Gluconeogenesis - Lecture Notes PDF

Gluconeogenesis Pathway for the synthesis of glucose from noncarbohydrate precursors Occurs when blood glucose levels drop Liver is the primary site of gluconeogenesis (kidney may produce glucose for self under extreme starvation) Glycolysis vs. Gluconeogenesis The gluconeogeni...

Gluconeogenesis Pathway for the synthesis of glucose from noncarbohydrate precursors Occurs when blood glucose levels drop Liver is the primary site of gluconeogenesis (kidney may produce glucose for self under extreme starvation) Glycolysis vs. Gluconeogenesis The gluconeogenic pathway is almost the reverse of glycolysis Glucose =>=> Pyruvate vs Pyruvate =>=> Glucose Also, the intermediates are the same Glycolysis vs. Gluconeogenesis 4 reaction steps shown in blue are -*- different: pyruvate carboxylase, PEP carboxykinase, fructose -*- bisphosphatase, glucose 6- phosphatase The unique enzymes allow control of the pathways (i.e. one pathway is inhibited while the other is activated) *Pyruvate carboxylase catalyzes an anaplerotic reaction previously discussed -*- *Glycerol (from TAG), lactate, and amino acids can also serve as a -*- precursors Sources of Blood Glucose In fed state, most glucose comes from the gut In fasting state glucose comes from the liver via glycogen breakdown and gluconeogenesis In the starved state most glucose comes from the liver via gluconeogenesis (all glycogen has been depleted) *glycerol, amino acids and lactate are precursors for gluconeogenesis Key Reactions of Gluconeogenesis Pyruvate carboxylase (pyruvate->oxaloacetate) Phosphophoenolpyruvate carboxykinase (oxaloacetate->phosphophenolpyruvate, a glycolytic intermediate) Phosphophenolpyruvate->F1,6-P via glycolytic enzymes Fructose 1,6-Bisphosphatase (F16P->F6P) F6P -> G6P via glycolytic enzymes Glucose 6-phosphatase (G6P->G)  Gluconeogenesis Precursors 1. Pyruvate from lactate via lactate dehydrogenase 2. Pyruvate from alanine via alanine aminotransferase 3. Dihydroxyacetone phosphate from glycerol (glycerol kinase followed by glycerol 3-phosphate dehydrogenase) *glycerol from TAG in adipose tissues  Alcohol Metabolism Ethanol metabolized to acetaldehyde and acetate These reactions produce NADH (leading to low NAD+) The gluconeogenesis precursors also generate NADH, but are inhibited by high levels of NADH =>alcohol consumption decreases gluconeogenesis The Pyruvate to Phosphoenolpyruvate Reaction 1. Pyruvate formed in the cytoplasm and transferred to the mitochondrial matrix 2. Pyruvate carboxylase (pyruvate->OAA, costs energy) 3. OAA converted to either malate or aspartate, shuttled back to cytoplasm, and then converted back to OAA 4. phosphoenolpyruvate carboxykinase forms PEP, which then goes onto to form glucose The Pyruvate to Oxaloacetate Reaction Catalyzed by pyruvate carboxylase Adds CO2 at the expense of ATP Biotin coenzyme (common theme) Product may enter TCA cycle or gluconeogenesis Generation of PEP From Gluconeogenic Precursors OAA to PEP catalyzed by Phosphoenolpyruvate carboxykinase Problem: OAA in mitochondria Solution: Use aspartate and malate intermediates to transfer to the cytoplasm (via the aspartate and malate shuttles) Formation of Glucose: Final Steps PEP forms glyceraldehyde 3-P (via glycolytic enzymes) glyceraldehyde 3-P + DHP -> F16P (via glycolytic enzyme) Phosphofructokinase 1 (from glycolysis) essentially irreversible so new enzyme required: fructose 1,6- bisphosphatase F6P->G6P via glycolytic enzyme Glucokinase (from glycolysis) also irreversible so another new enzyme required: glucose 6- phosphatase  Key Enzymes * Glucokinase vs glucose 6- phosphatase (high Km of glucokinase reduces amount of back reaction) * PFK-1 vs F16P (activated/inhibited by F26P) PK vs PC and PEPK *3 of the 4 enzymes of gluconeogenesis are induced (i.e. concentrations raised) *  Glucokinase vs Hexokinase High Km of glucokinase in liver vs hexokinase in other tissues reduces G->G6P rxn (i.e. glucose not broken down unless there are high concentrations in blood)  Regulation of Key Enzymes * * * * * * Key glycolytic enzymes induced by insulin (fed state) and inhibited by ATP Key gluconeogenic enzymes induced by fasting & glucagon, inhibited by insulin *induction = expression  Glucose, Insulin & Glucagon Concentrations Glucose Meal: glucose spikes and then goes down to set point, insulin goes up, glucagon goes down => glycogen storage, gluconeogenesis inhibited Protein Meal: glucose remains at set point, insulin changes very little, glucagon rises =>glycogen breakdown and gluconeogenesis activated  Tissue Dependent Glucose Metabolism: Effects of Insulin Liver: insulin stimulates formation of fuel stores (glycogen and FA) and inhibits glycogen breakdown Muscle: insulin stimulates glucose uptake and storage as glycogen Adipose: insulin stimulates uptake of glucose and FA and formation of FA and TAG (note the connections with glycolysis)  The Fasting State & Gluconeogenesis AAs from muscle, lactate from RBCs, and glycerol from adipose go to liver to form glucose Newly formed glucose exported to brain and RBC  Blood Fuels & Fasting =>glucose levels remain the same after 30 days of fasting due to gluconeogenesis in the liver  Sources of Glucose =>Transition between dietary glucose, glycogen stores, and glucose synthesis