobic respiration using a molecule of glucose, C6H12O6. Note that fatty acids and amino acids can be broken down using these same pathways, though some molecules can skip a few steps and enter the pathways farther down the line. The overall equation for aerobic respiration is C 6 H 1 2 O 6 + 6O 2 6CO 2 + 6H 2 O The reactants are glucose (which comes from our food) and oxygen (which we get by breathing). Ultimately, these will be rearranged into CO2 (which we breathe out) and H2O (which can be used in other reactions or eliminated through urine or sweat). We will be revisiting this reaction many times, so it is worth it to learn it by heart. Redox reactions The reaction for cellular respiration is known as a redox reaction, which is short for oxidation and reduction. When an atom or molecule loses electrons, it becomes oxidized. When it gains electrons, it gets reduced, since the negatively charged electrons reduce the charge on that molecule. The molecule that becomes oxidized is also called the reducing agent, since by losing electrons it forces another molecule to gain those electrons (become reduced). Similarly, the molecule that becomes reduced is called the oxidizing agent, since by gaining electrons it forces another molecule to lose them and become oxidized. If you think about an insurance agent, you think of a person who provides insurance to others. Similarly, an oxidizing or reducing agent is a molecule that causes something else to become oxidized or reduced. becomes oxidized (loses electron) becomes reduced (gains electron) Some reactions are slightly more complicated, since electrons are not actually transferred from one molecule to another. Instead, these molecules change the sharing of electrons. When an electron attaches to a more electronegative atom, it is held more tightly by that atom, and it is almost like that atom gained electrons. Similarly, when an electron moves to a less electronegative atom, it is held less tightly by that atom, and it is as if the atom lost electrons. Reactants Products becomes oxidized becomes reduced Methane (reducing agent) Oxygen (oxidizing agent) Carbon dioxide Water In the figure above, we have first drawn arrows from reactants to products. Since the first reactant, Methane, begins with Carbon, we draw an arrow between methane and carbon dioxide. Then we draw an arrow between the other reactant and product. Next, we determine how electrons are shared. Since C and H share electrons equally, we draw blue dots equidistant between them. In CO2, the oxygen is more electronegative than the carbon, so the blue dots are drawn closer to the oxygen atoms. Since the electrons are moving farther away from carbon as it turns from CH4 into CO2, it is as if the methane lost electrons and is oxidized. At this point, you can either work out the second arrow yourself or assume that since CH4 is oxidized, the other reactant must be reduced. The major pathways of aerobic respiration include Glycolysis, Formation of Acetyl CoA, the Citric Acid Cycle (also called the Kreb’s or TCA cycle), and Oxidative Phosphorylation. Throughout these pathways, electrons will ultimately be transferred away from glucose (the fuel) in many small steps, causing glucose to become oxidized and oxygen to become reduced. As we talk about each of these pathways, we will focus on the reactants that begin going through the pathway and the products that are formed at the end, not on each of the intermediate steps. We will be especially concerned with any ATP and electron carriers that are generated by the pathway. Electron carriers Electron carriers, as the name implies, are molecules that carry electrons. The two major electron carriers used in cellular respiration are NAD+ and FAD. They are made from parts of the B vitamins that you get from your food. These carriers strip electrons off of other molecules and carry them to other parts of the cell, specifically to the electron transport chain that is part of the last pathway, oxidative phosphorylation. If you like, you can think of the electron carriers as little carts that pick up electrons at one location and drop them off at another. When NAD+ picks up 2 electrons, it also picks up a hydrogen ion and turns into NADH in the reaction NAD+ + 2e- + H+ NADH. Thus, NAD+ is not currently carrying electrons (empty cart), while NADH is carrying 2 of them (full cart). Similarly, when FAD picks up 2 electrons, it also picks up 2 hydrogen ions and turns into FADH2 in the reaction FAD + 2e- + 2 H+ FADH2. FAD is not carrying electrons (empty cart), whereas FADH2 is carrying 2 of them (full cart). Glycolysis (“splitting of sugar;” glyc = glucose, lys = break) Glycolysis, which takes place in the cytoplasm, involves splitting a 6-carbon glucose molecule into two 3carbon pyruvate molecules. It is a 10-step metabolic pathway, with a different enzyme catalyzing each individual step. We will not go into each step here, but we will talk about some of the main points. Towards the beginning of glycolysis, some energy has to be added. This is called the investment phase, and 2ATP must be hydrolyzed to add the necessary energy. Figure by JohnyAbb (Own work) [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons At the end of glycolysis, energy is released and used to turn 4ADP + 4Pi into 4ATP. Since 2 ATP are used up and 4 are generated, glycolysis makes 2 net ATP. During glycolysis, 2NAD+ also strip electrons and H+ off of the glucose as it turns into pyruvate, turning into 2NADH. Therefore, while glycolysis begins with glucose and 2NAD+, it ultimately generates 2 pyruvate, 2 net ATP, and 2NADH. Formation of Acetyl CoA Pyruvate still contains a lot of chemical energy, so we are going to break it down further. In this next step, the 2 3-carbon pyruvate molecules that were formed at the end of glycolysis move into the mitochondrial matrix. One carbon is removed from each pyruvate, forming CO2. Electrons are pulled off of each pyruvate, turning 2 NAD+ into 2 NADH. Coenzyme A attaches to the remaining 2 carbons of each pyruvate, forming Acetyl-CoA. Note: A coenzyme is a molecule that helps an enzyme to work more effectively, usually by causing the active site to fit better with the substrate. In summary, we began this step with 2 molecules of pyruvate, 2 coenzyme A, and 2 NAD+. Ultimately, we made 2 Acetyl-CoA, 2 CO2, and 2NADH MITOCHONDRION CYTOSOL NAD + NADH 2 1 3 Pyruvate Transport protein CO2 Coenzyme A Acetyl CoA The Citric Acid Cycle (also called the Kreb’s or TCA cycle) Next, each acetyl-CoA, in turn, gets to join an existing 4-carbon molecule called oxaloacetate. Coenzyme A helps them to combine, then breaks off. Since Acetyl-CoA had 2 carbons, and oxaloacetate has 4, once they join up they form a 6-carbon molecule called citric acid or citrate. This is why we call it the Citric Acid cycle – the first molecule that forms after Acetyl-CoA is added is citric acid (it was first identified by Sir Hans Adolf Krebs, which is where the other name comes from). The citric acid cycle, like glycolysis, is a metabolic pathway with many steps (8 to be exact), each catalyzed by its own specific enzyme. Over the course of those 8 steps, citric acid is broken down and turns back into oxaloacetate, the molecule we began with. Since citric acid has 6 carbons and oxaloacetate has 4, what happens to the extra 2 carbons as we go around the cycle? Well, just like in the previous step where we broke off some carbons and made Acetyl CoA, these carbons break off and become CO2, which moves into the blood, which carries them to the lungs where they are exhaled. In addition, each Acetyl CoA that moves through the citric acid cycle gives electrons to 3 NAD+ and 1FAD, forming 3 NADH and 1 FADH2. We also release energy to turn 1 ADP and Pi into ATP. Once citric acid has gone through all the steps and turned back into oxaloacetate, another Acetyl-CoA can attach and the whole cycle begins again. Since we had 2 Acetyl CoA from our original glucose, the cycle will go around twice for each molecule of glucose that starts off cellular respiration. Overall, in the citric acid cycle we began with 2 Acetyl-CoA, 6 NAD+ (3 for each Acetyl-CoA), and 2FAD. By the end, we made 4 CO2, 6NADH, 2FADH2, and 2ATP. Acetyl CoA CoA—SH NADH +H 1 + H2O + NAD 8 Oxaloacetate 2 Malate Citrate Isocitrate + Citric acid cycle 7 H2O NAD NADH 3 +H + CO2 Fumarate CoA—SH 6 -Ketoglutarate 4 CoA—SH 5 FADH2 NAD FAD Succinate GTP GDP Pi CO2 + NADH Succinyl CoA +H + ADP ATP Oxidative Phosphorylation The glucose we began with is now completely broken down. Remember our overall equation for cellular respiration? It was C6H12O6 + 6O2 6CO2 + 6H2O. Glucose had 6 carbons, and in the past two stages we made them into 6 CO2 in the mitochondrial matrix. However, a lot of the chemical energy that glucose originally contained is still contained in the electrons that NADH and FADH2 are carrying. In this last stage, we will harvest that energy to make ATP. Embedded in the cristae (the folded inner membrane of the mitochondria) are many electron transport chains. These are chains of membrane proteins that move electrons from one protein to the next. All of the NADH that we formed in the previous steps now migrate to the cristae and drop off the electrons and H+ they Cristae are carrying at the first protein in the electron transport chain (FADH2 drops its electrons off at the 2nd protein in the chain). The first protein passes the electrons on to the 2nd protein, then Matrix the 3rd, and so on. Each successive protein in the chain is a little more electronegative (attractive to electrons) than the previous protein, so when the electrons jump from protein to protein, they Intermembrane space move closer to the more electronegative protein and give up a bit of energy each time. The energy released during these small jumps is used + to actively pump H from the matrix into the intermembrane space. This causes the concentration of H+ in the intermembrane space to become very high. Outer membrane + H + H + H + H + FADH2 NADH NAD FAD 1 2 H + /2O2 ATP Synthase H2O + ADP + P (carrying electrons from food) ATP i + H Electron transport chain At the very end of the electron transport chain, we need to remove the electron from the last protein by attaching it to something that is even more electronegative. In aerobic respiration, this “something” is oxygen, which is a highly electronegative atom. H+ travels with the electrons and attaches to the oxygen as well, forming H2O. Near the electron transport chain and also embedded in the cristae is a protein called ATP synthase, which looks a little like a turbine. As its name implies, ATP synthase is an enzyme that synthesizes ATP. Just as water running through a turbine in a dam can generate energy that is converted to electricity, H+ flowing through the ATP synthase “turbine” can generate energy that is used to combine ADP and Pi to form ATP. Since H+ has built up at high levels in the intermembrane space, it flows through ATP synthase into the matrix from its area of high concentration to its area of low concentration. As H+ flows through ATP synthase, energy is generated and used to power the endergonic reaction ADP + Pi ATP. The ATP is formed in the mitochondrial matrix. Under laboratory conditions, the electrons dropped off by each NADH have enough energy to make about 3 ATP, and those dropped off by each FADH2 make about 2 ATP. If you add up all the electron carriers that we got from glycolysis, formation of Acetyl-CoA, and the Citric Acid Cycle, you should get 10 NADH and 2 FADH2. 10 NADH x 3 ATP each + 2 FADH2 x 2 ATP each yields 34 total ATP from oxidative phosphorylation. Add this to the 2 ATP we produced in glycolysis and the 2 we made in the citric acid cycle, and we have a total of 38 ATP formed from one molecule of glucose. However, most textbooks will give you a range in the amount of ATP produced. Many say 36-38 ATP per glucose, so why the lower number? Well, in order for NADH to produce ATP, it has to get into the mitochondria and drop off its electrons. The NADH that we made in the mitochondria has no problem; it’s already there, but the 2NADH we made in the cytoplasm during glycolysis need to be transported in. Some cells have a transport protein that can bring them in without sacrificing any energy, but some cells use a different transport protein that, through slightly complicated means, ends up costing us two of our ATP. Ultimately, the amount of ATP produced depends on the type of organism, type of cell, and environmental conditions. Besides, once we make the ATP, we have to get it out of the matrix and to the locations where it’s needed, and that transport requires a bit of energy too. Different texts will give you slightly different numbers for the amount of ATP produced per glucose, but it’s generally somewhere in the 30s. But, you say, prokaryotes need ATP too! How can they manage without mitochondria? That’s a good point. If you remember that mitochondria likely evolved from ancient prokaryotes, it’s not too much of a stretch to think of the inside of a prokaryotic cell as being similar to the matrix, and its cell membrane as similar to the cristae. Thus, the electron transport chains in prokaryotes are located in their cell membranes. They pump H+ outside of the cell, and it flows back into the cell through ATP synthase. Energy flow Throughout this whole process, energy has mostly from glucose to electron carriers, then to the electron transport chain, building up a gradient of H+, which eventually formed ATP. It is important to release energy in many small steps to ensure that the cell has the means with which to harvest this energy for useful work. As an analogy, think about a car. The gasoline in the tank represents a huge store of potential energy. However, we would not want to set the entire gas tank on fire to release all this potential energy at once; such an action would not propel the car forward, but would destroy it. The car has no way to harvest such a large amount of energy at once. Instead, in a car, we light very small amounts of gasoline on fire at a time, releasing the energy in many small steps that the engine can harvest to turn the wheels and move the car forward. In the same way, cells need to release energy from food molecules in many small steps, so that they can harvest the energy in order to do the work of forming ATP. If they released all the energy from glucose at once, most of it would be lost as heat and become unusable. How is Anaerobic respiration different? Anaerobic respiration is mainly used by certain species of bacteria that live in oxygen-free environments. It utilizes the same stages as aerobic respiration; the major difference is that instead of oxygen picking up the electrons at the end of the transport chain, it’s some other molecule (often sulfate or nitrate) that acts as that final electron acceptor. These other molecules are not quite as electronegative as oxygen, which means that not quite as much energy gets released from the electrons and not quite as much ATP is formed. How is Fermentation different? Fermentation doesn’t require oxygen, and it only uses the first stage of cellular respiration, glycolysis, to generate ATP. Recall that reaction for glycolysis is: Glucose + 2NAD+ + 2ADP + 2Pi 2pyruvate + 2NADH + 2ATP Since organisms that do fermentation get all their ATP from glycolysis, they only make 2 ATP for each glucose. However, if they continued to do glycolysis over and over to get more ATP, eventually they would run out of NAD+. Without NAD+, we are missing one of the key reactants and glycolysis cannot continue. Therefore, we need to do a second reaction to turn the 2NADH back into 2NAD+. The second reaction looks like this: 2pyruvate + 2NADH Something + 2NAD+ The something that pyruvate turns into depends on what kind of fermentation we’re doing. In some organisms, the Something is lactic acid, and we call this process lactic acid fermentation. This is what humans do when we’re exercising so intensely that our muscle cells aren’t getting enough oxygen, and the lactic acid can cause temporary soreness during the exercise. Many bacteria that are useful for making milk products such as yogurt and cheese also do lactic acid fermentation. 2 ADP + 2 Pi Glucose 2 ATP Glycolysis + 2 NAD 2 NADH 2 Pyruvate In other organisms, the Something that pyruvate turns into is ethanol (alcohol) and CO2. Many yeasts do alcohol fermentation, and humans take advantage of their byproducts to make beer, wine, and bread (the alcohol burns off when you make bread, and the air bubbles inside the bread come from the CO2). It’s important to remember that organisms don’t make lactic acid or ethanol and CO2 because they need those byproducts – they’re 2 Lactate making them as part of a Lactic Acid Fermentation process that gives them NAD+, because without + NAD they can’t do glycolysis to make ATP, and without ATP they can’t do the cellular work that keeps them alive. The lactic acid, ethanol, and CO2 are waste products, just like urine and CO2 are human waste products that we ultimately excrete. Other molecules besides glucose We followed glucose through these pathways because it’s one of the easiest organic molecules for our bodies to break down, and it starts at the very beginning of the first pathway and goes through all the steps. Recall that other molecules, such as amino acids and fatty acids, can enter at different steps of these pathways. For example, fatty acids can skip glycolysis and be converted directly into Acetyl-CoA. Can you have too much ATP? ATP is an excellent molecule for transferring energy, but it’s not great for long term energy storage. In fact, we can store about 90 times the amount of energy of ATP in glucose, in a smaller space. Fats store even more energy for their size. So how do we ensure that we only make as much ATP as we currently need? If you remember the process of feedback inhibition from your previous study, you will recall that sometimes the end product of a metabolic pathway can inhibit an enzyme that is necessary to catalyze one of the first steps of that pathway. While the enzyme is inhibited, the pathway cannot make anymore end product. This is what happens in cellular respiration – ATP inhibits one of the enzymes that is important at the beginning of glycolysis (phosphofructokinase). As long as we have plenty of ATP, the enzyme cannot begin breaking down glucose to make more. When ATP is low, the enzyme will be uninhibited and we will continue to make more ATP. What sources of energy do our bodies use preferentially? If you are beginning a physical activity, your muscles will only be able to use the ATP they currently have stored to power that activity for a few seconds. After that, they will begin breaking down glucose to make more. If the exercise is especially intense and you aren’t getting enough oxygen to your muscles, they can function using fermentation for 1-2 minutes. Since fermentation only makes 2 ATP per glucose and causes lactic acid buildup, you can’t sustain it for long. Any long term exercise in humans requires the use of aerobic respiration. After we use up all our blood glucose, we will begin to break down glycogen. Recall that glycogen is the human storage form of sugar, a polysaccharide made of chains of glucose that is stored inside liver and muscle cells. As we break glycogen down, we obtain more glucose. Generally it takes 15-20 minutes of exercise to use up all of your glycogen. Only then will your body preferentially break down fats and fatty acids through cellular respiration.