Cell Metabolism PDF

Cellular Metabolis m Chapter 5 Cell Respiration and Metabolism Human Physiology Sixteenth Edition Stuart Ira Fox Krista Rompolski Copyright 2022 © McGraw Hill LLC. All rights reserved. No reproduction or distribution without the prior written consent of McGraw Hill LLC. Metabolism...

Cellular Metabolis m Chapter 5 Cell Respiration and Metabolism Human Physiology Sixteenth Edition Stuart Ira Fox Krista Rompolski Copyright 2022 © McGraw Hill LLC. All rights reserved. No reproduction or distribution without the prior written consent of McGraw Hill LLC. Metabolism Metabolism: All of the chemical reactions in the body. ◦Anabolism: Chemical reactions requiring the input of energy (endergonic) to synthesize large molecules ◦Catabolism: Chemical reactions releasing energy (exergonic) by breaking down large molecules into small molecules Catabolism Drives Anabolism ◦The catabolic reactions that break down glucose, fatty acids, and amino acids serve as energy sources for the anabolism (production) of ATP. ◦Complete catabolism of glucose requires oxygen as the final electron acceptor for the oxidation-reduction reactions that occur. ◦The entire process of energy making in the presence of oxygen is called aerobic cellular respiration.  Respiration of glucose Occurs in three steps: 1. Glycolysis – The break down of glucose into pyruvate that occurs in the cytoplasm and does not require oxygen (anaerobic) 2. Citric acid (Krebs) cycle – The conversion of pyruvate to acetyl CoA, which is then used in a cycle of reactions that result in NADH and FADH2, occurs in the matrix of the mitochondria (aerobic) 3. Electron transport ADP + chain Pi – Making + C6H12O6 + O2  6 CO2 + 6 ATP by reduction H2O + ATP of O2. Occurs on inner membrane of+mitochondria (ADP) (aerobic) (Phosphate) + (Glucose) + (Oxygen)  (Carbon Dioxide) + Glycolysis First step in catabolism of glucose occurs in cytoplasm. 1. Glucose is phosphorylated: Glucose needs addition of 2 phosphate groups from 2 ATP so that it can not diffuse back through the plasma membrane and return to bloodstream. ◦Glucose  Glucose-6-phosphate Glycolysis 2. Glucose is then split into two pyruvic acid molecules through multiple enzymatic steps ◦6-carbon sugar  2 molecules of 3-carbon pyruvic acid: C6H12O6  2 molecules C3H4O3 ◦Note the loss of 2 pairs of hydrogens. These reduce the coenzyme NAD to form NADH: 2NAD + 4H+  2NADH + H+ ◦Types of enzymes involved in glycolysis: ◦ Kinases and phosphatases – transfer phosphate groups ◦ Isomerases – rearrange atoms ◦ Dehydrogenases – remove hydrogens Glycolysis Net Energy Gain in Glycolysis: ◦Glycolysis is exergonic, so some energy transferred to ADP to make 2 total ATP: ◦ 2 ATP used to phosphorylate glucose ◦ 4 ATP made ◦ Net total of 2 ATP made Products of Glycolysis: Glucose  2 pyruvic acid + 2 NADH + 2 ATP Decision Point Once created in glycolysis, pyruvic acid can move into one of two pathways: Lactic acid pathway Which pathway is chosen depends on the presence of oxygen. The Lactic Acid pathway Anaerobic respiration or lactate fermentation When there is no oxygen available in the cell to complete the breakdown of glucose, NADH gives its electrons to pyruvic acid. ◦This is another oxidation-reduction moment: pyruvic acid is reduced while NADH is oxidized. ◦Results in the reformation of NAD to allow glycolysis to continue and the conversion of pyruvic acid to lactic acid. (LDH = lactic acid dehydrogenase)  The Lactic Acid pathway No new ATP is made, so net gain still stands at 2 ATP from glycolysis when oxygen is not present. ◦This is a tiny fraction of ATP production compared to other aerobic steps. High energy areas like the brain and heart can’t survive. ◦ If there isn’t enough blood flow to an organ to supply enough oxygen, this is called ischemia. In the heart, myocardial cells are forced to use the much less efficient lactate fermentation. Prolonged ischemia will cause these cells to die, causing a heart attack (myocardial infarction). ◦Skeletal muscle cells can survive for a little while using the lactic acid pathway, but lactic acid build up is associated with muscle fatigue ◦Red blood cells can only use lactic acid fermentation because they lack mitochondria (they Complete LP2 Lecture Assignment – Q1 11 Citric Acid Cycle Lactic acid pathway Also known as the Krebs cycle. The citric acid cycle begins with glycolysis which has already produced 2 pyruvic acids, 2 NADH, and 2 ATP. If oxygen is present, pyruvic acid leaves the cytoplasm and enters the matrix of the mitochondria.  Citric Acid Cycle X2 Transition step before the citric per gluco acid cycle: se Pyruvate has CO2 removed and is X2 combined with coenzyme A to per form acetyl CoA, and 1 NAD is gluco reduced to NADH. se 1 glucose  2 pyruvic acid molecules  2 acetyl CoA + 2 CO2 + 2 NADH  2 citric acid cycles per glucose Citric Acid Cycle 1. Acetyl CoA combines with a 4-carbon molecule (oxaloacetic acid) to form a 6-carbon molecule (citric acid) ◦The citric acid moves through a cycle of reactions to produce oxaloacetic acid again. The Complete Citric Acid Cycle Citric acid cycle intermediates (and pyruvic acid) = keto acids Access the text alternative for slide images. 15 Citric Acid Cycle Important Events in the Citric Acid Cycle: ◦ 1 GTP (guanosine triphosphate) is produced, which donates a phosphate to ADP to make ATP ◦ CO2 is removed from citric acid twice ◦ 3 NAD is reduced to 3 NADH ◦ 1 FAD is reduced to FADH2 Products of the Citric Acid Cycle: ◦ Significant amounts of NADH are produced: ◦ 3 NADH, 1 FADH2, 1 ATP, 2 CO2, Heat ◦ So for each glucose: 6 NADH, 2 FADH2, 2 ATP, 4 CO2 Complete LP2 Lecture Assignment – Q2 17 Electron Transport Chain The electron transport chain (ETC) converts NADH and FADH2 coenzyme energy into ATP It happens in the cristae (folds) of the mitochondria: Mitochondria membrane: ◦Outer membrane ◦Intermembrane space ◦Inner membrane (cristae) ◦ Electron transporters are built into this inner membrane Electron Transport Chain Important events of the ETC: ◦NADH and FADH2 pass electrons (via hydrogen) to the electron transport chain, reducing the first protein in the chain. ◦ The oxidized FAD+ and NAD+ are reused in the citric acid cycle and glycolysis. ◦Electron transport proteins (cytochromes) and coenzymes pass the electrons to the next molecule in a chain with each being reduced when they receive them, and then oxidized as they pass them to the next. Electron Transport Chain ◦The flow of electrons from one protein to the next are exergonic reactions ◦ This enery is used to pump H+ from the matrix to intermembrane space of the mitochondria. ◦ This sets up a huge concentration gradient of H+ to return to the matrix. ◦H+ can only exit across inner membrane to matrix through the enzyme ATP synthase which uses the movement like a power plant uses water. This movement converts ADP to ATP. ◦ The production of ATP is endergonic and is using the energy of the exergonic reactions to be produced. Electron Transport Chain The Function of Oxygen: ◦Oxygen serves as the final electron acceptor in the electron transport chain, accepting 2 hydrogens to form water (a waste product of the ETC) ◦Without a final acceptor for the electrons, the last ETC protein would stay reduced and can’t accept more electrons, which would stop the citric acid cycle and electron transport chain. ◦ Because it requires oxygen to happen it is an aerobic process Electron Transport Chain Oxidative phosphorylation: The production of ATP through the coupling of the electron transport chain with the phosphorylation of ADP to ATP. Coupling is not 100% efficient: some energy is lost as heat, which is used to maintain our internal body temperature. Putting it together: ATP Balance Sheet ATP yield from one glucose molecule: Therefore 1 Glycolysis 2 ATP (produces 2 pyruvates) Citric acid cycle 2 ATP (1 per pyruvate) glucose will yield Oxidative phosphorylation in electron transport chain yields varying38 ATP amounts of ATP, depending on the cell and conditions. We will go with generally accepted totals: ◦ NADH generally yields 3 ATP and FADH2 yields 2 ATP produced in the electron transport chain: ◦ 2 NADH from glycolysis ◦ 1 NADH from converting pyruvate to acetyl CoA+3 NADH made in the Citric acid cycle = 4 NADH multiply by 2 for each glucose = 8NADH ◦ 1 FADH2 is formed per citric acid cycle = 2 cycles per glucose = 2 FADH 2 10 NADH = 3 x 10 ATP = 30 ATP 2 FADH2 = 2 x 2 ATP = 4 ATP Electron Transport6O2 + C6H12= Chain O6 30 + 38ADP + 4 =+ 34 38PiATP  38ATP from+ 6CO ETC2 + 6H2O Putting it together: ATP Balance Sheet Theoretical yield = ~38 ATP Actual yield: ~30-32 ATP ◦This takes into account the energy cost of transporting ATP out of the mitochondria and into the cytoplasm. Chemiosmotic theory: theory that oxidative phosphorylation within mitochondria is driven by the development of a H+ gradient across the inner mitochondrial Complete LP2 Lecture Assignment – Q3 25  Interconversion of glucose, lactic acid, and glycogen Glucose enters cells by facilitated diffusion with help from insulin. ◦ This is a passive process that does not allow the cell to contain glucose at a higher concentration than present in the bloodstream. To promote glucose movement into the cell from the bloodstream, the cell reduces the glucose concentration inside the cell by modifying glucose by phosphorylation to create glucose-6- phosphate ◦ The cell membrane is impermeable to glucose-6- phosphate, so it effectively "traps" glucose inside the cell, allowing the movement of more glucose from the bloodstream. Storing Glucose Cells can’t store any significant quantity of glucose because it attracts water into the cell via osmosis: ◦If a high concentration of glucose was in the cell: 1. Many solutes inside the cell that are osmotically active (can’t exit the plasma membrane) 2. Means an increased solute concentration INSIDE the cell 3. Means less water inside the cell compared to plasma 4. Would cause the osmosis of water INTO the cell 5. Would cause the cell to swell and lyse. ◦This is why glucose is either used immediately or stored in a different form.  Glycogenesis Glucose cannot be kept free floating in the cytoplasm, so the cell stores it as a larger molecule called glycogen in the liver, skeletal muscles, and cardiac muscles. Glycogen is formed from glucose via glycogenesis. ◦ Glycogen synthase is the enzyme that removes the phosphate group and joins glucose molecules together in a polymer called glycogen.  Glycogenolysis When a cell needs glucose, it can break down the stored glycogen. ◦This is called glycogenolysis. Glycogen phosphorylase catalyzes glycogen breakdown: glucose 1-phosphate (G1P) is made which can be converted to glucose 6-phosphate (G6P). G6P cannot leave the cell. Once glycogen breakdown happens, the glucose is then used for energy within the same cell, not released into the blood stream*.  Glycogenolysis *One exception to this rule is that the liver has an enzyme called glucose 6- phosphatase that removes the phosphate to restore glucose to its original form; which can reenter the bloodstream. Glycogenolysis is a major function of ◦Therefore, the liver can use the liver in how it helps to regulate its glycogen stores to elevate blood glucose levels. Cardiac blood glucose levels. and skeletal muscle use Cori Cycle and Gluconeogenesis 1-3) In anaerobic conditions, skeletal muscles make lactic acid from pyruvate by using the lactic acid pathway. ◦ 4) The lactic acid leaves the muscle cell and is transported in the blood stream to the liver. 5) In the liver, the enzyme lactic acid dehydrogenase converts lactic acid back to pyruvic acid and NADH.  Cori Cycle and Gluconeogenesis 6) Unlike most cells, the liver can also convert pyruvic acid to glucose 6- phosphate. ◦ This ability unique to the liver can be used to make glycogen or glucose in a reverse of glycolysis. ◦ 7) This conversion of Pyruvic acid  Glucose is called gluconeogenesis (the production of glucose from noncarbohydrates) Cori Cycle and Gluconeogenesis ◦ 8) Because the liver can release its glucose, the glucose made in gluconeogenesis can return to the muscle cells, which completes the Cori Cycle. ◦ 9) During rest, the glucose can be used to restore the glycogen levels in the muscle. Cori Cycle and Gluconeogenesis Cori Cycle: The cycle of 1) a muscle cell performing glycolysis, producing lactic acid due to anaerobic conditions. 2) The lactic acid is transported to the liver where it is converted back to pyruvic acid, and 3) by gluconeogenesis is made back into glucose which can be sent back to the muscle through the blood stream. Complete LP2 Lecture Assignment – Q4 36 Metabolism of Lipids & Proteins When more food energy is taken into the body than is needed to meet energy demands, ATP levels in the cell are elevated. We can’t store ATP for later. Instead, glucose is converted into glycogen and triglycerides, and ATP production is inhibited. Lipids and proteins can also be used for energy via the same pathways used for the Copyright © 2018 Clinidiabet, S.L. metabolism of pyruvic Lipid Metabolism: Lipogenesis If ATP is not needed (resting conditions) = make fats: ◦ Glucose is converted in glycolysis to pyruvic acid and then acetyl CoA. ◦ The acetyl CoA is then joined together to produce a variety of lipids, cholesterol, ketone bodies, and fatty acids. ◦ Fatty acids combine with glycerol to form triglycerides in the adipose tissue and liver. This process is called lipogenesis. Lipid Metabolism: Lipolysis If ATP is needed (exercise/mobilization) = break down fats: ◦Triglycerides are broken down into fatty acids and glycerol using the enzyme lipase: ◦Glycerol is taken up by the liver and converted to glucose through gluconeogenesis. ◦Fatty acids can then enter the blood stream to be transported where needed and undergo β-oxidation to harvest energy from them. This process is called lipolysis. Copyright © 2018 Clinidiabet, S.L. Lipid Metabolism: β-oxidation β-oxidation: How fatty acids are broken down into usable energy - enzymes remove pairs of carbons from the chain to form acetyl CoA. ◦ For every 2 carbons on the fatty acid chain, 1 acetyl CoA can be formed. ◦ E.g. 16-carbon fatty acid  16/2 = 8 acetyl CoA ◦ Each acetyl CoA goes to citric acid cycle = 1 ATP + 3 NADH + 1 FADH2 ◦ Taking into account the energy needed to transport the ATP out of the cell: Net 2.5 ATP per NADH and 1.5 ATP per FADH2  1 + 7.5 + 1.5 = 10ATP ◦ 8 acetyl CoAs x 10 ATPs from Krebs cycle + ETC = 80 ATP ◦ 1 NADH and 1 FADH2 produced 7 times - each time acetyl CoA is formed = (2.5 ATP +1.5 ATP ) x 7 = 28 ATP A 16-carbon fatty acid  80 + 28 in electron transport = 108 ATP! What about a 20-carbon fatty acid? Lipid Metabolism: Ketones 1. When the rate of lipolysis exceeds the rate of fatty acid utilization (as in dieting, starvation, or diabetes), the concentration of fatty acids in the blood increases. 2. Liver cells convert the fatty acids into acetyl CoA and then into ketone bodies. ◦The formation of ketones is called ketogenesis. 3. These are water-soluble molecules that circulate in the blood and can be used to make energy 4. Build-up of ketone bodies in the blood eventually causes ketosis (increased ketone bodies in the blood). ◦The brain during fasting can use ketone bodies for some of its energy ◦Excessive ketosis = ketoacidosis Amino Acid Metabolism Amino acids from dietary proteins are needed to replace proteins in the body. ◦Think uses like structure, movement, enzymes, pumps/carriers If more amino acids are consumed than are needed, the excess amino acids can be used for energy or converted into carbohydrates or fat. The formation of glucose from amino acids is also gluconeogenesis because glucose is produced from a noncarbohydrate. Amino Acid Metabolism If amino acids are needed and we are not taking them in via the diet: ◦ Keto acids (pyruvic acid and several citric acid cycle intermediates) can be converted to amino acids by transamination: transferring an amine group (NH2) from one amino acid to another ◦ These amino acids that the body can produce are called nonessential amino acids. ◦ Amino acids that cannot be created by the body are called essential amino acids Several amino acids can be converted into glutamic acid via transamination. (ALT = alanine transminase) Amino Acid Metabolism If we have an excess of amino acids: ◦The amino acids of the protein can be broken down by removing amine groups from glutamic acid and incorporating them into urea. Oxidative deamination: metabolic pathway that removes amine groups from amino acids leaving a keto acid and ammonia (NH3)  Amino Acid Metabolism Therefore other amino acids can be used to produce keto acids (e.g. pyruvic acid and Krebs Cycle acids) These keto acids are then used in the citric acid cycle for energy. Summary: Different Energy Sources Different organs prefer different energy sources. Some are very efficient with one source and cannot use another source at all! Definitions Complete LP2 Lecture Assignment – Q5 49