Glucose Metabolism Glycolysis By Amr S Moustafa M

Glucose Metabolism: Glycolysis By Amr S. Moustafa, M. D. ; Ph. D. Assistant Prof. & Consultant, Medical Biochemistry Dept. College of Medicine, KSU amrsm@hotmail. com

Glycolysis: Objectives Ø Major oxidative pathway of glucose Ø The main reactions of glycolytic pathway Ø The rate-limiting enzymes/Regulation Ø ATP production (aerobic/anaerobic) Ø Pyruvate kinase deficiency hemolytic anemia

Glycolysis: An Overview Ø Glycolysis, the major pathway for glucose oxidation, occurs in the cytosol of all cells. Ø It is unique, in that it can function either aerobically or anaerobically, depending on the availability of oxygen and intact mitochondria. Ø It allows tissues to survive in presence or absence of oxygen, e. g. , skeletal muscle. Ø RBCs, which lack mitochondria, are completely reliant on glucose as their metabolic fuel, and metabolize it by anaerobic glycolysis.

Aerobic Vs Anaerobic Glycolysis

Aerobic Glycolysis-1 Hexokinase: Most tissues Glucokinase: Hepatocytes Hexokinase Glucokinase

PFK-1 : Regulation

Aldolase and Triose Isomerase

Glyceraldehyde 3 -Phosphate Dehydrogenase 2 2 For each NADH, 3 ATP will 2 be produced by ETC in the mitochondria 2 i. e. , 6 ATP are produced 2 2

2 Phosphoglycerate Kinase 2 2 2 Substrate. Level Phosphorylation

2 2 2 Pyruvate Kinase 2 Substrate. Level Phosphorylation

Substrate-level phosphorylation Vs. Oxidative phosphorylation • Phosphorylation is the metabolic reaction of introducing a phosphate group into an organic molecule. • Oxidative phosphorylation: The formation of high-energy phosphate bonds by phosphorylation of ADP to ATP coupled to the transfer of electrons from reduced coenzymes to molecular oxygen via the electron transport chain (ETC); it occurs in the mitochondria. • Substrate-level phosphorylation: The formation of highenergy phosphate bonds by phosphorylation of ADP to ATP (or GDP to GTP) coupled to cleavage of a high-energy metabolic intermediate (substrate). It may occur in cytosol or mitochondria

Pyruvate Kinase Covalent Modification

Long-Term Regulation of Glycolysis Insulin: Induction Glucagon: Repression

Summary: Regulation of Glycolysis Regulatory Enzymes (Irreversible reactions): Glucokinase/hexokinase PFK-1 Pyruvate kinase Regulatory Mechanisms: Rapid, short-term: Allosteric Covalent modifications Slow, long-term: Induction/repression Apply the above mechanisms for each enzyme where applicable

Pyruvate Kinase Deficiency Hemolytic Anemia PK Mutation Altered Enz. kinetics Decreased Enz. stability Altered response to activator

Aerobic Glycolysis: ATP Production ATP Consumed: 2 ATP 4 6 ATP 10 AT ATP Produced: Substrate-level Oxidative-level Total 2 X 2 = 2 X 3 = Net: 10 – 2 = 8 ATP

Aerobic Glycolysis: Total Vs Net ATP Production

Anaerobic Glycolysis

Lactate Dehydrogenase

Anaerobic Glycolysis: ATP Production ATP Consumed: 2 ATP Produced: Substrate-level Oxidative-level Total 2 X 2 = 2 X 3 = 4 6 ATP 4 AT Net: 4 – 2 = 2 ATP

2 Anaerobic Glycolysis: RBCs 2, 3 -BPG Shunt 2 2 2

Glycolysis in RBCs: ATP Production ATP Consumed: ATP Produced: Substrate-level 2 X 2 = OR 1 X 2 = Oxidative-level 2 X 3 = Total Net: 4 – 2 = OR 2 – 2 = 2 ATP 4 2 6 ATP ATP 4 AT ATP 2 0

Glycolysis in RBCs: Summary End product: Lactate No net production or consumption of NADH Energy yield: No 2, 3 -BPG shunt 2 ATP 0 ATP PKD hemolytic anemia depends on: Degree of PKD Compensation by 2, 3 -BPG

Take Home Message Ø Glycolysis is the major oxidative pathway for glucose Ø Glycolysis is employed by all tissues Ø Glycolysis is a tightly-regulated pathway Ø PFK-1 is the rate-limiting regulatory enzyme

Take Home Message Ø Glycolysis is mainly a catabolic pathway for ATP production, But …. . Ø It has some anabolic features (amphibolic) Ø Pyruvate kinase deficiency in RBCs results in hemolytic anemia

Take Home Message Ø Aerobic glycolysis: 8 ATP Ø Anaerobic glycolysis: 2 ATP Ø Glycolysis in RBCs: Without 2, 3 BPG synthesis: 2 ATP With 2, 3 BPG synthesis: 0 ATP