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Citric acid cycle • What are the functions of Citric Acid Cycle? • What are the reactions of Citric Acid Cycle? • How does a mitochondrion look like? 1 The third step of the energy metabolism The third step of the energy metabolism comprises the citric acid cycle and the oxidative phosphorylation. Electrons are transferred from reduced electron carriers to oxygen, and ATP is formed via a proton gradient. The mitochondrion The mitochondrion has two membranes of which the inner one is selective and folded. The degree of folding depends on the energy need of the cell Outer membrane: All molecules with MW<5000 can pass Inner membrane: Selective, contains electron transport chain and ATP-synthase Matrix: Contains the enzymes of citric acid cycle and fatty acid oxidation Outer membrane Matrix Inner membrane 2 The pyruvate dehydrogenase complex catalyses the conversion of pyruvate to acetyl-CoA Pyruvate + CoA + NAD+ Acetyl-CoA + CO2 + NADH +H+ Citric acid cycle An acetyl group is oxidised in the citric acid cycle and the electrons transferred to NAD+ or FAD In Out 1 Acetyl group 2 CO2 3 NAD+ 3 NADH 1 FAD 1 FADH2 1 GDP 1 GTP 3 The citric acid cycle can be drained of intermediaries The second purpose of the tricarboxylic acid cycle is to provide the cell with building blocks for the biosynthesis of e.g. amino acids , heme and fatty acids. A consequence is that a lack of intermediaries can impair the oxidative function. REFILLING Refilling using pyruvate carboxylase Pyruvat + CO2 +ATP Oxaloacetate+ ADP + Pi + H2O Summary: • The tricarboxylic acid cycle takes place in the mitochondrion • The tricarboxylic acid cycle generates reduced electron carriers and GTP • The tricarboxylic acid cycle has two purposes: - Oxidise acetyl-CoA - Provide the cell with building blocks for biosynthesis 4 Oxidative phosphorylation • How are electrons transported from NADH to oxygen? • How is ATP formed? • How are electron transport and ATP formation coupled? • How much ATP is formed when one molecule glucose is oxidised? Principle of oxidative phosphorylation 5 Oxidative phosphorylation (1) Oxidative phosphorylation can be divided into three parts: 1. Electron transport from reduced electron carriers to oxygen 2. Creation of a membrane potential and a pH-gradient 3. Synthesis of ATP These three parts are coupled 6 Oxidative phosphorylation (2) – Electron transport chain Electrons from NADH take the following path: 1. Complex I (Integral membrane protein, transfers protons) 2. CoQ (quinone, transfers electrons between complex I and complex III) 3. Complex III (Integral membrane protein, transfers protons) 4. Cytochrome c (protein, transports electrons between complex III and complex IV) 5 Complex IV (Integral membrane protein 5. protein, transfers protons protons, conveys electrons to oxygen) 6. Oxygen is reduced to water Electrons from FADH2 are delivered to CoQ via complex II (peripheral membrane protein) H+ H+ H+ H+ cyt c C Q CoQ I 2e- III II IV V 2eO2 + 4e- + 4H+ NADH + H+ 2H2O NAD+ FADH2 FAD H+ Oxidative phosphorylation (3) - CoQ CoQ is a quinone, which can take up two electrons. Its hydrophobic side chain makes it comfortable in the inner membrane of the mitochondrion. 7 Oxidative phosphorylation (4) – Prosthetic groups Electron transport by a number of reductions and oxidations NADH NAD C- I (red) CoQ (red) C- I (ox) CoQ(ox) C- III (red) Cyt c (red) C- III (ox) Cyt c (ox) C- IV (red) C- IV (ox) H2O O2 Prosthetic groups in the complexes are reduced and oxidised: Flavin mononucleotide: Heme group: Iron-Sulphur Iron Sulphur clusters: Copper: FMN Fe3+ Fe3+ Cu2+ FMNH2 Fe2+ Fe2+ Cu+ • Prosthetic groups are organised in order to enable electron transfer • Specificity in electron transfer: E.g. NADH can't reduce cytochrome c • All components of the electron transfer diffuse in the membrane Reactive intermediaries in the electron transport chain Reactive oxygen species (ROS) like e.g. the superoxide radical are generated during transport of electrons from NADH and FADH2 to oxygen. They can react with other biomolecules and cause damage (and possibly diseases). We have some protection from some enzymes, which take care of ROS. Superoxide dismutase - . 2O2 + 2H+ O2 + H2O2 Catalase 2 H2O2 H 2 O + O2 8 Uncoupler (1) Electron transport, proton transfer and phosphorylation of ADP are usually coupled processes but they can be uncoupled under certain circumstances. Uncouplers can lead to formation of heat instead of ATP, e.g. hibernating animals and newborn children use an uncoupling protein to lead the protons b k inside back i id the th mitochondrion. it h d i Uncoupler (2) Also low molecular weight substances can act as uncouplers. In the example below, protonated dinitrophenol can diffuse through the membrane thereby ”destroying” the membrane potential. Outside In the membrane O OH NO2 O NO2 + NO2 Inside NO2 H+ + NO2 H+ NO2 Electron transfer driven transport of protons 9 10 11 Summary • Oxidative phosphorylation takes place in the mitochondrial inner membrane • The membrane is an integral part of the mechanism • The electron transport chain brings electrons from NADH and FADH2 to oxygen • A proton gradient is established when electrons passes the chain • ADP is phosphorylated to ATP when the protons return to the mitochondrion • NADH (the electrons) from glycolysis enter the mitochondrion by a shuttle • Uncouplers generate heat Metabolism of Fatty Acids • Oxidation of fatty acids • Ketone bodies and their use • Synthesis S th i off fatty f tt acids id Fatty acids • • • • Phospholipids osp o p ds in membranes e b a es Glycolipids in membranes Fatty acid derivatives as hormones Fuel for the cell, energy store 12 Fat (Triacylglycerol) A triacylglycerol is a glycerol esterified with three fatty acids. The fatty acids can be saturated, mono-unsaturated or poly-unsaturated. Usually they have an even number of carbon atoms (12-20). H H C H C O O O C O C O H C O C H Digestion, mobilization and transport of dietary triacylglycerols 13 Chylomicron Lipase reactions The enzyme lipase catalyses the hydrolysis of two of the fatty acids in the intestine. 14 Uptake of fat in the intestine Fat is first hydrolysed in the intestine and then taken up through the cell wall. The triacylglycerol is then regenerated before its transport as part of a chylomicron (a lipoprotein) to fat cells where it can be stored. Triacylglycerol in fat cells is degraded to fatty acids and glycerol, which can be used in other cells 15 Degradation of fatty acid has three steps: 1. Activation 2. Transport into mitochondrion 3. β-oxidation Activation of the fatty acid consists of esterification to CoA at the expense of ATP O O C O - CoA + R ATP R C S CoA AMP + PP i 2P i Transport of fatty acid into mitochondrion The acyl group is transported into mitochondrion using carnitine. A translocase brings in acylcarnitine and expels carnitine. A l C A iis regenerated Acyl-CoA t d iinside id mitochondrion. Carnitine CH3 H H3C + C C C COO H2 H2 CH3 OH N - Position of the fatty acid 16 β-oxidation 17 How much ATP can be formed by oxidation of fatty acid? It is now possible to calculate the amount of ATP formed during complete oxidation of a fatty acid, e.g. palmitic acid 8 Acetyl-CoA y in the tricarboxylic y acid cycle: y 8 x 3 = 24 NADH 8 x 1 = 8 FADH2 8 x 1 = 8 GTP β-Oxidation yields: 7 NADH 7 FADH2 In total: 7 + 24 = 31 NADH corresponds to 31 x 2,5 = 77,5 ATP 7 + 8 = 15 FADH2 corresponds to 15 x 1,5 = 22,5 ATP 8 GTP corresponds d to t 8 ATP Summarised: 8 + 77,5 + 22,5 = 108 ATP Two ATP are used during the initial activation of the fatty acid The total ATP-yield will be 106 Formation and use of ketone bodies Succinyl CoA Succinate Acetoacetate CoA Acetoacetyl CoA 2 Acetyl-CoA Citric acid cycle Ketone bodies are formed in the liver from surplus of acetylCoA when degradation g of fat dominates and the supply of carbohydrates is limited, as during starvation and fasting. The ketone bodies are exported to other organs where they can be oxidised. 18 Fatty acid synthesis • Fat is an efficient way to store energy • It is usually surplus of carbohydrates that are converted to fat • The reactions are in principle a reversed β-oxidation The synthesis of a fatty acid starts with the carboxylation of acetyl-CoA to malonyl-CoA. This is the committed step, malonyl CoA can only be used for synthesis of fatty acid. O H3C C O O S CoA + ATP + HCO 3 C O Acetyl-CoA C H2 C S Malonyl-CoA O H3C C O O S + ACP C C H2 O Reaction sequence during fatty acid synthesis + ADP + Pi + H+ CoA C S ACP Condensation ACP + CO2 O H3C O C C H2 C S ACP Acetoacetyl-ACP NADPH Reduction NADP+ OH H3C C O C H2 C S ACP D-3-Hydroxybutyryl-ACP H Dehydration H2O H3C C H O C C S ACP Crotonyl-ACP H NADPH Reduction NADP+ O H3C C H2 C H2 C S ACP Butyryl-ACP 19 Summary: • • • • • It is efficient to store energy as fat The fatty acid is bound to albumin during transport to target cells The fatty acid is activated in the cytoplasm The fatty acid is transported into the mitochondrion using carnitine The fatty acid is oxidised by β-oxidation yielding NADH, FADH2 and acetyl-CoA • Ketone bodies are formed when acetyl-CoA is in surplus • Acetyl-CoA (from carbohydrates) is starting material for fatty acid synthesis 20