Transcript Regulation of carbohydrate metabolism

Regulation of carbohydrate
metabolism
Alice Skoumalová
Glycolysis
Gluconeogenesis
Metabolism of
glycogen
Overview of the major
pathways of glucose
metabolism
Regulation of enzymes:
Types of regulations
Mechanism
Example
Substrate concentration
Saturation kinetics
(Michaelis-Menten
equation)
Glucokinase (activation after a
meal - high Km)
Allosterically
A conformational change
after an allosteric activator
binding
Enzymes of glycolysis and
gluconeogenesis (allosteric
efectors: ATP, AMP, citrate)
Covalent modification
A 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
Ca2+-calmodulin)
Zymogen cleavage
Activation by proteolysis of
a precursor molecule
Blood clotting proteins
Enzyme synthesis
Induction or represion of
enzyme synthesis
Enzymes of gluconeogenesis
(induction during fasting)
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 Km 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:
Regulation of liver and muscle glycogen metabolism:
State
Regulators
Response
Fasting
Glucagon ↑, Insulin ↓
cAMP ↑
Glycogen degradation ↑
Glycogen synthesis ↓
Carbohydrate meal
Glu ↑, Glucagon ↓, Insulin ↑
cAMP ↓
Glycogen degradation ↓
Glycogen synthesis ↑
Exercise and stress
Adrenalin ↑
cAMP ↑, Ca2+-calmodulin ↑
Glycogen degradation ↑
Glycogen synthesis ↓
Fasting (rest)
Insulin ↓
Glycogen synthesis ↓
Glucose transport ↓
Carbohydrate meal (rest)
Insulin ↑
Glycogen synthesis ↑
Glucose transport ↑
Exercise
Epinephrine ↑
AMP ↑, Ca2+-calmodulin ↑,
cAMP ↑
Glycogen synthesis ↓
Glycogen degradation ↑
Glycolysis ↑
Liver
Muscle
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:
Blood glucose levels at various stages of fasting:
Stage of fasting
Glucose (mg/dL)
Glucose (mM/L)
Normal level
80-100
4,4-5,6
Fasting (12 h)
80
4,4
Starvation (3 d)
70
3,9
Starvation (5-6 wk)
65
3,6
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)