HUN3324 Exam II Rafaela Feresin Spring 2012 TCA Cycle Other names Krebs cycle Citric Acid cycle Occurs in MITOCHONDRIA Represents a common metabolic pathway Acetyl CoA is common molecule linking all of these pathways i e proteins lipids and CHO are ultimately converted to Acetyl CoA before TCA Cycle Main purpose TCA cycle oxidization of 2 carbons regeneration of oxaloacetate Most molecules in this cycle are gluconeogenic except Acetyl CoA ketogenic Reactions enzymes in red 1 Oxaloacetate Acetyl CoA Citrate Coenzyme A CoASH via Citrate Synthetase a Coenzyme A CoASH is being released in this step b Citrate synthetase produces citrate 2 Citrate cis aconitate isocitrate via aconitase a Citrate to cis aconitate releases H2O b Cis aconitate to isocitrate uses H2O c Reason why citrate is converted to cis aconitate first remember CoASH was released has 2 carbons Aconitase binding to Citrate causes asymmetrical shape this is so that the carbons released are not the ones from Acetyl Aconitase also catalyzes the dehydration rehydration occurring in this step Acetyl without CoASH 3 Isocitrate ketoglutarate via isocitrate dehydrogenase a Causes oxidative decarboxylation b Oxidation NAD NADH H 2H s from isocitrate to form NADH H c Decarboxylation CO2 formed and released 4 ketoglutarate Succinyl CoA via ketoglutarate dehydrogenase HUN3324 Exam II Rafaela Feresin Spring 2012 a Note oxidative decarboxylation of keto acid b The CoASH Coenzyme A released in the first reaction is used in this reaction c CO2 released NAD NADH H formed d ketoglutarate dehydrogenase is an enzyme complex requires the same cofactors as PDH complex TPP FAD e Succinyl CoA high energy bond 5 Succinyl CoA Succinate via succinic thiokinase a Note substrate level phosphorylation because of high energy bond b 1ATP because GTP is basically the same concept c CoASH is once again released d Link between TCA cycle gluconeogenesis converted to PEP step in gluconeogenesis this GTP is used for oxaloacetate 6 Succinate Fumarate via succinate dehydrogenase a FAD FADH2 2H s from succinate to FAD to form FADH2 7 Fumarate Malate via fumarase a Hydration reaction H2O used 8 Malate Oxaloacetate via malate dehydrogenase a NAD NADH H 2H s from malate to NAD to form NADH H b Cycle may now repeat itself Fumarate Malate Oxaloacetate reaction favors malate when too much oxaloacetate is present but oxaloacetate keeps being used so cycle continues fasting low carb diet low oxaloacetate Energetics for TCA cycle HUN3324 Exam II Rafaela Feresin Spring 2012 For each GTP 1 ATP For each NADH H 3 ATP For each FADH2 2 ATP Only one ATP is actually formed within TCA cycle GTP but once transferred to Electron Transport Chain all NADH H and FADH2 become ATP s resulting in 12 overall Beginning with Acetyl CoA 12 ATP s formed above calculations But beginning with pyruvate 15 ATP s formed Pyruvate forms an extra NADH H in the step of pyruvate Acetyl CoA via pyruvate dehydrogenase resulting in 3 extra ATP s TOTAL ENERGY PRODUCTION FROM 1 MOLECULE OF GLUCOSE UNDER AEROBIC CONDITIONS Glycolysis Krebs ATP NADH FADH GTP Total 2 4 6 2 2 Total 10 x3 2 x2 2 2 ATP 2 30 4 2 38 NADH and FADH multiplied by 3 and 2 in total column because NADH yields 3ATP and FADH yields 2ATP once converted to ETC chain When under aerobic conditions 2 pyruvate 2 acetyl CoA so TCA cycle happens twice which is why 6 NADH 2 FADH and 2 GTP are being formed The shuttle systems Malate Shuttle Moves NADH into Mitochondria ETC Active in liver kidney heart 38 ATP s formed because we re using NADH Glycerol 3 PO4 shuttle HUN3324 Exam II Rafaela Feresin Spring 2012 NADH FADH enters thru complex II of ETC chain FADH only yields 2 ATP so 36 ATP s formed overall Active in muscle and brain Intermediates for other uses Citrate Fatty Acids ketoglutarate glutamate Succinyl CoA Heme Oxaloacetate Aspartate Pyrimidines Oxaloacetate Glucose Rate Limiting Enzymes for TCA cycle Citrate synthase synthetase and synthase is same thing Isocitrate dehydrogenase ketoglutarate dehydrogenase remember works as complex Regulation of TCA cycle Based on availability of substrate o Low Oxaloacetate levels inhibit citrate synthase in fasting low CHO situations o This will increase Acetyl CoA leading to increase in ketone bodies acetone breath Increase NADH H inhibits dehydrogenases Increase in citrate inhibits citrate synthase Increase in ATP inhibits citrate synthase isocitrate dehydrogenase Increase in Succinyl CoA inhibits ketoglutarate dehydrogenase and citrate synthase Electron Transport Chain Purpose capture energy in form of ATP by coupling 2 processes of oxidation phosphorylation Occurs in MITOCHONDRIA Oxidation loss of electrons or hydrogen NADH2 NAD 2H s released Phosphorylation addition of phosphorous ADP ATP 1P added to ADP to form ATP Proton gradient must maintain higher concentration of protons in outer mitochondrial space particles will diffuse from area of higher conc to area of lower conc Components of ETC Complexes that remove electrons from coenzymes located in inner mitochondrial space and or pump protons into outer mitochondrial space Complex 1 NADH dehydrogenase complex Complex 2 Cytochrome B C complex Complex 3 Cytochrome oxidase complex Electron transporters transport electrons between complexes in the electron transport chain Ubiquinone complex II or Coenzyme Q o Transports electrons between complex I and complex III Cytochrome C o Transports electrons between complex III and IV HUN3324 Exam II Rafaela Feresin Spring 2012 OVERALL Complex I II contain coenzyme Q Complex I contains NADH dehydrogenase Accepts H s from NADH only H s transferred to Coenzyme Q Complex II contains succinate dehydrogenase Only accepts H s from FADH2 H s transferred to Coenzyme Q Coenzyme Q gets H s from complex I and II and brings to complex III Cytochrome C will accept H s and transfer them to complex IV o Cytochrome C is part of complex III but it is also mobile and will move around transferring H s Coenzyme Q is mobile as well Complex III for every NADH 4 H s will be released to inner membrane space Only 2 H s are pumped out in complex IV because 2 H s are used to convert O2 to H2O So 10 H s overall are pumped creating proton gradient pH changed voltage changed free energy formed in inner membrane space HUN3324 Exam II Rafaela Feresin Spring 2012 This energy can be used to pump protons back into inner membrane space creating gradient translocation of H s back into matrix by complex IV F0 portion As protons flow back into
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