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Lecture 7

BIOC13Winter2013 Lecture 7 and 8 Notes.docx

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Biological Sciences
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Daman Bawa

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BIOC13Winter2013 Lecture 7 and Lecture 8: The Electron Transport and Oxidative Phosphorylation Systems Biological Redox Reactions o Oxidation is always accompanied by an electron acceptor o Respiration: the process by which cells derive energy in the form of ATP from controlled reaction of hydrogen with oxygen to form water o One of the most complicated metabolic pathways  numerous enzymes and coenzymes/cofactors and is highly organized o Oxidation of glucose can be divided into 2 half reactions o Oxidation of glucose:6C 12O6+ 6 H2O  6 CO 2 24H + 25e - o Reduction of Oxygen: O2+ 24H + 25e  12 H O 2 o The electrons are not transferred to oxygen directly o Complete oxidation of glucose = glycolysis + pyruvate dehydrogenase reaction + citrate cycle = net reaction o Glucose + 2 H2O + 10 NAD + 2 FAD + 4 ADP + 4 Pi  6 CO2+ 10 NADH + 6 H + 2 FADH +24 ATP Energy production in complete oxidation of glucose o Oxidative phosphorylation turns NADH and FADH2 into ATP  2.5 ATP/ NADH and 1.5ATP/FADH2 o Total about 28 ATP / glucose molecule How is ATP produced from NADH and FADH2? o Enter the mitochondrial electron transport chain o ETC: a system of electron carriers located in the inner mitochondrial membrane (IMM) o NAD and FADH2 transfer their electrons (LEO) to complexes in mitochondria that can readily accept electrons (GER) o Under aerobic conditions the ETC converts reducing equivalents into ATP using oxidative phosphorylation What is reducing equivalent? o Reducing agent that is equivalent to one electron  H (one proton + one electron), an electron, hydride ion (hydrogen with an extra electron H-) Overview of ETC and Oxidative Phosphorylation o Process which forma ATP as a result of transferring e- from NADH or FADH2 to O2 through a series of carriers o Major source of ATP for aerobic organisms o Generates 28/32 ATP (88%) obtained from glucose catabolism o NADH and FADH2 contain electron pairs with high transfer potential o Membrane bound system that creates a proton gradient and the electromotive force that drives ATP synthesis o From NADH overall production of ATP o 2 NADH + 2 H + 5 ADP + 5 P +iO 2 NAD + 5 ATP + 2 H O 2 What is required for OP? o a specialized ion impermeable membrane structure o mechanism for moving protons acoss the membrane to produce an energy rich proton gradient o a mechanism to capture the energy generated by the proton gradient o all fulfilled within the mitochondria o there are about 2000 mitochondria in a typical eukaryotic cell  20% of cell volume o has outer membrane, inner memebrane, intermembrane space, cristae and matrix Mitochondria o the size and shape of the mitochondria varies dependin on the cell type and the metabolic state of the cell  average size is the size of a small E.coli o number of mitochondria in a cell is related to overall energy requirement of the cell o white muscle cells have few mitochondria  rapid contratctions but cant be sustained  mostly anaerobic production of ATP o red muscle have a large amount of mitochondria  sustained contractions  mosly aerobis production of ATP o OMM  encloses the entire organelle (similar to the plasma membrane), 30-40% lipid and 60-70% protein, few enzymatic or transport proteins, rich in porin (allows free diffusion of ions and small molecules; <10kDa) o The concentration of ions and metabolites in the intermembrane space is similar to that of the cytosol o IMM  80% proteins and 20% lipids, high levels of cardiolipin ( critical in the functioning of energy producing enzymes), contains enzymes complexes of ETC and OP, several transport systems that transfer metabolites etc., freely permeable only to O2, CO2 and H2O, allows for compartmentalization, contains highly folded cristae o Cristae  increases the surface area, can range in shae from simple tubular structures to more complicated structure that merge with the rest of the IMM, form microcompartments that restrict the diffusion of metabolites and ions between the intercristal and intermembrane spaces  results in local control of concentrations and pH o Matrix  high concentration of protein so gel like consistency, high concentrations of metabolite cofactors and inorganic ions, mitochondrial genetic and protein synthesis machinery  mtDNA, ribosomes, and other proteins necessary for 1 transcription and translation, enzymes involved in oxidative metabolism  PDH complex, TCA, fatty acid oxidation, enzymes involved in other pathways (urea, heme synthesis etc.) Metabolites can enter and leave mitochondria by different means o NADH cannot penetrate IMM from cytosol (where it is produced) due to lack of a transport protein  oly electrons are transported into mitochondrion in form of reducing equivalents using shuttle systems o Malate-aspertate shuttle and glycerophosphate shuttle o ADP is imported into the matrix in exchange for export of ATP to the cytosol  ADP – ATP Translocator o Inorganic phosphate generated from the hydrolysis of ATP is cytosol is transported into the mitochondrion  phosphate carrier or phosphate translocase Malate-aspartate shuttle o Cytosolic oxaloacetate is reduced to malate by malate dehydrogenase while oxidizing NADH o Malate is then transported into the mitochondrion where it is reoxidized to produce oxaloacetate by malate dehydrogenase and NAD+ is reduced to NADH Glycerophosphate Shuttle o Cytosolix NADH is oxidized to NAD+ by 3-phosphoglycerol dehydrogenase (made from DHAP  3 phosphoglycerol) o Reducing equivalents from 3-phosphoglycerol are transferred to flavoprotein dehydrogenase to form FADH2  supplies the ETC directly ADP-ATP Translocator o Adenine nucleotide translocase (ANT) o ATP made in the mitochondria needs to be transported out and ADP and Pi sources need to be replenished o ANT can bind either ATP or ADP o Conformation change occurs upon binding which results in the nucleotide being flipped across the membrane o Net charge export is -1  ATP net charge is -4 and ADP net chare is -3; driven by positively charged intermembrane space o Phosphate Transporter o o Pi must be imported from the cytosol o Pi-H symport  driven by ΔpH  high [H+] in Intermembrane space drives the movement of Pi o Electroneutral  the net charge transfer is 0 Electron Transport Chain o 4 large protein complexes o Complex I  NADH – ubiquinone oxidoreductase (NADH dehydrogenase) o Complex II  succinate-ubiquinone reductase (succinate dehydrogenase –TCA enzyme) o Complex III  ubiquinone-cytochrome c oxidoreductase 2 o Complex IV  cytochrome c oxidase o o e- are transferred between Complex I and Complex II by membrane soluble coenzyme-Q o e- are transferred between Complex III and IV by peripheral membrane protein Cytochrome C o these are mobile electron carriers o 4H+ in complex I and III and 2H+ in complex IV  10 H+/ NADH and 6H+ per FADH2 o NADH and FADH2 coming from the citric acid cycle and fatty acid oxidation pathways eneter the electron transport chain o NADH and FADH2 donate pairs of electrons (2e-) to complex I and II respectively o The electrons flowing through the electron transport chain ultimately reducing oygen to form water o The ETC requires 2 moble electron carriers to transfer electrons between complexes  coenzyme Q (ubiquinone) and cytochrome C o o reduction potential increase this way  and this is also the way that electron flow spontaneously o deltaEº = acceptorºdonor o reductant (reducing agent)= e- donor = oxidized o oxidant (oxidizing agent) = e- acceptor = reduced Cytochromes o heme containing proteins o classified as a, b or c based on absorption spectrum o cyta, cyta3, bL and bH and c1 are integral proteins o cyt c is peripheral membrane protein on outer surface of IMM o they carry 1 electron per heme iron Complex I : NADH-ubiquinone oxidoreductase o largest protein complex in IMM o 46 subunits with MW of 900kDA o L shaped protein with one arm in IMM and the other into matrix o Contains one FMN and 8-9 Fe-S clusters o Passes 2e- obtained from the oxidation of NADH to CoQ using a copled reaction mechanism that results in the net movement of 4H+ acoss the membrane o o contains a covalently bound FMN (flavin monoc=nucleotide) that accets 2e- from NADH as well as at least 8-9 FE-S clusters that carry one electron at a time from one end of the complex to the other o the poison retenone blocks e- transfer between 2 Fe-S centers, preventing redox reaction o NADH donates 2e- to FMN  FMNH2 (reduced) which passes them to the Fe-S clusters which then passes them to coenzyme Q which becomes CoQH2 (reduced) o 4 H+ are also transferred to the intermembrane space via conformation changes in the protein by altering pKa values of functional groups located on the inner and outer faces of the membrane o proton wire  series of Hydrogen bonded protein groups plus water that form a chain along with protons can be relayed Complex II: Succinate – coQ oxidoreductase o aka succinate dehydrogenase turns succinate to fumerate during which FAD becomes reduced to FADH2 o FADH2 then transfers the electrons via Fe-S clusters to CoQ o No protons are translocated across the IMM by complex II due to low deltaG (-5.6kJ/mol) Ubiquinone (CoQ) o CoQ can difuse through the lipid bylayer among the respiratory complexes therefore serves as an electron shuttle 3 o Isoprenoid units act as a hydrophobic tail that allows it to become soluble in the IMM bilayer  in mammals consists of 10 isoprenoid units hence the name CoQ10 o Tissues that have the highest energy requirements have the highest concentration of CoQ o One of the major dietary supplements that is thought to promote better cellular health Complex III: Ubiquinone-cytochrome c oxidoreductase o Also called cytochrome bc1 complex o Docking sit of QH2 o Consists of 11 protein subunits in each of the 2 monomer subunits o There are 2 binding sites for Q called Qp and Qn  play crucial role in diverting one electron at a time to cytochrome c via the Q cycle o Qp = is closer to the positive side of the membrane which is near the intermembrane space and Qn is near the negatice side of the membrane which is near the matrix o o contains cytochrome b which contains 2 heme groups – bL and bH o cytochrome c1 which contains one heme group o rieske iron sulfur protein (ISP) which contains 2Fe-S2 cluster The Q cycle o mobile electron carrier and transfoermer that converts the 2e- transport system used by complexes I and II into a 1 e- transport system required by cytochrome c o CoQH2 carries 2 e- and can reduce 2 molecules of cyt c o Q cycle requires 2 QH2 molecules to get oxidized by complex III with one of the two being reformed by reduction to give a net oxidation of 1QH2 molecule CYtocho
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