Regulation of Metabolism

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1 Regulation of Metabolism Pratt and Cornely Chapter 19 Regulation by Compartmentalization Form of reciprocal regulation Degradation vs biosynthesis Requires transporters 1

2 Specialization of organs Fuel Storage Total amounts Availability at time of need 2

3 Liver: Tissue Specific Gluconeogenesis ketogenesis Urea production Lactate recycling Alanine recycling Liver: Fed state Glucose uptake Glycogen synthesis Convert excess sugar, amino acids to fatty acid Make, transport TAG 3

4 Glycogen breakdown Maintain blood sugar level Catabolize glucogenic amino acids to maintain glucose and citric acid cycle Catabolize fats and ketogenic amino acids for ketone body Liver: Fast state Muscle Glucose trapped as glycogen (no blood sugar regulation) Source of energy in starvation 4

5 Muscle: Active State Immediate ATP/creatine Anaerobic muscle glycogen Aerobic muscle glycogen Aerobic liver glycogen Adipose fatty acids Adipose Fed state: uptake of fats AND glucose (why?) Fast state: release of fats by hormone sensitive lipase (HSL) 5

6 Kidney Elimination of waste Maintenance of ph With liver, carries out gluconeogenesis Cori Cycle 6

7 Alanine Glucose Cycle Chemical Regulation Local allosteric regulation Hormone mediated allosteric regulation Covalent modification 7

8 Major points of Regulation Urea: Role of citrate in multiple pathways Regulation by energy charge (ATP, AMP ratio) [ATP] does not change much AMP dependent protein Kinase (AMPK) acts as energy sensor High [AMP] activates kinase to switch off anabolism and switch on catabolism Local Regulation 8

9 Hormone Regulation: Insulin Small protein hormome Released at high [glucose] Pancreatic cells Release probably triggered by glucose metabolism, not cell surface glucose receptor May be mitochondrial difference, explaining why diabetes changes with age May be difference between hexokinase and glucokinase isozyme in pancreas Hexokinase Most tissues except pancreas and liver First irreversible reaction Linked to glucose uptake Locks glucose in cell Many isozymes Most inhibited by glucose 6 phosphate Product inhibition 9

10 Isozyme in liver and pancreas Higher K m Hexokinase always saturated, but glucokinase sensitive to [glucose] Not inhibited by glucose 6 P Why? Liver serves to modulate blood sugar Glucokinase Isozyme kinetics Looks allosteric, but this is monomeric enzyme May be due to conformational change upon product release stays in active state at high concentration of glucose 10

11 Insulin Signal Transduction Glucose Entry into Cells Tissues have unique function Isozymes of glucose transporter, GLUT Insulin dependent in muscle Higher [glucose] required for liver uptake 11

12 Covalent modification Signal transdution leads to phosphatase and/or kinase activity Covalent modification Glycogen phosphorylase Phosphatase inactivates (b form) Kinase activates (a form) Insulin Regulation of Glycogen Insulin 12

13 Glucagon and Epinephrine Glucagon released with low blood sugar (pancreas cells) Epinephrine released by adrenal glands Oppose insulin Activates glycogen breakdown Activates gluconeogenesis Activates hormone sensitive lipase Glucagon Regulation of Glycogen Glucagon 13

14 Obesity Hereditary, age, and environmental Set point Leptin Appetite suppressant Made in adipose Brown fat Diabetes Type 1 (Juvenile onset) Insulin dependent Type 2 Insulin resistance Body feels like a fast Gluconeogenesis increase Lower fat storage Increase in fat utilization ketogenesis 14

15 Hyperglycemia Non enzymatic glycosylation Sorbitol production leads to tissue damage Drugs aimed at undoing metabolic problems Metformin Activates AMPK» Suppress gluconeogenesis Actuvates glucose and fatty acid uptake in muscle Review Central molecules Relate to reactions Enzyme classes Cofactors Basic reactions Redox Decarboxylation energetics Reaction motifs 15

16 Central Molecules 16

17 Enzyme classes Problem Propose a name for the enzyme, and indicate metabolic purpose of reaciton. Cofactors 17

18 Problem Identify the metabolic pathway. Indicate which redox cofactor is necessary. Problem 33: Identify the necessary cofactors 18

19 Reaction Motifs 19