PL1003 Cellular Respiration Lecture 3.3 PDF

PL1003 - Topic 3 Cellular Respiration Dr. Lobke Starr-Vaanholt  Learning Outcomes By the end of this session you will be able to: Describe the different pathways in cellular respiration Compare and contract aerobic and anaerobic metabolism...

PL1003 - Topic 3 Cellular Respiration Dr. Lobke Starr-Vaanholt  Learning Outcomes By the end of this session you will be able to: Describe the different pathways in cellular respiration Compare and contract aerobic and anaerobic metabolism Discuss glucose metabolism in tumour cells  Glycolysis Glycolysis Cellular Respiration Glucose Glucose A series of reactions that break down glucose (the fuel) Pyruvate Pyruvate and produce ATP (the energy currency of the cell) Aerobic Anaerobic Glycolysis Pyruvate Oxidation Fermentation Pyruvate oxidation Citric Acid Cycle (Kreb’s cycle) Alcohol or Lactate ATP Oxidative Phosphorylation (electron transport chain and Citric Acid chemiosmosis) Cycle Oxidative Phosphorylation CO2 + H2O ATP 05 September 3 2023  Oxidation and Reduction Always coupled – one substance is oxidised, while H2 + ½ O2  H2O + Energy another is reduced. Oxidation = removal of electrons (hydrogen) H2  2 H+ + 2 e- The hydrogen is picked up by coenzymes for transfer to Each of the two Hydrogen atoms loses 1 electron  oxidised another compound. ½ O2 + 2 e-  O2- Reduction = gain of electrons (hydrogen) The oxygen takes two electrons  reduced OIL RIG Oxidation and reduction review from biological point-of- view (video) | Khan Academy 05 September 4 2023  ATP: The energy currency of the cell Nitrogenous Base (Adenine) Adenosine triphosphate (ATP) is a nucleotide. Nucleotides consist of a nitrogenous base (nucleobase) a five-carbon sugar (pentose) and one to three phosphates Adenosine monophosphate is a building block (monomer) of RNA Triphosphate Adenosine triphosphate provides energy to drive cellular Group processes Ribose How much ATP does the body store? How long could you power maximal exercise with the ATP stored? AMP 05 September 5 2023  ATP: the primary energy currency of the cell Mediates the transfer of chemical energy from reactions that release energy (exergonic), to those that require energy (endergonic) ATP “stores” this energy in the form of a high energy phosphoanhydride bond Hydrolysis of ATP splits the phosphoanhydride bond releasing energy. ATP + H2O  ADP + Pi + Energy The cell is constantly using this energy, so ATP energy stores need to be replaced! Energy released in an exergonic reaction can be used to add a phosphate group to ADP, regenerating ATP. 05 September 6 2023  Mechanisms for generating ATP Substrate level phosphorylation Transfer of a phosphate from a substrate directly to ADP, forming ATP. Energy comes from the substrate which is converted from a higher to lower energy product in the process. Occurs in glycolysis and citric acid cycle. Oxidative phosphorylation Covered later in the lecture. 05 September Muessig, CC BY-SA 3.0 , via Wikimedia Commons, https://commons.wikimedia.org/wiki/File:ADP_ATP_cycle.png 7 2023  What type of “work” does ATP power? The phosphate group is transferred from the ATP to another molecule (helped by enzymes) The molecule that accepts the phosphate can now perform transport, mechanical or chemical “work” Chapter 7: Concept 7.3 (mtchs.org) 05 September 8 2023  NAD+ / NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme important in cellular respiration It can exist in an oxidised (NAD+) and reduced (NADH) High energy form molecule Energy used It acts as a carrier of energy, trapping and transporting electrons from one reaction to another (in the form of a hydride ion) Energy released When another molecule is oxidised, 2 hydrogen atoms are removed as a hydride ion (H-) and a hydrogen ion (H+). The H- is transferred to NAD+, and the H+ is released into solution. Low energy FADH/FADH2 is another electron carrier used molecule 05 September 9 2023  Glycolysis 05 September 10 2023  Energy requiring Glycolysis Occurs in the cytosol Begins with glucose (6 carbons) and ends with 2 x pyruvate (3 carbons) Energy-requiring and Energy-releasing phases Energy-releasing phase creates ATP and NADH Energy releasing 05 September Concepts of Biology. Authored by: Open Stax. Located at: http://cnx.org/contents/b3c1e1d2-839c-42b0-a314- 11 2023 [email protected]:1/Concepts_of_Biology. License: CC BY: Attribution  Glycolysis: Energy-requiring phase 1. Phosphate group transferred from ATP to glucose 2. Glucose-6-phosphate is converted into its isomer, fructose-6-phosphate 3. Phosphate group transferred from ATP to fructose-6- phosphate 4. Fructose-1,6-bisphosphate splits to form two three- carbon sugars: DHAP and glyceraldehyde-3-phosphate. These three carbon sugars are isomers. DHAP converts easily to glyceraldehyde-3-phosphate  Glyceraldehyde-3-phosphate enters the energy-releasing phase Deficiency of 2 ATP per molecule of glucose 05 September Rozzychan, Public domain, via Wikimedia Commons 12 2023  Glycolysis: Energy releasing phase glyceraldehyde-3-phosphate Glyceraldehyde-3-phosphate generated in the energy- requiring phase is turned into pyruvate. Glyceraldehyde 3-phosphate is oxidised, while NAD+ is reduced This reaction is exergonic overall, and the extra energy generated is used to phosphorylate glyceraldehyde 3-phosphate Generates 4 x ATP and 2 x NADH per molecule of glucose A phosphate group is donated to ADP 05 September 13 2023  Glycolysis Output - Output Total yield per molecule of glucose: 2 NADH (yields 2.5 ATP in ETC) 2 ATP (net yield) Pyruvate will be oxidised to AcetylCoA which will enter the Krebs Cycle 05 September 14 2023  Pyruvate Oxidation 05 September 15 2023  Aerobic conditions Pyruvate Oxidation Pyruvate transported into mitochondria Pyruvate is decarboxylated (a carboxyl group is removed, releasing CO2) The two-carbon molecule generated is then oxidised to form an acetyl group. NAD+ is reduced to NADH The acetyl group is attached to Coenzyme A: Acetyl- CoA Captures remaining energy from pyruvate molecules and generates a substrate for the citric acid cycle 05 September Access for free at https://openstax.org/books/biology/pages/1-introduction. Creative Commons — Attribution 16 2023 4.0 International — CC BY 4.0  What is oxygen is limited? Anaerobic conditions Aerobic conditions Anaerobic pathway Pyruvate is reduced to lactate Electrons come from NADH/H+ NAD+ is ready to be used in glycolysis again 05 September 17 2023  Krebs Cycle 05 September 18 2023  Citric Acid (Krebs) Cycle Occurs in the mitochondrial matrix A series of decarboxylation reactions  release CO2 oxidation-reduction reactions  Acetyl CoA derivatives are oxidised, NAD+ and FAD are reduced to NADH and FADH2. This transfers chemical energy to NADH and FADH2 ATP is generated 05 September 19 2023  Citric Acid (Krebs) Cycle For each complete turn of the citric acid cycle (stored energy!): 3 NADH/H+ 1 FADH Oxidation-reduction 1 ATP reactions Substrate level phosphorylation NOTE each glucose generates 2 x acetyl CoA 05 September Access for free at https://openstax.org/books/biology/pages/1-introduction 20 2023  Oxidative Phosphorylation 05 September 21 2023  Oxidative Phosphorylation Occurs in the inner mitochondrial membrane Uses the electron transport chain – a series of membrane protein complexes and other molecules that act as electron carriers Carriers in the chain gain electrons (are reduced) and lose electrons (are oxidised). This releases energy. Chemiosmosis Where do these electrons come from?? Oxidative Phosphorylation What is the energy used for? Eventually oxygen is reduced, and the reduced oxygen picks up hydrogen ions to make water 05 September Access for free at https://openstax.org/books/biology/pages/1-introduction 22 2023  Electron Transport Chain The electron transport chain (ETC) is a series of proteins that transfer electrons from donors to acceptors  NADH and FADH2 produced in glycolysis and Krebs cycle donate electrons to the ETC ETC is made up of: 4 complexes (I-IV) I. NADH-Q oxidoreductase II. Succinate-Q reductase III.Q-cytochrome c oxidoreductase IV.Cytochrome c oxidase 2 mobile electron carriers Coenzyme Q (or ubiquinone) Cytochrome C 05 September Created with BioRender.com 23 2023  Electron Transport Chain NADH is oxidised! (NADH  NAD+ + H+ + 2e-)* As electrons pass through the chain, energy is used by the electron carrier complexes to pump H+ ions (protons) across the mitochondrial membrane Produces a concentration gradient, i.e., proton motive force *Note that NADH cannot easily cross the mitochondrial membrane, so a shuttle system is used to deliver the electrons to the electron transport chain 05 September Created with BioRender.com 24 2023  Chemiosmosis Chemiosmosis is the use of energy in a H+ gradient to drive cellular work The pH gradient provides a proton motive force that is used to convert ADP to ATP The enzyme complex that catalyzes the reaction is ATP Synthase 1 NADH yields 2.5 ATP 1 FADH2 yield 1.5 ATP Total entering from glycolysis, link reaction and Krebs cycle per molecule of glucose = 10 NADH and 2 FADH2  28 ATP 05 September Created with BioRender.com 25 2023  Brown adipocytes Contain “Uncoupling Protein 1” instead of ATP Synthase What happens to all the energy harvested in the earlier stages of respiration? UCP1 Chemiosmosis Oxidative Phosphorylation 05 September 26 2023  Glucose Metabolism in Tumours 05 September 27 2023  Glucose metabolism in tumour cells Tumours take up huge amounts of glucose Glucose Even in the presence of adequate oxygen, a lot of this glucose in converted to lactate Pyruvate  “Warburg effect” Acetyl-CoA Lactate Why? Citric Acid Cycle OXPHOS Oxygen plentiful Oxygen limited Article - The Warburgh Effect: How does it benefit cancer cells 05 September 28 2023  Glucose metabolism in tumour cells Does glycolysis or oxidative phosphorylation Glucose produce more ATP? Is it faster to produce lactate or to complete Pyruvate X10-100 oxidative phosphorylation? speed Acetyl-CoA Lactate Citric Acid Cycle 2 ATP A cell can generate just as much ATP (and faster) by favouring aerobic glycolysis over complete oxidation of OXPHOS glucose Oxygen plentiful 32 ATP 05 September 29 2023  Benefits for Tumour Cells Glucose to lactate is 10-100X faster than complete oxidation of glucose and thus can generate sufficient ATP anaerobically High consumption of glucose limits availability to other cells, including immune cells Production of lactate also benefits the tumour: lactate dampens immune responses, while acidification of the environment favours invasion Provides additional glucose-derived metabolites for nucleotide, lipid or protein biosynthesis DNA replication and RNA transcription Membrane production PROLIFERATION!!! Protein translation 05 September 30 2023  Therapeutic targeting of glucose metabolism The Warburg effect has been a topic of interest in cancer research and therapy  understanding the metabolic differences between cancer cells and normal cells may lead to the development of targeted therapies aimed at disrupting cancer cell metabolism Block Fasentin, STF-31, genistein glucose uptake Lonidamine Inhibit (In clinical trials, selective aerobic inhibition in cancer cells – different isoforms) glycolysis 05 September Article - The Warburgh Effect: How does it benefit cancer cells 31 2023