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BIOC/DENT/PHCY 230 LECTURE 11 How long will glucose reserves last? glucose requirements: 160g/day whole body (120g/day brain) glucose reserves: 190g glycogen 20g in body fluids need to synthesise glucose during prolonged periods of fasting Gluconeogenesis synthesis of glucose from a variety of non-carbohydrate metabolites lactate, glycerol and the carbon skeletons of certain amino acids can all be used as substrates (propionyl-CoA can also be used) most of the reactions of gluconeogenesis are simply the reverse of the corresponding steps in glycolysis hexokinase phosphofructokinase (PFK) however those reactions which represent irreversible steps in glycolysis need to be by-passed pyruvate kinase By-passing pyruvate kinase Converting pyruvate back to phosphoenolpyruvate (PEP) is a two step process Reaction 1: pyruvate + CO2 + H2O + ATP oxaloacetate + ADP + Pi + 2H+ catalysed by pyruvate carboxylase mitochondrial reaction oxaloacetate transported out of mitochondria as malate allosterically activated by acetyl-CoA there is no mitochondrial transporter for oxaloacetate oxaloacetate is converted to malate which can be transported out of the mitochondria the reverse reaction occurs in the cytoplasm Reaction 2: oxaloacetate + GTP PEP + CO2 + GDP DG’ = -25kJ/mol for the combined reactions catalysed by phosphoenolpyruvate carboxykinase (PEPCK) synthesis of PEPCK is stimulated by glucagon By-passing phosphofructokinase fructose-1,6-bisphosphate + H2O fructose-6-P + Pi DG0’ = -16.3kJ/mol catalysed by fructose-1,6-bisphosphatase allosterically inhibited by fructose-2,6-BP and AMP PFK-1 PFK-2 P [F-2,6-BP] increases as [F-6-P] increases Glucose - hexokinase Glucose-6-P Fructose-6-P Fructose-2,6-BP + PFK Fructose-1,6-BP By-passing glucokinase Glucose-6-phosphate + H2O glucose + Pi DG0’ = -12.1kJ/mol catalysed by glucose-6-phosphatase most tissues lack this enzyme primarily expressed in liver allows liver to release glucose into the bloodstream A comparison of energy input and output from glycolysis and gluconeogenesis Whilst the DG’ for both glycolysis and gluconeogenesis is negative, gluconeogenesis is a net consumer of energy Entry points into gluconeogensis glycerol amino acids lactate lactate amino acids glycerol TAG DHAP NAD+ DAG G-3-P DHase glycerol-3-phosphate glycerol kinase glycerol Ketone Bodies ketone bodies are synthesised from acetyl-CoA they represent a means of using the energy available in fatty acids for tissues that may not be able to use fatty acids themselves particularly important for the brain, as water soluble ketone bodies can cross the blood-brain barrier help supplement the energy requirements of brain, which may not be met solely by glucose during prolonged fasting Ketone Bodies Synthesis of ketone bodies occurs primarily in liver mitochondria Degradation of ketone bodies in mitochondria of target tissues Ketoacidosis What do I need to study for the final exam? You do not: need to memorise pathways need to memorise structures need to learn the names of all the intermediates and enzymes involved in the various pathways need to understand the regulation mechanism for glycogen phosphorylase know which specific amino acids are glucogenic and which are ketogenic You do not: need know equations for whole pathways reaction mechanisms You do need to know: the logic of pathways eg. Why does flux through glycolysis decrease in the presence of oxygen? What is the significance of the LDH isozymes and the reactions they catalyse? Why is b-oxidation a cyclic series of reactions? how pathways are regulated and linked eg. What are the regulatory steps of pathways? What are the key enzymes and how are they regulated? Is the pathway regulated by substrate supply or subcellular location? Is there hormonal regulation of the pathway? Are the products of one pathway used in another? how is metabolism integrated between tissues eg. How are muscle and liver metabolism linked? How are liver and brain metabolism linked? What effect does any given hormone have on various tissues? be able to describe the metabolism of the fed and fasted state How are these states regulated by hormones? What are the features of fuel synthesis and degradation that characterise each state? How do tissues co-operate in these states? How are pathways that carry out opposite sets of reactions reciprocally regulated? LOGIC/INTEGRATION/REGULATION