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Transcript
Glucose Metabolism: Gluconeogenesis By Reem M. Sallam, MD, PhD Assistant Prof. , Clinical Chemistry Unit, Pathology Dept., College of Medicine, KSU [email protected] Objectives The importance of gluconeogenesis as an important pathway for glucose production The main reactions of gluconeogenesis The rate-limiting enzymes of gluconeogenesis Gluconeogensis is an energy-consuming, anabolic pathway Gluconeogenesis: An Overview • In the absence of dietary intake of carbohydrate, liver glycogen is an important source of glucose (through glycogenolysis) to meet the tissue needs for 10-18 hours. • During prolonged fasting, liver glycogen stores are depleted, and glucose is formed by gluconeogenesis. • During Overnight fast: • 90% of gluconeogenesis occurs in liver • 10% of gluconeogenesis occurs in Kidneys • During Prolonged fast: • 60% of gluconeogenesis occurs in liver • 40% of gluconeogenesis occurs in Kidneys • Gluconeogenesis requires both mitochondrial & cytosolic enzymes (exception: if gluconeogenesis starts by Glycerol, it will need only the cytosol) Gluconeogenic Pathway Seven glycolytic reactions are reversible & are used in gluconeogenesis from lactate or pyruvate. Three glycolytic reactions are irreversible & must be reversed (by 4 alternate reactions) in gluconeogenesis. These reactions are: Glyolysis Gluconeogenesis Pyruvate Kinase: (PEP Pyruvate) 1- Pyruvate Caroxylase: Carboxylation reaction, requires Biotin and ATP, occurs in the mitochondria, allosterically activated by acetyl CoA. OAA has to be transported from mitochondria to cytosol. (PyruvateOxaloacetate “OAA”) 2- PEPCK: Decarboxylation & phosphorylation reaction, requires energy (GTP), occurs in cytosol, the enzyme’s gene is induced by glucagon & repressed by insulin (Oxaloacetate PEP) PFK-1: (Fructose 6-P Fructose 1,6 Bisphosphate) 3- Fructose 1,6 Bisphosphatase: Dephosphorylation reaction. It is inhibited by high levels of AMP, and activated by high levels of ATP & low levels of AMP. It is allosterically inhibited by Fructose 2,6-bisphosphate (reciprocal regulation with glycolysis) (Fructose 1,6 BisphosphateFructose 6-P ) Hexokinase: (Glucose Glucose 6-P) 4- Glucose 6-Phosphatase: Dephosphorylation reaction, enzyme is found only in liver and kidney (Glucose 6-P Glucose) Gluconeogenic Substrates They are molecules that can be used to produce glucose through gluconeogenesis pathway. They include: Intermediates of glycolysis and of TCA cycle Glycerol Lactate & Pyruvate Glucogenic amino acids The most important gluconeogenic precursors Gluconeogenic Substrates: Glycerol Glycerol is released during the hydrolysis of Triacylglycerol (TAG) in adipose tissue. In liver and kidney, glycerol will be phosphorylated by glycerol kinase to glycerol-P. Glycerol-P will be oxidized by glycerol-P dehydrogenase to dihydroxyacetone phosphate(DHAP: an intermediate of glycolysis). Gluconeogenic Substrates: Glucogenic Amino Acids (AAs) AAs can be derived from hydrolysis of tissue proteins. Example of Glucogenic AA are: Amino Acids Sites of entrance to the Krebs Cycle Glutamate and Glutamine Alpha keto Glutarate (KG) Methionine & Valine Succinyl CoA Phenylalanine & Tyrosine Fumarate Aspartate & Asparagine OAA Alanine & Glycine amino acids are gluconeogenic substrates through conversion to Pyruvate Gluconeogenic Substrates: Lactate (Cori Cycle) Lactate is released into the blood by exercising skeletal muscle & by cells lacking mitochondria (Anaerobic glycolysis of glucose). Lactate is taken up by the liver and reconverted to glucose (gluconeogenesis) Glucose will then be released to the circulation to be used by skeletal muscles. Gluconeogensis: Energy Consumed With the formation of each molecule of glucose from pyruvate: six high-energy phosphate bonds are cleaved & two NADH are oxidized Regulation of Gluconeogenesis: by AMP Elevated AMP stimulates glycolysis (at the PFK-1 step) & inhibits gluconeogenesis (at the Fructose 1,6-bisphosphatase step) Regulation of Gluconeogenesis: Pruvate Carboxylase regulation by Acetyl CoA Fasting ↑lipolysis in adipose tissue ↑ Free Fatty Acid (FFA) to liver The capacity of the liver for FA oxidation is exceeded accumulation of Acetyl CoA allosteric activation of pyruvate carboxylase to increase the Gluconeogensis rate Gluconeogenesis: Regulation by Glucagon ↑Glucagon (or ↓ Insulin/Glucagon ratio): stimulates gluconeogenesis by the following mechanisms: 1. Allosteric (glucagon lowers the level of Fructose 2,6-Bisphosphate activation of Fructose 1,6-Bisphosphatase & inhibition of PFK-1 (Reciprocal regulation of gluconeogenesis & glycolysis) 2. Induction (glucagon induction of PEP-CK gene) Gluconeogenesis: Summary for Regulation • Reciprocal control Gluconeogenesis & Glycolysis • Allosteric: ↑Acetyl CoA stimulates Pyruvate carboxylase ↓ AMP or ↑ ATP (i.e. energy-rich state in cells) ↓ F 2,6-Bisphosphate Stimulate F 1,6-bisphosphatase • ↑Glucagon (or ↓ I/G ratio): stimulates gluconeogenesis by: Allosteric regulation (glucagon ↓ F 2,6-Bisphosphate) Induction (glucagon induction of PEP-CK gene) Take Home Message • Gluconeogenesis: •Synthesis of glucose from noncarbohydrates •Anabolic •Energy-consuming • 4 Unique enzymes are required for reversal of the 3 irreversible reactions of glycolysis • Both gluconeogenesis & glycolysis are reciprocally-regulated