Metabolism of glucose in lungs for BDs students

For MBBS, BDS and nursing students

1. Metabolism of glucose in the lungs and other sources of energy Dr. Apeksha Niraula Assistant Professor Clinical Biochemistry Institute of Medicine

2. Objectives Introduction to Metabolism of glucose in the lungs O ther sources of energy Electron Transport Chain Oxidative Phosphorylation

3. Lung: often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other organs, including the heart, kidney, and brain For most cells in the lung, energy consumption is relegated to performing common cellular tasks, like mRNA transcription and protein translation However, certain lung cell populations engage in more specialized types of energy-consuming behaviors, such as the beating of cilia or the production of surfactant Introduction

4. Lung was only considered to be a passive conduit for gas exchange, it is now appreciated that the lung consumes, on a per gram basis, as much as or even more energy than almost any other organ in the body, including the brain, kidney, and liver Energy consumption in the lung : for performing usual cellular tasks, like rearrangement of cytoskeletal elements, gene transcription and protein translation, and replication and repair of DNA Lungs: also contains several populations of highly specialized cells that engage in more unique forms of energy-consuming behaviors, such as airway clearance (phagocytosis and ciliary motility), bronchial gland secretion, constriction of airways and blood vessels, and production of pulmonary surfactant

5. A complex set of chemical reactions that permit cells, organs, and entire organisms to function and thrive Survival of an organism is ultimately dependent on the integration of all metabolic pathways. In fact, other than glycolysis, no major metabolic pathway functions entirely on its own For example: Pentose phosphate pathway most commonly relies on glucose-6-phosphate from glycolysis to proceed, and lipid synthesis cannot move forward without input of both nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine 5′-triphosphate (ATP) from at least two other metabolic pathways Cellular Metabolism and Its Major Pathways

6. Common Metabolic Pathways in L u ngs Glycolysis HMP Shunt pathway TCA cycle Electron Transport Chain and Oxidative Phosphorylation Fatty Acid Oxidation Fatty Acid Synthesis

7. Electron Transport Chain

8. Site for ETC: Mitochondria

9. The electrons for the ETC are released during catabolic pathways of biomolecules such as carbohydrates, fats, and amino acids by action of the enzymes known as Dehydrogenases Electrons are then funneled into the ETC For example: During glycolytic sequence a pair of electrons is removed from glyceraldehyde 3-phosphate In TCA cycle, an electron pair is removed from each of the following substrates: Isocitrate, -ketoglutarate, succinate and malate by specific dehydrogenases Sources of Electrons for ETC

10. These dehydrogenases remove a pair of hydrogen atoms initially Since each hydrogen atom contains an electron, removal of two hydrogen atoms implies removal of an electron pair These electrons travel down the ETC, and combine with the last acceptor, i.e. oxygen, and two protons are also taken up from the surrounding medium This results in the formation of water

11. The electron transport chain in the mitochondrial membrane has been separated in 4 (four) complexes or components as follows: Complex I: NADH-CoQ reductase Complex II: Succinate-CoQ reductase Complex III: CoQ-cytochrome C reductase Complex IV: Cytochrome C oxidase

12.  This system has two functions: Electron transfer Acts as a proton pump Permits one ATP Formation (Site I) Complex I: NADH-CoQ Reductase

13. The flow of electrons from succinate to CoQ occurs via FADH 2 The standard reduction potential for the transfer of electrons from FADH 2 to CoQ is + 0.113V (much lower than +0.420 V energy change for the reaction of complex I) The small energy change does not allow the “succinate-CoQ reductase” system to pump protons across the mitochondrial membrane, hence this protein complex does not contribute to the proton gradient Hence, no ATP is formed Complex II: Succinate-CoQ Reductase

14. Functions as Proton pump, and Catalyses transfer of electrons This system catalyses transfer of electrons from CoQ.H2 to Cyt-c via Cyt-b and Cyt-c1 Fe+++ accepts electron and is oxidized to Fe++ The system also acts as a proton pump It is believed that 4 (four) protons are pumped across the mitochondrial membrane during the oxidation  Complex III: CoQ-Cyt.C Reductase

15.  The system functions: As proton pump Catalyses transfer of electrons to molecular O 2 to form H 2 O Complex IV: Cyt-c Oxidase

16. Inhibitors of ETC

17. In oxidative phosphorylation: ATP is produced by combining ADP and Pi with the energy generated by the flow of electrons from NADH to molecular oxygen in the electron transport chain Three sites in the respiratory chain where ATP is formed by oxidative phosphorylation These sites have been proved by the free energy changes of the various redox couples Since hydrolysis of ATP to ADP + Pi releases around 7.3 K. Cal/mole, the formation ATP from ADP + Pi requires a minimum of around 8 KCal/mole The formation of ATP is therefore not possible at the sites where free energy released is less than 8 KCal/mole OXIDATIVE PHOSPHORYLATION

18.  There are three sites in the respiratory chain where ATP can be formed: Site I: This involves the transfer of electrons from NADH –CoQ This step is omitted by succinic dehydrogenase whose FADH2 prosthetic group transfers its electrons directly to CoQ bypassing NAD This step is blocked by piericidin, rotenone, amobarbital, certain drugs like chlorpromazine, guanethidine Site II: This involves the transfer of electrons from Cytb–Cyt-c1 This step is blocked by BAL, Antimycin A, Hypoglycaemic drug like phenformin. Sites of ATP formation

19. Transfer of electrons from Cyt-a3 to molecular oxygen Blocked by CO, CN, H 2 S, and azide Site III:

20. Certain shuttle systems are known to operate in mitochondria that transport reducing equivalents from cytosol into mitochondria The reducing equivalents (in the form of NADH) are generated in the cytosol (during glycolysis) They have to be transported to mitochondrial matrix for oxidation and generation of ATP However, the IMM is impermeable to NADH Therefore, specific shuttle systems, namely malate aspartate shuttle and glycerol phosphate shuttle, accomplish their transport Shuttle Systems

21. It operates in the liver and heart muscles in the following steps: The reducing equivalents are transferred from NADH to oxaloacetate to form malate The reaction is catalyzed by the cytosolic enzyme malate dehydrogenase 2. Malate is then transported across the IMM by the dicarboxylate carrier. 3. Within the mitochondrial matrix, the reducing equivalents are transferred from malate to NAD + to form NADH The enzyme that catalyzes this reaction is mitochondrial malate dehydrogenases Malate aspartate shuttle

22. In skeletal muscle and brain, another type of shuttle, called glycerol phosphate shuttle , is present It transfers the hydrogen first to dihydroxyacetone phosphate forming glycerol phosphate (in the cytosol) , and then to the FAD prosthetic group of the mitochondrial glycerol phosphate dehydrogenase The latter is an integral protein of the inner mitochondrial membrane, which regenerates its FAD by direct transfer of electrons to the respiratory chain Only two ATPs are therefore produced for each pair of reducing equivalents transferred Glycerol phosphate shuttle

23. Three major proposals for the mechanism of oxidative phosphorylation have been considered The synthesis of ATP is carried out by a molecular assembly in the inner mitochondrial membrane This enzyme complex is called Mitochondrial ATPase or H+-ATPase It is also called ATP synthase Mechanism of Oxidative Phosphorylation

24. Theories The three hypothesis do make use of the information available on ATP synthase 1. The chemical coupling hypothesis: This is developed from the concept of a high energy intermediate common to both electron transport and phosphorylation of ADP However, such intermediate has not been identified so far

25. 2. The conformational coupling hypothesis: According to this hypothesis the mitochondrial cristae undergo conformational changes and these changes in architecture of the mitochondrial cristae reflect the changes in the different components of the electron chain to one another It is believed that these conformational change represents the formation of high energy state

26. This is the most accepted view of oxidative phosphorylation postulated by Peter Mitchell in 1961 Mitchell’s chemiosmotic theory postulates that the energy from oxidation of components in the respiration chain is coupled to the translocation of hydrogen ions (Protons, H+) from the inside to the outside of the inner mitochondrial membrane Each of the respiratory chain complexes I, III and IV acts as a proton pump The inner membrane is impermeable to ions in general but particularly to protons, which accumulate outside the membrane, creating an electrochemical potential difference across the membrane ( Δμ H+) This consists of a chemical potential (difference in pH) and an electrical potential The electrochemical potential resulting from the asymmetric distribution of the hydrogen ion is used to drive the mechanism responsible for the formation of ATP C. Chemiosmotic theory:

27. Thank You