BMS100_BCH1.05_W23_Glycolysis and gluconeogenesis student.pdf

Introduction to Gluconeogenesis • Gluconeogenesis is the synthesis of glucose de novo from non carbohydrate precursors • Gluconeogenesis occurs in the liver and kidney § Provides a source of glucose for other tissues in the body • Particularly important during times of fasting Glycolysis review –...

Introduction to Gluconeogenesis • Gluconeogenesis is the synthesis of glucose de novo from non carbohydrate precursors • Gluconeogenesis occurs in the liver and kidney § Provides a source of glucose for other tissues in the body • Particularly important during times of fasting Glycolysis review – Thinking question • Is Gluconeogenesis simply a reversal of Glycolysis? Why or why not? Gluconeogenesis overview Glycolysis Gluconeogenesis Gluconeogenesis pathway: 1 Glycolysis Gluconeogenesis Gluconeogenesis – Reaction 1a • By-pass reaction 1: § A) Enzyme: Pyruvate carboxylase • Biotin is coenzyme, helps add a CO2 (carboxylation) Biotin Gluconeogenesis – Reaction 1b • By-pass reaction 1: § B) Enzyme: Phosphoenolpyruvate carboxykinase Gluconeogenesis pathway: 3à7 Glycolysis Gluconeogenesis Glucogeneogenesis – Reactions 2 à 7 • Phosphoenolpyruvate is a glycolytic intermediate and can continue through the reversible reactions of glycolysis 4 3 2 Glucogeneogenesis – Reaction 2 à 7 • Reversible reactions continue until we reach Fructose 1,6bisphosphate 7 6 5 Gluconeogenesis pathway: 8 à 10 Glycolysis Gluconeogenesis Gluconeogenesis – Reaction 9 • Bypass reaction 2 § Enzyme: Fructose 1,6-bisphosphatase *Note: no ATP is generated Gluconeogenesis – Reaction 10 • Enzyme: phosphoglucose isomerase § Reversal of glycolysis Gluconeogenesis – Reaction 10 • Bypass reaction 3 § Enzyme: Glucose-6 Phosphatase *Note: no ATP is generated Gluconeogenesis: Bypass reactions Bypass 3 Glycolysis Gluconeogenesis Bypass 2 Bypass 1 Substrates for gluconeogenesis • Remember gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors. § Let’s consider some of the precursors: • Lactate • Glycerol • Glucogenic amino acids § Alanine Substrates - Lactate • Lactate is a product of anaerobic glycolysis § Review: How does conversion of pyruvate to lactate under anaerobic conditions support glycolysis? § In addition: Lactate travels from tissues to the liver via the blood. • Once in the liver it is converted back to pyruvate and used to build glucose via gluconeogenesis § Cori Cycle Lactate dehydrogenase Substrates – Lactate – Cori Cycle Liver Muscle Glucose Glucose Glycolysis Gluconeogenesis 2 NADH 2 NAD+ 6 ATP Blood 2 ATP 2 pyruvate 2 NADH Glucose 2 pyruvate LDH 2 lactate 2 NAD+ LDH 2 lactate 2 lactate Gluconeogenesis: Lactate substrate Glycolysis Gluconeogenesis Lactate Substrate - Glycerol • Glycerol can enter gluconeogenesis pathway by being converted to DHAP. § Where might the body get glycerol? Glycerol kinase Glycerol-3-phosphate dehydrogenase Gluconeogenesis: Glycerol substrate Glycolysis Glycerol Gluconeogenesis Substrate – Glucogenic amino acids • Amino acids that can serve as a substrate for gluconeogenesis are called glucogenic amino acids • All amino acids except leucine and lysine are glucogenic § These glucogenic amino acids can either be converted directly into pyruvate or into a citric acid cycle intermediate • TCA cycle intermediates are eventually converted into oxaloacetate to serve as substrate for gluconeogenesis § Glucogenic amino acids that are particularly important are alanine and glutamine. Glucogenic amino acids Glucose Substrate – Alanine • Alanine can be converted to pyruvate • Enzyme: Alanine Transaminase (ALT) § Transamination reaction (transfer of an amino group) • Requires pyridoxal phosphate (PLP) as coenzyme § PLP is derived from B6 PLP Substrate - Alanine • Transamination involves transferring an amino group from an amino acid to an alpha ketoacid NH2 and O switch places Alanine (amino acid) Alpha ketoglutarate (ketoacid) Pyruvate (amino acid) Glutamate (ketoacid) Glucogenic amino acids Glucose Gluconeogenesis: Alanine substrate Glycolysis Gluconeogenesis Alanine Substrates: summary Glycolysis Gluconeogenesis Glycerol Alanine Lactate Shuttle systems • Gluconeogenesis begins in the mitochondria: § Alanine is converted to pyruvate inside the mitochondria § Lactate is converted to pyruvate in the cytosol and pyruvate is immediately shuttled into the mitochondria § Once inside the mitochondria, pyruvate is converted to oxaloacetate • What does that tell us about the cellular location of pyruvate carboxylase? • However, oxaloacetate cannot cross the inner mitochondrial membrane to get back into the cytosol to feed into gluconeogenesis. • Requires shuttle systems • Shuttle systems are slightly different based on the substrate 1. Malate shuttle • Also called malate-aspartate shuttle • Used when the starting substrate is alanine (or any other glucogenic amino acid) • Malate shuttle: § Oxaloacetate is converted to malate § Malate crosses the inner mitochondrial membrane (with the help of an antiporter) 1. Malate shuttle continued • Malate shuttle continued § Once in the cytosol malate is converted back to oxaloacetate § Oxaloacetate be converted to phosphoenolpyruvate to continue gluconeogenesis 2. Shuttle for lactate substrate • Lactate is converted to pyruvate in the cytosol • Pyruvate enters the mitochondria & is converted to oxaloacetate • Oxaloacetate is converted to phosphoenolpyruvate (PEP) § Phosphoenolpyruvate is shuttled out of the mitochondria to continue with gluconeogenesis