Regulation of carbohydrate metabolism Alice Skoumalová

Glycolysis

Gluconeogenesis

Metabolism of glycogen

Overview of the major pathways of glucose metabolism

Types of regulationsMechanismExample Substrate concentrationSaturation kinetics (Michaelis-Menten equation) Glucokinase (activation after a meal - high K m ) AllostericallyA conformational change after an allosteric activator binding Enzymes of glycolysis and gluconeogenesis (allosteric efectors: ATP, AMP, citrate) Covalent modificationA conformational change after phosphorylation by a protein kinase Phosphorylation of glycogen synthase and glycogen phosphorylase (glucagon) Protein-protein interaction A conformational change after a modulator protein binding Muscle glycogen phosphorylase (activation by Ca 2+ -calmodulin) Zymogen cleavageActivation by proteolysis of a precursor molecule Blood clotting proteins Enzyme synthesisInduction or represion of enzyme synthesis Enzymes of gluconeogenesis (induction during fasting) Regulation of enzymes:

Michaelis-Menten kinetics

Production of cAMP:

Regulation of gluconeogenesis and glycolysis:  inactivation of the glycolytic enzymes and activation of the enzymes of gluconeogenesis  1. Pyruvate ↔ PEP Pyruvate kinase - inactivation by cAMP (glucagon) Phosphoenolpyruvate carboxykinase - induced by glucagon, epinephrine, and cortisol 2. Fructose 1,6-P ↔ Fructose 6-P Phosphofructokinase - activated by fructose 2,6-P Fructose 1,6-bisphosphatase - inhibited by fructose 2,6-P 3. Glucose 6-P ↔ Glucose Glucokinase - high K m for glucose, induced by insulin Glucose 6-phosphatase - induced during fasting

Regulation of glycogenolysis in the liver by glucagon: cAMP → protein kinase A: 1. inactivates glycogen synthase 2. activates glycogen phosphorylase

Regulation of glycogenolysis in muscle:

StateRegulatorsResponse Liver FastingGlucagon ↑, Insulin ↓ cAMP ↑ Glycogen degradation ↑ Glycogen synthesis ↓ Carbohydrate mealGlu ↑, Glucagon ↓, Insulin ↑ cAMP ↓ Glycogen degradation ↓ Glycogen synthesis ↑ Exercise and stressAdrenalin ↑ cAMP ↑, Ca 2+ -calmodulin ↑ Glycogen degradation ↑ Glycogen synthesis ↓ Muscle Fasting (rest)Insulin ↓Glycogen synthesis ↓ Glucose transport ↓ Carbohydrate meal (rest)Insulin ↑Glycogen synthesis ↑ Glucose transport ↑ ExerciseEpinephrine ↑ AMP ↑, Ca 2+ -calmodulin ↑, cAMP ↑ Glycogen synthesis ↓ Glycogen degradation ↑ Glycolysis ↑ Regulation of liver and muscle glycogen metabolism:

Glucose homeostasis:  maintenance of blood glucose levels near 80 to 100 mg/dL (4,4-5,6 mmol/l)  insulin and glucagon (regulate fuel mobilization and storage) Hypoglycemia prevention: 1.release of glucose from the large glycogen stores in the liver (glycogenolysis) 2.synthesis of glucose from lactate, glycerol, and amino acids in liver (gluconeogenesis) 3.release of fatty acids from adipose tissue (lipolysis) Hyperglycemia prevention: 1.conversion of glucose to glycogen (glycogen synthesis) 2.conversion of glucose to triacylglycerols in liver and adipose tissue (lipogenesis)

Pathways regulated by the release of:  glucagon (in response to a lowering of blood glucose levels)  insulin (in response to an elevation of blood glucose levels)

Major sites of insulin action on fuel metabolism: The storage of nutriens glucose transport into muscle and adipose tissue glucose storage as glycogen (liver, muscle) conversion of glucose to TG (liver) and their storage (adipose tissue) protein synthesis (liver, muscle) inhibition of fuel mobilization

Major sites of glucagone action on fuel metabolism: Mobilization of energy stores 1.release of glucose from liver glycogen 2.stimulating gluconeogenesis from lactate, glycerol, and amino acids (liver) 3.mobilizing fatty acids (adipose tissue)

Production of blood glucose Glycogenolysis  2 hours after a meal  the primary source of blood glucose during the first few hours of fasting Gluconeogenesis  after consumption of the liver glycogen  lactate (muscle, erythrocytes), amino acids (muscle), glycerol (adipose tissue)

Sources of blood glucose in fed, fasting, and starved states:

Stage of fastingGlucose (mg/dL)Glucose (mM/L) Normal level ,4-5,6 Fasting (12 h)804,4 Starvation (3 d)703,9 Starvation (5-6 wk)653,6 Blood glucose levels at various stages of fasting:

Repetition: 1.3 key enzymes for the regulation of glycolysis (their activation). The role of Fructose 2,6-P in the regulation of glycolysis and gluconeogenesis. 2.3 key sites for the regulation of gluconeogenesis (their activation). 3.The signal pathway for the activation of glycogen degradation by glucagon. 4.Main regulators of glycogen degradation in liver and muscle. 5.Pathways preventing hypoglycemia and hyperglycemia.

Pictures used in the presentation: Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks)