MSc_Cellular Respiration_students 3.pptx

They speak of molecular cell respiration and physiology

1. CELLULAR RESPIRATION Associate Professor, Dr. Alfonse Opio

2. Introduction The reactions that extract energy from molecules like glucose are called  catabolic reactions . They involve breaking a larger molecule into smaller pieces. When glucose is broken down in the presence of oxygen, it’s converted into six carbon dioxide molecules and six water molecules. C 6 H 12 O 6 + 6O 2 6CO 2 + 6H 2 O + Energy Energy contained in the bonds of glucose is released in small bursts, and some of it is captured in the form of  adenosine triphosphate (ATP) . Much of the energy from glucose is dissipated as heat , but enough is captured to keep the metabolism of the cell running.

3. During respiration, a phosphate group is transferred from a pathway intermediate straight to ADP , a process known as  substrate-level phosphorylation . Electrons from glucose are also transferred to small molecules known as electron carriers . The electron carriers take the electrons to a group of proteins in the inner membrane of the mitochondrion, called the electron transport chain . As electrons move through the electron transport chain, they go from a higher to a lower energy level and are ultimately passed to oxygen (forming water).

4. As an electron passes through the electron transport chain, the energy it releases is used to pump protons out of the matrix of the mitochondrion, forming an electrochemical gradient . When the flow back down their gradient, they pass through an enzyme called ATP synthase , driving synthesis of ATP. This process is known as  oxidative phosphorylation . 

5. There are two types of electron carriers that are particularly important in cellular respiration:  NAD+ ( nicotinamide adenine dinucleotide) , and  FAD ( flavin adenine dinucleotide) .

6. Steps of cellular respiration Cellular respiration is a metabolic pathway that breaks down glucose and produces ATP . There are 4 major stages of cellular respiration: Glycolysis Pyruvate oxidation The citric acid or Krebs cycle Oxidative phosphorylation. The processes involve the; Gradual breakdown of a glucose molecule into carbon dioxide and water. Some ATP is produced directly in the reactions that transform glucose . Much more ATP , is produced later in a process called oxidative phosphorylation .

7. Oxidative phosphorylation is powered by; the movement of electrons through the electron transport chain , a series of proteins embedded in the inner membrane of the mitochondrion. The electrons come originally from glucose and are transported to the electron transport chain by electron carriers  NAD+ and  FAD , which become NADH and  FADH 2 when they gain electrons. NAD + + 2e - NADH + H + FAD + 2e - FADH 2 The molecules are just being converted to electron-carrying form .

8. Glycolysis phase Glucose (a six-carbon sugar) undergoes a series of chemical transformations. In the end, it gets converted into two molecules of pyruvate (a three-carbon organic) molecule. In these reactions, ATP is made , and  NAD+ is converted to  NADH . Pyruvate oxidation Each pyruvate from glycolysis goes into the mitochondrial matrix (innermost compartment of mitochondria). Gets converted into a two-carbon molecule bound to Coenzyme A ( acetyl CoA ). Carbon dioxide is released and  NADH is generated.

9. Citric acid cycle The acetyl CoA made in the last step combines with a four-carbon molecule and goes through a cycle of reactions, ultimately; Regenerating the four-carbon starting molecule - ATP, NADH , FADH  are produced, and carbon dioxide is released. Oxidative phosphorylation The  NADH and  FADH made in other steps deposit their electrons in the electron transport chain , turning back into their "empty" forms NAD+ and FAD. As electrons move down the chain , energy is released and used to pump protons out of the matrix , forming a gradient. Protons flow back into the matrix through an enzyme called ATP synthase , making ATP . At the end of the electron transport chain, oxygen accepts electrons and takes up protons to form water .

10. Glycolysis can take place without oxygen in a process called fermentation . The other three stages of cellular respiration; Pyruvate oxidation, the citric acid cycle , and oxidative phosphorylation require oxygen in order to occur. Note: Only oxidative phosphorylation uses oxygen directly , but the other two stages ( Pyruvate oxidation, the citric acid cycle ) can't run without oxidative phosphorylation.

11. Oxidative phosphorylation is made up of two closely connected components : In the electron transport chain , electrons are passed from one molecule to another, and energy released in these electron transfers is used to form an electrochemical gradient. In chemiosmosis , the energy stored in the gradient is used to make ATP . Oxygen sits at the end of the electron transport chain, where it accepts electrons and picks up protons to form water. If oxygen isn’t there to accept electrons (for instance, because a person is not breathing in enough oxygen), the electron transport chain will stop running, and ATP will no longer be produced by chemiosmosis. Without enough ATP, cells can’t carry out the reactions they need to function, and, after a long enough period of time, may even die.

12. The  electron transport chain  is a series of proteins and organic molecules found in the inner membrane of the mitochondria. Electrons are passed from one member of the transport chain to another in a series of redox reactions. Energy released in these reactions is captured as a proton gradient , which is then used to make ATP in a process called  chemiosmosis . Together, the electron transport chain and chemiosmosis make up oxidative phosphorylation. Delivery of electrons by NADH and FADH .  Reduced electron carriers (NADH and FADH) from other steps of cellular respiration transfer their electrons to molecules near the beginning of the transport chain. In the process, they turn back into NAD+ and FAD, which can be reused in other steps of cellular respiration. Electron transfer and proton pumping . As electrons are passed down the chain, they move from a higher to a lower energy level , releasing energy. Some of the energy is used to pump H+ ion s, moving them out of the matrix and into the inter membrane space. This pumping establishes an electrochemical gradient .

13. Splitting of oxygen to form water . At the end of the electron transport chain, electrons are transferred to molecular oxygen, which splits in half and takes up H+ to form water. Gradient-driven synthesis of ATP.  As H+ ions flow down their gradient and back into the matrix, they pass through an enzyme called ATP synthase , which harnesses the flow of protons to synthesize ATP . Electron transport chain - A collection of membrane-embedded proteins and organic molecules , most of them organized into four large complexes labeled I to IV . In eukaryotes, many copies of these molecules are found in the inner mitochondrial membrane . In prokaryotes , the electron transport chain components are found in the plasma membrane .

14. Energy is released in the “ downhil l” electron transfers. Several of the protein complexes use the released energy to pump protons from the mitochondrial matrix to the inter membrane space, forming a proton gradient

15. Complex I.   NADH transfers its electrons to complex I . Complex I is quite large , and the part of it that receives the electrons is a flavoprotein , meaning a protein with an attached organic molecule called flavin mononucleotide (FMN) . FMN is a  prosthetic group , a non-protein molecule tightly bound to a protein and required for its activity, and it’s FMN that actually accepts electrons from NADH . FMN passes the electrons to another protein inside complex I, one that has iron and sulfur bound to it (called an Fe-S protein ), which in turns transfers the electrons to a small, mobile carrier called ubiquinone (Q in the diagram above).

16. Complex II. FADH deposits its electrons in the electron transport chain via complex II , bypassing complex I entirely. As a matter of fact, FADH is a part of complex II , as is the enzyme that reduces it during the citric acid cycle Unlike the other enzymes of the cycle, it’s embedded in the inner mitochondrial membrane . FADH transfers its electrons to iron-sulfur proteins within complex II, which then pass the electrons to ubiquinone (Q) - the same mobile carrier that collects electrons from complex I.

17. Beyond the first two complexes Electrons from NADH and FADH travel exactly the same route - Both complex I and complex II pass their electrons to a small, mobile electron carrier called  ubiquinone  ( Q ). Q is reduced to form QH 2 and travels through the membrane, delivering the electrons to complex III . As electrons move through complex III, more H+  ions are pumped across the membrane, and the electrons are ultimately delivered to another mobile carrier called  cytochrome C  ( cyt C ). Cyt C carries the electrons to complex IV , where a final batch of H+ ions is pumped across the membrane. Complex IV passes the electrons to O 2 , which splits into two oxygen atoms and accepts protons from the matrix to form water . Four electrons are required to reduce each molecule of O 2 and two water molecules are formed in the process.

18. Overall, what does the electron transport chain do for the cell? - functions: Regenerates electron carriers . NADH and FADH pass their electrons to the electron transport chain, turning back into NAD+ and FAD. This is important because the oxidized forms of these electron carriers are used in glycolysis and the citric acid cycle and must be available to keep these processes running. Makes a proton gradient . The transport chain builds a proton gradient across the inner mitochondrial membrane , with a higher concentration of H+ in the inter membrane space and a lower concentration in the matrix . This gradient represents a stored form of energy , and, which is used to make ATP .

19. Chemiosmosis H+ pumping forms an electrochemical gradient across the inner mitochondrial membrane. The gradient is sometimes called the  proton-motive force – It is a form of stored energy, kind of like a battery. Like many other ions, protons can't pass directly through the phospholipid bilayer of the membrane because its core is too hydrophobic. Instead, H+ ions can move down their concentration gradient only with the help of channel proteins that form hydrophilic tunnels across the membrane. Note : In the inner mitochondrial membrane, H+ ions have just one channel available : a membrane-spanning protein known as  ATP synthase . ATP synthase is turned by the flow of H+ ions moving down their electrochemical gradient. As ATP synthase turns , it catalyzes the addition of a phosphate to ADP , capturing energy from the proton gradient as ATP .

20. More broadly, chemiosmosis can refer to any process in which energy stored in a proton gradient is used to do work . Although chemiosmosis accounts for over 80% of ATP made during glucose breakdown in cellular respiration, it’s not unique to cellular respiration . What would happen to the energy stored in the proton gradient if it weren't used to synthesize ATP or do other cellular work? It would be released as heat, and interestingly enough. Some cells deliberately use the proton gradient for heat generation rather than ATP synthesis. This might seem wasteful, but it's an important strategy for animals that need to keep warm. Hibernating mammals (such as bears) have specialized cells known as brown fat cells. In the brown fat cells,  uncoupling proteins  are produced and inserted into the inner mitochondrial membrane. These proteins are simply channels that allow protons to pass from the inter membrane space to the matrix without traveling through ATP synthase. By providing an alternate route for protons to flow back into the matrix, the uncoupling proteins allow the energy of the gradient to be dissipated as heat.

21. ATP yield Most current sources estimate that the maximum ATP yield for a molecule of glucose is around 30-32 ATP . This range is lower than previous estimates because it accounts for the necessary transport of ADP into, and ATP out of, the mitochondrion . The 38 ATP Assumes that every single proton pumped in the electron transport chain as a result of electrons harvested from glucose goes towards synthesizing ATP . In other words, none of the energy of the proton gradient is used to power other transport processes. Assumes that an efficient shuttle mechanism is used to carry electrons from NADH made in glycolysis to the electron transport chain . With an inefficient shuttle , the maximum number in this scenario would be 36 ATP .

22. The 30-32 ATP In a real cell, not all of the energy of the proton gradient can go towards making ATP . Instead, some of it must be used to transport molecules into and out of the mitochondrial matrix. For instance, ADP must be transported into the matrix so it can be made into ATP, and ATP must be transported out so it can be used by the cell. Accounts for transport of ATP and ADP , which uses up energy from the proton gradient - meaning that there is less energy left to drive ATP synthesis, yielding fewer ATP. In real cells, the yield of ATP per glucose molecule would likely be even lower than 30-32 ATP. Cells often use the proton gradient to transport other molecules, in addition to ATP and ADP. Some of the proton gradient's energy may also be lost, if the inner mitochondrial membrane is "leaky" to protons.

23. Where does the figure of 30-32 ATP come from? Two net ATP are made in glycolysis , and another two ATP (or energetically equivalent GTP) are made in the citric acid cycle . Beyond those four, the remaining ATP all come from oxidative phosphorylation . Based on a lot of experimental work, it appears that four H+ ions must flow back into the matrix through ATP synthase to power the synthesis of one ATP molecule . When electrons from NADH move through the transport chain, about 10 H+ ions are pumped from the matrix to the inter membrane space, so each NADH yields about 2.5 ATP . Electrons from FADH which enter the chain at a later stage, drive pumping of only 6 H+ ions leading to production of about 1.5 ATP .

24. Stage Direct products (net) Ultimate ATP yield (net) Glycolysis 2 ATP 2 ATP 2 NADH 3-5 ATP Pyruvate oxidation 2 NADH 5 ATP Citric acid cycle 2 ATP/GTP 2 ATP 6 NADH 15 ATP 2 FADH _2 2​ start subscript, 2, end subscript 3 ATP Total 30-32 ATP

25. One number in this table is still not precise: the ATP yield from NADH made in glycolysis. This is because glycolysis happens in the cytosol, and NADH can't cross the inner mitochondrial membrane to deliver its electrons to complex I. Instead, it must hand its electrons off to a molecular “shuttle system” that delivers them, through a series of steps, to the electron transport chain. Some cells in the body have a shuttle system that delivers electrons to the transport chain via FADH. In this case, only 3 ATP are produced for the two NADH of glycolysis. Other cells of the body have a shuttle system that delivers the electrons via NADH, resulting in the production of 5 ATP. In bacteria, both glycolysis and the citric acid cycle happen in the cytosol, so no shuttle is needed and 5 ATP are produced.

26. 30-32 ATP from the breakdown of one glucose molecule is a high-end estimate, and the real yield may be lower. Some intermediates from cellular respiration may be siphoned off by the cell and used in other biosynthetic pathways, reducing the number of ATP produced. Cellular respiration is a nexus for many different metabolic pathways in the cell, that’s larger than the glucose breakdown pathways alone. QUESTION Cyanide acts as a poison because it inhibits complex IV, making it unable to transport electrons. How would cyanide poisoning affect; the electron transport chain and the proton gradient across the inner mitochondrial membrane? Dinitrophenol (DNP) is a chemical that acts as an uncoupling agent, making the inner mitochondrial membrane leaky to protons. It was used until 1938 as a weight-loss drug. How would DNP affect the amount of ATP produced in cellular respiration? Why do you think it is now off the market?

27. Fermentation and anaerobic respiration These processes can happen through alternative glucose breakdown pathways that occur when normal, oxygen-using (aerobic) cellular respiration is not possible . when oxygen isn't around to act as an acceptor at the end of the electron transfer chain. Fermentation pathways consist of glycolysis  with some extra reactions tacked on at the end. In yeast , the extra reactions make alcohol , while in human muscles, they make lactic acid . Some living systems instead use an inorganic molecule other than  O 2 , such as sulfate , as a final electron acceptor for an electron transport chain. For example in bacteria and archaea Some archaea called methanogens can use carbon dioxide as a terminal electron acceptor, producing methane as a by-product. Methanogens are found in soil and in the digestive systems of ruminants, a group of animals including cows and sheep.

28. Fermentation and anaerobic respiration These processes can happen through alternative glucose breakdown pathways that occur when normal, oxygen-using (aerobic) cellular respiration is not possible. when oxygen isn't around to act as an acceptor at the end of the electron transfer chain. Fermentation pathways consist of glycolysis with some extra reactions tacked on at the end. In yeast, the extra reactions make alcohol, while in your muscles, they make lactic acid. Some living systems instead use an inorganic molecule other than  O 2 , such as sulfate , as a final electron acceptor for an electron transport chain. For example in bacteria and archaea Some archaea called methanogens can use carbon dioxide as a terminal electron acceptor , producing methane as a by-product . Methanogens are found in soil and in the digestive systems of ruminants , a group of animals including cows and sheep. Sulfate-reducing bacteria and Archaea use sulfate as a terminal electron acceptor , producing hydrogen sulfide   as a byproduct.

29. Fermentation The only energy extraction pathway is glycolysis , with one or two extra reactions tacked on at the end. The pyruvate made in glycolysis does not continue through oxidation and the citric acid cycle , and the electron transport chain does not run . Because the electron transport chain isn't functional, the NADH made in glycolysis cannot drop its electrons off there to turn back into NAD+ The purpose of the extra reactions in fermentation is to regenerate the electron carrier  (NAD+) from the  NADH produced in glycolysis. The extra reactions accomplish this by letting  NADH drop its electrons off with an organic molecule (such as pyruvate, the end product of glycolysis). This drop-off allows glycolysis to keep running by ensuring a steady supply of NAD+ .

30. Lactic Acid Fermentation NADH transfers its electrons directly to pyruvate , generating lactate as a byproduct. Lactate, (the deprotonated form of lactic acid), gives the process its name. The bacteria that make yogurt carry out lactic acid fermentation , as do the red blood cells in your body , which don’t have mitochondria and thus can’t perform cellular respiration.

31. Lactic Acid Fermentation NADH transfers its electrons directly to pyruvate , generating lactate as a byproduct. Lactate (the deprotonated form of lactic acid), gives the process its name. The bacteria that make yogurt carry out lactic acid fermentation Red blood cells in your body, which don’t have mitochondria and thus can’t perform cellular respiration. Lactic acid produced in muscle cells is transported through the blood stream to the liver - it’s converted back to pyruvate and processed normally in the remaining reactions of cellular respiration .

32. Alcohol Fermentation The process NADH donates its electrons to a derivative of pyruvate , producing ethanol . Going from pyruvate to ethanol is a two-step process . In the first step, a carboxyl group is removed from pyruvate and released in as carbon dioxide , producing a two-carbon molecule called acetaldehyde . In the second step,  NADH passes its electrons to acetaldehyde , regenerating  NAD+ and forming ethanol . Alcohol fermentation by yeast produces the ethanol found in alcoholic drinks like beer and wine. Alcohol is toxic to yeasts in large quantities (just as it is to humans), which puts an upper limit on the percentage alcohol in these drinks . Ethanol tolerance of yeast ranges from about 5 – 21 %, depending on the yeast strain and environmental conditions .

33. Facultative and obligate anaerobes Many bacteria and archaea are  facultative anaerobes : They can switch between aerobic respiration and anaerobic pathways (fermentation or anaerobic respiration) depending on the availability of oxygen.  Allows for more ATP from glucose molecules when oxygen is available - since aerobic cellular respiration makes more ATP than anaerobic pathways Important for keeping metabolizing and stay alive when oxygen is scarce . Other bacteria and archaea are  obligate anaerobes : They can live and grow only in the absence of oxygen - Oxygen is toxic to microorganisms and injures or kills them on exposure . The  Clostridium bacteria responsible for botulism (a form of food poisoning) are obligate anaerobes. Some multicellular animals have even been discovered in deep-sea sediments that are free of oxygen

34. Connections between cellular respiration and other pathways Not every molecule that enters cellular respiration - complete the entire pathway . Just as various types of molecules can feed into cellular respiration through different intermediates, Intermediates of glycolysis and the citric acid cycle may be removed at various stages and used to make other molecules . For instance, many intermediates of glycolysis and the citric acid cycle are used in the pathways that build amino acids. In a similar way, amino acids, lipids , and other carbohydrates can be converted to various intermediates of glycolysis and the citric acid cycle , Allowing them to slip into the cellular respiration pathway through a multitude of side doors. Once the molecules enter the pathway, it makes no difference where they came from: they simply go through the remaining steps, yielding NADH, FADH and ATP.

35. How carbohydrates enter the pathway Most carbohydrates enter cellular respiration during glycolysis . In some cases, entering the pathway simply involves breaking a glucose polymer down into individual glucose molecules.  Glucose polymer glycogen is made and stored in both liver and muscle cells. The glycogen will be broken down into phosphate-bearing glucose molecules, which can easily enter glycolysis when blood sugar level drops.

36. Non-glucose mono saccharides can also enter glycolysis. Sucrose (table sugar) is made up of glucose and fructose . When sugar is broken down, the fructose can easily enter glycolysis : Addition of a phosphate group turns it into fructose-6-phosphate , the third molecule in the glycolysis pathway. Because it enters so close to the top of the pathway, fructose yields the same number of ATP as glucose during cellular respiration.

37. How proteins enter the pathway The body breaks down protein into amino acids before they can be used by the cells. Most of the time, amino acids are recycled and used to make new proteins , not oxidized for fuel. If there are more amino acids than the body needs, or if cells are starving, some amino acids will get broken down for energy via cellular respiration .  The amino acids must first have their amino group removed . This step makes ammonia  (NH3​)  as a waste product , and in humans and other mammals, Ammonia is converted to urea and removed from the body in urine. After deaminated , different amino acids enter the cellular respiration pathways at different stages. The chemical properties of each amino acid determine what intermediate it can be most easily converted into.

38. For example, the amino acid glutamate , which has a carboxylic acid side chain, gets converted into the citric acid cycle intermediate α- ketoglutarate . This point of entry for glutamate makes sense because both molecules have a similar structure with two carboxyl groups.

39. How lipids enter the pathway Fats , known more formally as triglycerides, can be broken down into two components that enter the cellular respiration pathways at different stages.  A triglyceride is made up of; A three-carbon molecule called glycerol , and of three fatty acid tails attached to the glycerol. Glycerol can be converted to glyceraldehyde-3-phosphate , an intermediate of glycolysis, and continue through the remainder of the cellular respiration breakdown pathway. Fatty acids, on the other hand, must be broken down in a process called  beta-oxidation Takes place in the matrix of the mitochondria . During the process, the fatty acid tails are broken down into a series of two-carbon units that combine with coenzyme A, forming acetyl CoA . This acetyl CoA feeds smoothly into the citric acid cycle .

40. Cellular respiration: It's a two-way street Molecules in the cellular respiration pathway can be pulled out at many stages and used to build other molecules , including amino acids, nucleotides, lipids, and carbohydrates. Acetyl CoA produced in cellular respiration can be diverted from the citric acid cycle and used to build the lipid cholesterol . Cholesterol forms the backbone of the steroid hormones in our bodies , such as testosterone and estrogens . Note : Whether it's better to "burn" molecules for fuel via cellular respiration or use them to build other molecules depends on the needs of the cell , and which specific molecules they're used to build.

41. Regulation of cellular respiration If the cell’s supply of ATP is low , it would do well to break down glucose as quickly as possible , replenishing the ATP it needs to “keep the lights on.” If the supply of ATP is high , on the other hand, it might not be such a good idea to oxidize glucose at top speed . ATP is an unstable molecule , and if it sits around in the cell too long, it’s likely to spontaneously hydrolyze back to ADP . Note : the cell has spent glucose to make ATP, and that ATP ends up going to waste. How do cells turn cellular respiration pathways “up” or “down” in response to ATP levels and other metabolic signals?

42. How do cells turn cellular respiration pathways “up” or “down” in response to ATP levels and other metabolic signals? Allosteric enzymes and pathway control If a cell wants to control the activity of a metabolic pathway , it needs to regulate the activity of one or more of the enzymes in that pathway. A number cellular respiration enzymes are controlled by the binding of regulatory molecules at one or more allosteric sites . An  allosteric site  is just a regulatory site other than the active site. Binding of a regulator to the allosteric site of an enzyme changes its structure , making it more or less active.

43. The molecules ( ATP, ADP, and NADH ) that bind cellular respiration enzymes act as signals , giving the enzyme information about the cell's energy state . ATP is a "stop" signal - high levels mean that the cell has enough ATP and does not need to make more through cellular respiration. This is a case of  feedback inhibition , in which a product "feeds back" to shut down its pathway .

44. Regulation of glycolysis Several steps in glycolysis are regulated , but the most important control point is the third step of the pathway, which is catalyzed by an enzyme called phosphofructokinase  (PFK). This reaction is the first committed step, making PFK a central target for regulation of the glycolysis pathway as a whole. PFK is regulated by ATP , an ADP derivative called Adenosine monophosphate ( AMP) , and citrate , as well as some other molecules. ATP is a negative regulator of PFK, which makes sense: if there is already plenty of ATP in the cell, glycolysis does not need to make more. Adenosine monophosphate (AMP) is a positive regulator of PFK. When a cell is very low on ATP, it will start squeezing more ATP out of ADP molecules by converting them to ATP and AMP (ADP + ADP → ATP). High levels of AMP mean that the cell is starved for energy, and that glycolysis must run quickly to replenish ATP Citrate , the first product of the citric acid cycle, can also inhibit PFK. If citrate builds up, this is a sign that glycolysis can slow down , because the citric acid cycle is backed up and doesn’t need more fuel.

45. Pyruvate oxidation The next key control point comes after glycolysis, when pyruvate is converted to acetyl CoA. This conversion step is irreversible in many organisms and controls how much acetyl CoA “fuel” enters the citric acid cycle . The enzyme that catalyzes the conversion reaction is called pyruvate dehydrogenase . ATP and NADH make this enzyme less active , while ADP makes it more active . So, more acetyl CoA is made when energy stores are low . Pyruvate dehydrogenase is also activated by its substrate, pyruvate , and inhibited by its product , acetyl CoA . This ensures that acetyl CoA is made only when it’s needed (and when there's plenty of pyruvate available)

46. Citric acid cycle Entry into the citric acid cycle is largely controlled through pyruvate dehydrogenase , the enzyme that produces acetyl CoA. However, there are two additional steps in the cycle that are subject to regulation. These are the two steps in which carbon dioxide molecules are released , and also the steps at which the first two NADH molecules of the cycle are produced . Isocitrate dehydrogenase  controls the first of these two steps, turning a six-carbon molecule into a five-carbon molecule. This enzyme is inhibited by ATP and NADH, but activated by ADP. α- Ketoglutarate dehydrogenase  controls the second of these two steps, turning the five-carbon compound from the previous step into a four-carbon compound bound to CoA ( succinyl CoA). This enzyme is inhibited by ATP, NADH, and several other molecules, including succinyl CoA itself.

47. Putting it all together There are lots of other regulatory mechanisms for cellular respiration. For instance, the speed of the electron transport chain is regulated by levels of ADP and ATP, and many other enzymes are subject to regulation. However, these examples give a feel for the kind of logic and strategies cells use to regulate metabolic processes. At each stage, there are similar elements. For instance, feedback inhibition at many stages, at the level of pathways and of individual reactions. Monitoring of the cell's energy state through levels of molecules like ATP, ADP, AMP, and NADH is another common feature.

48. Summary of Feedback Controls in Cellular Respiration Pathway Enzyme affected Elevated levels of effector Effect on pathway activity glycolysis hexokinase glucose-6-phosphate decrease phosphofructokinase low-energy charge (ATP, AMP), fructose-6-phosphate via fructose-2,6-bisphosphate increase high-energy charge (ATP, AMP), citrate, acidic pH decrease pyruvate kinase fructose-1,6-bisphosphate increase high-energy charge (ATP, AMP), alanine decrease pyruvate to acetyl CoA conversion pyruvate dehydrogenase ADP, pyruvate increase acetyl CoA, ATP, NADH decrease citric acid cycle isocitrate dehydrogenase ADP increase ATP, NADH decrease α - ketoglutarate dehydrogenase Calcium ions, ADP increase ATP, NADH, succinyl CoA decrease electron transport chain ADP increase ATP decrease