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BIOCHEMISTRY Electron Transport Chain/ Oxidative Phosphorylation BIOB111 CHEMISTRY & BIOCHEMISTRY Session 22 Session Plan • Electron Transport Chain • Oxidative Phosphorylation • Hormonal Control of Carbohydrate Metabolism The Electron Transport Chain (ETC) • Coenzymes NADH & FADH2 are oxidized in this process. • Finally water is formed when e- & H interact with molecular O2. O2 + 4e- + 4 H+ → 2H2O ETC • The enzymes & electron carriers of the ETC are located within the inner mitochondrial membrane (IMM) as 4 distinct protein complexes, tightly bound to the IMM. • Complex I: NADH-Coenzyme Q Reductase • Complex II: Succinate-Coenzyme Q Reductase • Complex III: Coenzyme Q-Cytochrome c Reductase • Complex IV: Cytochrome c Oxidase • There are 2 mobile electron carriers – Coenzyme Q & Cytochrome c – that shuttle electrons between the complexes & are not tightly bound to the IMM. The Electron Transport Chain (ETC) • A series of biochemical reactions, in which e- & H+ from NADH & FADH2 (produced in the CAC) are passed to intermediate carriers & are finally accepted by molecular O2 to produce H2O. • Transfer of e- – Redox reactions. Stoker 2014, p871 Complex I • NADH from CAC is the source of e- for this complex. • It contains >40 subunits, including Flavin Mononucleotide (FMN) & several Iron-Sulfur Proteins (FeSP). • Facilitates transfer of e- from NADH to Coenzyme Q – several steps & several intermediate carriers are involved. Complex I • The 1st step involves e- transfer from NADH to FMN. • The NADH is oxidized to NAD+ (returns back to the CAC) & passes 2H+ & 2e- to FMN, which is reduced to FMNH2. Complex I • NADH supplies both e- & one of the H+ ions (the other H+ comes from the cellular solution) • FMN accepts 2 H+ & 2 e- Complex I • The next steps involve transfer of electrons from reduced FMNH2 through series of FeSPs. • 2 molecules of FeSP are needed to accept the 2e- (1e- each). • Fe3+ + e- Fe2+ Complex I • The final Complex I reaction involves conversion of reduced 2Fe(II)SP to oxidized 2Fe(III)SP, as the 2 e- are passed to the mobile CoQ which becomes reduced to CoQH2. Coenzyme Q • A mobile e- carrier • A Quinone derivative Complex II • Is much smaller than Complex I. • Contains only 4 subunits, including 2 FeSPs. • Processes FADH2 from the CAC • Succinate is converted to Fumarate by this complex, while reduced FADH2 is oxidized to FAD (returns back to the CAC). • CoQ is the final recipient of the efrom FADH2. CoQH2 carries e- from both, Complexes I & II to Complex III. Stoker 2014, Figure 23-15 p869 NADH is the substrate for Complex I & FADH is the substrate for Complex II. CoQH2 is the common product from both e- transfer processes. Stoker 2014, Figure 23-13b p868 Complex III • Contains 11 different subunits. • The e- carriers in this complex include several FeSPs & Cytochromes. • Cytochromes • Haeme-containing proteins, in which reversible oxidation & reduction of an Fe atom occurs (similarly to FeSP). • Various cytochromes – cyt a, cyt b, cyt c – differ by: – Their protein constituents – The manner in which the haeme is bonded to the protein – Attachments to the haeme ring Haeme Stoker 2014, p869 Complex III • The initial substrate for Complex III is CoQH2 carrying e- from Complex I (from NADH) & Complex II (from FADH2). • The electron transfer proceeds form CoQH2 → FeSP → cyt b → another FeSP → cyt c1 → cyt c – another mobile carrier. Stoker 2014, p870 Complex III • The flow of e- through Complex III. • The 2H+ from oxidation of CoQH2 go into cellular solution. • All other redox reactions involve only electrons. Stoker 2014, Figure 23-16 p870 Complex IV • Contains 13 subunits, including 2 cytochromes – cyt a & cyt a3. • The e- flow from cyt c to cyt a to cyt a3. • In the final step of electron transfer, the e- from cyt a3 & H+ from cellular solution combine with O2 to form H2O. O2 + 4e- + 4 H+ → 2H2O • It is estimated that 95 % of the O2 used by cells serves as the final e- acceptor in the ETC. Complex IV • Each of the cyt a & cyt a3 also contain a Cu atom, in addition to their Fe atoms. Stoker 2014, Figure 23-17 p870 Summary of the Flow of Electrons Through the 4 Complexes of the ETC Stoker 2014, p871 Oxidative Phosphorylation (OP) • The process by which ATP is synthesized from ADP & Pi, using the energy released in the ETC. • The central concept to OP involves coupled reactions. • Coupled reactions – are pairs of concurrently occurring biochemical reactions, in which energy released by one reaction is used in another reaction. • The OP & the oxidation reactions of ETC are coupled systems. • The interdependence (coupling) of ATP synthesis & the ETC is related to the movement of H+ across the IMM. • Besides of e- transport, Complexes I, III & IV of the ETC have a 2nd function as “proton pumps” transferring H+ from the mitochondrial matrix into the intermembrane space. Complexes I,III & IV also function as “proton pumps”. For every 2e- passed through the ETC, 10 H+ are transferred from the matrix into intermembrane space. Stoker 2014, Figure 23-18 p873 Oxidative Phosphorylation • For every 2e- passed through the ETC, 4H+ cross the IMM through Complex I, 4H+ through Complex III & 2H+ through Complex IV – causes build-up of H+ in the intermembrane space. • Increased [H+] in intermembrane space & decreased [H+] in the matrix create a difference in [H+] forming a Electrochemical (Proton) Gradient. • Chemical gradient – difference in [H+] • Electrical gradient – H+ has an electrical charge Oxidative Phosphorylation • H+ tend to flow from high [H+] to low [H+], however the IMM is not permeable for H+. • They pass through an enzyme complex – ATP-synthase within the IMM & provide energy for ATP synthesis. • The ATP-synthase complexes are the coupling factors that link the ETC & OP. • ATP-synthase has 2 subunits: • F0 = channel for H+ flow • F1 = ATP synthesis Regulation of the ETC / OP • The ETC is: • Down-regulated by low levels of ADP, Pi, O2 & NADH. • Up-regulated by high levels of ADP. • Uncoupling agents • Allows the ETC to take place but the energy that would usually be used for ATP synthesis is released as heat. • Thyroxine – thyroid hormone • Thermogenin – a protein found in brown adipose tissue of newborn mammals & hibernating mammals. Stoker 2014, Figure 23-19 p874 ATP Production • 1 mole of NADH form the CAC produces 2.5 ATP in the ETC/OP • 1 mole of FADH2 from the CAC produces 1.5 ATP in the ETC/OP • 1 mole of GTP is an equivalent to 1 mole of ATP The total energy yield in the CMP. For every Acetyl CoA entering the CMP 10 ATPs are produced. Importance of ATP • The constant conversion between ATP & ADP in metabolic processes is the primary medium for energy exchange in biochemical processes. • Powers life processes – biosynthesis of essential compounds, muscle contraction, nutrient transport, etc. • Occurs in food catabolism & regenerates ATP. The interconversion of ATP & ADP is the principal medium for energy exchange in biochemical processes Stoker 2013, Figure 23-19 p877 The relationships among 4 metabolic pathways that involve glucose Stoker 2014, Figure 24-16 p910 Glucose Metabolism Stoker 2014, p912 Hormonal Control of Carbohydrate Metabolism • • • • • • • • INSULIN Produced by β-cells of pancreas 51 amino acid polypeptide Promotes utilization of glucose by cells Its function is to lower blood glucose levels Also involved in lipid metabolism The release of insulin is triggered by high blood-glucose levels The mechanism for insulin action involves insulin binding to protein receptors on the outer surfaces of cells which facilitates the entry of glucose into the cells • Insulin also increases the rate of glycogenesis Hormonal Control of Carbohydrate Metabolism • • • • • GLUCAGON 29 amino acid peptide hormone Produced by the α-cells of pancreas Released when blood glucose levels are low Principal function is to increase blood glucose concentration by speeding up Glycogenolysis & Gluconeogenesis in the liver • Glucagon elicits the opposite effects of insulin Hormonal Control of Carbohydrate Metabolism • ADRENALIN • Also called epinephrine (US) • Released by the adrenal glands in response to anger, fear or excitement • Function is similar to glucagon – stimulates Glycogenolysis • Primary target are muscle cells – promotes energy generation for quick action • It also functions in lipid metabolism B vitamins & Carbohydrate Metabolism • Many B vitamins function as coenzymes in carbohydrate metabolism – without these the body would be unable to utilize carbohydrates as an energy source. • • • • • • • 6 B vitamins in carbohydrate metabolism: Thiamin – as TPP Riboflavin – as FAD, FADH2 & FMN Niacin – as NAD+ & NADH Pantothenic acid – as CoA Pyridoxine – as PLP (pyridoxal 5-phosphate) Biotin Stoker 2014, Figure 24-19 p916 Readings & Resources • • • • • • • • Stoker, HS 2014, General, Organic and Biological Chemistry, 7th edn, Brooks/Cole, Cengage Learning, Belmont, CA. Stoker, HS 2004, General, Organic and Biological Chemistry, 3rd edn, Houghton Mifflin, Boston, MA. Timberlake, KC 2014, General, organic, and biological chemistry: structures of life, 4th edn, Pearson, Boston, MA. Alberts, B, Johnson, A, Lewis, J, Raff, M, Roberts, K & Walter P 2008, Molecular biology of the cell, 5th edn, Garland Science, New York. Berg, JM, Tymoczko, JL & Stryer, L 2012, Biochemistry, 7th edn, W.H. Freeman, New York. Dominiczak, MH 2007, Flesh and bones of metabolism, Elsevier Mosby, Edinburgh. Tortora, GJ & Derrickson, B 2014, Principles of Anatomy and Physiology, 14th edn, John Wiley & Sons, Hoboken, NJ. Tortora, GJ & Grabowski, SR 2003, Principles of Anatomy and Physiology, 10th edn, John Wiley & Sons, New York, NY.