Gluconeogenesis Lecture Notes PDF

Gluconeogenesis Tue Oct 22, 2024  What is gluconeogenesis? The process of making glucose (gluconeogenesis) from non carbohydrate precursors (gluconeogenesis)  What is it’s function? To make glucose when insufficient dietary/plasma glucose available to the tissue –postprandial/...

Gluconeogenesis Tue Oct 22, 2024  What is gluconeogenesis? The process of making glucose (gluconeogenesis) from non carbohydrate precursors (gluconeogenesis)  What is it’s function? To make glucose when insufficient dietary/plasma glucose available to the tissue –postprandial/starvation/malfunction Specific tissues have the greatest need for continuous supply of glucose – Brain – Red blood cells (RBCs) – Kidney medulla – Lens and cornea of the eye – Testes – Exercising muscle  Sources of glucose Food Stored glycogen From non-CHO sources  Need for glucose? Energy not the only source of energy but the preferred source for some tissues e.g. brain Required source cells with few or no mitochondria e.g RBCs Synthesis of ribose for nucleotides (e.g.DNA /RNA) Synthesis of glycoproteins and glycolipids  When does it take place? When blood glucose drops to levels too low to meet the needs of individual cells/tissues  Substrates for Gluconeogenesis 1. Glycerol (source?) 2. Lactate (source?) 3. Amino acids (source?)-particularly alanine Note: Interconversion of metabolites  Substrates for Gluconeogenesis 1. Glycerol-derived from triacylglycerol (TAG) i.e. storage fat in adipose tissue. Delivered by the blood to the liver In the liver glycerol is phosphorylated to glycerol phosphate by glycerol kinase Glycerol phosphate is then oxidized by glycerol phosphate dehydrogenase to dihydroxyacetone phosphate (an intermediate of Glycolysis) Note: phosphorylated molecule is now trapped in the cell – remember phosphorylation of glucose as the first step in glycolysis 2. Lactate- derived from Cori Cycle anerobic glycolysis e.g exercising muscles/ RBCs Lactate delivered back to liver and converted to glucose - Cori cycle Question: 1. Why/When would muscle use anaerobic glycolysis and not aerobic glycolysis? 2. Why RBCs?  Amino acids –from tissue protein Major source of glucose during fasting Catabolism generates -keto acids e.g -ketoglutarate (TCA intermediate) and form oxaloacetate Oxaloacetate in turn is a direct precursor of Phosphoenol pyruvate (PEP)  Glycolysis/Gluconeogenesis Question: why not just go in reverse of glycolysis? Remember – 3 major control points of glycolysis - same 3 step irreversible steps Therefore – bypass the irreversible steps of glycolysis The reactions 1-4 are UNIQUE to gluconeogenesis  unique rxns (1) to (4) Pyruvate to phosphoenolpyruvate a) Pyruvate is carboxylated by (i) pyruvate carboxylase to form oxaloacetate (OAA) i) Rxn requires biotin ii) Anaplerotic rxn of TCA b) OAA is decarboxylated and phosphorylated to PEP in the cytosol by (ii) PEP-carboxykinase Conversion of PEP to Fructose 1,6- bisphosphate These steps are run in the reverse direction as the glycolysis reactions (iii)Dephosphorylation of fructose 1,6- bisphosphate Hydrolysis of F1,6-bisphosphate by iii) fructose 1,6- bisphosphatase Bypasses the PFK-1 rxn of glycolysis (irreversible) An important regulatory site of gluconeogenesis – Inhibited by high conc of AMP – Stimulated by low conc of AMP – Inhibited by F2,6-bisphoshate –an allosteric regulator whose conc is regulated by insulin to glucagon ratio Note: what was the role of Fructose 2,6 bisphosphate in glycolysis? Dephosphorylation of glucose 6-phosphate By iv) glucose 6-phosphatase Bypasses the irreversible glucokinase/hexokinase rxn Liver and kidney are the only organs that release free glucose from G 6-P Note: skeletal muscle glycogen – no value from raising blood glucose in times of hypoglycemia  Regulation of Gluconeogenesis Glucagon Changes in allosteric effectors –Fructose 2,6-bisphosphate (recall its role in glycolysis) Covalent modification of enzyme activity – phosphorylated (inactive) hepatic PK Induction of enzyme synthesis – PEP-carboxykinase Substrate availability – indirectly influenced by insulin:glucagon ratio Allosteric activation by acetyl CoA-pyruvate carboxylase  fasting (high lipolysis) Allosteric inhibition by AMP