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BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A; Krebs cycle; electron transport chains and chemiosmotic phosphorylation mechanism: [email protected] FAD NAD+ FADH2 NADH BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A Pyruvate and acetyl CoA are important metabolites at the intersection of many carbonmetabolising pathways. BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A Pyruvate and acetyl CoA are important metabolites at the intersection of many carbonmetabolising pathways. Metabolic relationship between carbohydrate and fat catabolism Pyruvate Carboxylase Pyruvate Dehydrogenase Complex Some amino acids The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 1. Glycolysis by either the EMP pathway, or variants such as PPP/HMP. BC21D: Bioenergetics & Metabolism Recall that PK is an important regulatory enzyme in some cells. The formation of Acetyl Coenzyme A The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 2. Aerobic oxidation of lactate, e.g. by heart or liver isoenzymes of Lactate dh. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 3. Oxidative deamination of alanine, e.g. by liver after release from skeletal muscle during fasting. BC21D: Bioenergetics & Metabolism Lets us now look at pyruvate dehydrogenase The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism pdh reaction mechanism E1 = Pyruvate dehydrogenase E2 = Dihydrolipoyl transacetylase E3 = Dihydrolipoyl dehydrogenase The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A Pdh is regulated by reversible, inhibitory phosphorylation of E1. BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A Pdh is regulated by 4 reversible, inhibitory kinases of E1. The kinases have differing tissue specificities. The kinases are activated by increasing the ratios of: [NADH]/[NAD]; [acetyl CoA]/[CoA]; [ATP]/[ADP] The kinases are inhibited by pyruvate. Insulin stimulates dephosphorylyation. Regulation of the Pyruvate Dehydrogenase Complex Pyruvate dehydrogenase phosphatase “Pyruvate dehydrogenase kinase”, actually…. Pyruvate dehydrogenase complex Phosphorylation sites on Pdh subunit E1 Pyruvate dehydrogenase kinases 1 – 4, with different tissue specificities The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Apart from carbohydrates, carbons from other molecules can form acetyl CoA. CHO BC21D: Bioenergetics & Metabolism Parts of leucine isoleucine tryptophan are degraded to acetyl CoA The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A Lets us now look at fatty acid degradation BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A The formation of Acetyl Coenzyme A BC21D: 3Bioenergetics & Metabolism Figure Modulation of CPT I activity by carbohydrates The pathway shown in red is the established pathway for the inhibition of hepatic CPT activity by carbohydrates. The other pathways shown are alternative routes that may be operative in heart Abbreviations : CPT, carnitine palmitoyl transferase ; CAT, carnitine acetyl transferase. BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A Just to remind you where we are going with this! The major metabolic role of the Krebs cycle in most aerobes is the oxidative degradation of acetate to two molecules of CO2 and some high energy reducing equivalents. BC21D: Bioenergetics & Metabolism The Krebs cycle BC21D: Bioenergetics & Metabolism This is control point in some bacteria: the Krebs cycle is not partitioned from the cytosol. ATP is a negative modulator, raising the enzyme’s Km value for acetyl CoA Citrate synthase BC21D: Bioenergetics & Metabolism Aconitase Aconitase contains an iron-sulphur centre Aconitate is not normally released from the enzyme Aconitase BC21D: Bioenergetics & Metabolism This is one of the control points of the Krebs cycle. It is an allosteric enzyme: ADP is the positive modulator enhancing the binding of isocitrate and NAD+. NADH is a competitive inhibitor of NAD+ binding. ATP also inhibits. Isocitrate dehydrogenase NAD+ NADH + H+ BC21D: Bioenergetics & Metabolism Another control point of the Krebs cycle NAD+ α-ketoglutarate dehydrogenase complex NADH + H+ BC21D: Bioenergetics & Metabolism (a) animal α-KG dh is very sensitive to ADP, Pi, and Ca2+; (b) these positive effectors increase the affinity of α-KG dh to α -ketoglutarate; (c) α-KG dh is inhibited by ATP, NADH, and succinyl-CoA; (d) the ATP effect is realized mainly via opposition to ADP activation; (e) NADH, in addition to inhibiting the dihydrolipoamide dehydrogenase component of the enzyme complex (competitively versus NAD+), decreases the affinity of α -ketoglutarate dehydrogenase to its substrate; (f) bacterial and plant α-KG dh are activated by AMP instead of ADP. These main effects form the basis of short term regulation of α-KG dh. BC21D: Bioenergetics & Metabolism Succinate thiokinase GTP GDP + Pi BC21D: Bioenergetics & Metabolism FADH2 Succinate dehydrogenase complex BC21D: Bioenergetics & Metabolism NADH + H+ Malate dehydrogenase BC21D: Bioenergetics & Metabolism Amino acids can feed their carbons into the Krebs cycle for gluconeogenesis. Recall when and in which cells this occurs. BC21D: Bioenergetics & Metabolism Amino acids with direct linkages to the Krebs cycle are especially important. BC21D: Bioenergetics & Metabolism Possible metabolic outputs from the Krebs cycle From Nelson & Cox BC21D: Bioenergetics & Metabolism From Stryer BC21D: Bioenergetics & Metabolism Anaerobes lacking α-KG dh therefore have an incomplete Krebs cycle. BC21D: Bioenergetics & Metabolism Some plants, invertebrates and fungi have the glyoxylate cycle for converting two acetates into succinate, thus are able to use fatty acids for gluconeogenesis. BC21D: Bioenergetics & Metabolism BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics Collecting light energy from the solar (or an artificial) source is a major alternative to carbon catabolism. BC21D: Bioenergetics & Metabolism electron transport & bioenergetics Recall this image from last year. It highlights the similarities between different energy metabolisms. BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics Diagram from Lodish et al BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism electron transport & bioenergetics BC21D: Bioenergetics & Metabolism chemiosmotic mechanism The generation of a proton motive force across a biomembrane is a common bioenergetic mechanism. 78 BC21D: Bioenergetics & Metabolism chemiosmotic mechanism Proton gradients are used to drive a number of energy consuming reactions. 79 BC21D: Bioenergetics & Metabolism chemiosmotic mechanism 80 BC21D: Bioenergetics & Metabolism chemiosmotic mechanism 81 BC21D: Bioenergetics & Metabolism chemiosmotic mechanism 82 83 84 85 86 87