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Gluconeogenesis
Suggested Reading:
Lippincot’s Ilustrated reviews: Biochemistry
Glucose Synthesis is Required for Survival
• Brain is dependent on glucose 120g/day
• Body glucose reserve is limited≈ 20 g (extra cellular fluid)
≈ 75 g ( liver glycogen); enough for 16 hours
≈ 400 g (muscle glycogen); for muscle use only
Main source of energy for resting muscle in postabsorptivestate
• 70 Kg man has ≈ 15 Kg fat – Fatty acids can not be converted to glucose
– Utilization of FA is increased 4-5 X in prolonged fasting
– In prolonged fasting; FA ➔ ketone bodies at high rate
Gluconeogenesis occurs mainly in the liver
Tissues that do not oxidize glc. completelye.g RBCsExercising muscle
Muscle A.Acids
Adipose tissue
Lactate
alanine
glycerol
Glucose
Peripheral tissues
Entrance of substrates into gluconeogenesis
Lactate Pyruvate Amino acids
Amino acids oxaloacetate propionate
Glycerol Triosephosphates Fructose
Galactose Glucose
Glucose
Glucose 6-phosphate
Fructose 1,6- bisphosphate
2 Phosphoenolpyruvate
Oxaloacetate
2 Pyruvate
Fructose 6-phosphate
Formation and Hydrolysis of Glucose 6-phosphate
1) Glc. + Pi Glc. 6-phosphate + H2O ΔG = +ve2) ATP + H2O ADP + Pi ΔG = -ve
Glc. + ATP Glc. 6-phosphate + ADP ΔG = -ve
Glc. 6-phosphate + H2O Glc. + Pi ΔG = -ve
HK
Phosphatase
Carboxylation of Pyruvate Produces Oxaloacetate
ADPATP >CO2
Glucose
Glucose 6-phosphate
Fructose 1,6- bisphosphate
2 Phosphoenolpyruvate
Oxaloacetate
2 Pyruvate
Fructose 6-phosphate
ATP
GTP
ATP X 2
X 2
X 2
Regulation of Glycolysis and Gluconeogenesis
Regulation by ATP and AMP;
why AMP
ADP + ADP ATP + AMP
Regulation of PFK by
Fructose 2,6-bisphosphate
Fruc. 6-phosphate + ATP Fruc. 2,6 bisphosphate + ADP
Glucose
Phosphenolpyruvate
Glucose 6-P
Fructose 6-P
Fructose 1,6-bis-P
Pyruvate
Glucagon
Insulin-
+
Glucagon
Insulin-
+
Glucagon
Insulin-
+
Glucokinase
PFK
PK
T
2 ADP2 ATP
The Cori Cycle
Glucose
Phosphenolpyruvate
Glucose 6-P
Fructose 6-P
Fructose 1,6-bis-P
Pyruvate
Glucagon
Insulin-
+
Glucagon
Insulin-
+
Glucagon
Insulin-
+
Glucokinase
PFK
PK
PFK
Pyruvate kinase
Pyruvate carboxylase
Glycogen Metabolism
Suggested Reading:
Lippincott’s Ilustrated reviews: Biochemistry
Sources of Blood Glucose
• Diet– Starch, mono and disahccarides, glucose – Sporadic, depend on diet,
• Gluconeogenesis– Sustained synthesis– Slow in responding to falling blood glucose level
• Glycogen – Storage form of glucose– Rapid response and mobilization. – Limited amount– Important energy source for exercising muscle.
* Extensively branched homopolysaccharide
* One molecule consists of hundreds of thousands of glucose units
Reducing end
Nonreducingend
Degradation of glycogen
Degradation of glycogenOne glucose unit is removed at a time
From the nonreducingends
Released in the form of glucose 1-phosphate
Phosphate Ribose Uracil
Glycogen is synthesized by adding glucose one by oneUDP-Glucose s the active donor of glucose units
Formation of UDP-Glucose
Formation of UDP-Glucose
Glucose- P P P P
Ribose-Uracil
Glucose- P P
Ribose-Uracil
P P
Pyrophosphate
~~
~
~
Glycogen Storage Diseases
• Genetic diseases
• Defect in an enzyme required for synthesis or degradation ➔
• Accumulation of excessive amount of glygcogen
• In one or more tissue
• Severity: FATAL in Infancy……. Mild disorder
Glycogen Storage Diseases (examples)
• I Glucose-6-phosphatase (von Gierk’s) disease
– Liver, kidney and intestine.
– Severe fasting hypoglycemia
– Hepatomegaly fatty liver.
– Normal glycogen structure.
– Progressive renal disease.
– Growth retardation.
Glucose 6+ Phosphatase Deficiency
Glycogen Storage Diseases (examples)
• V Muscle glycogen phosphorylase (McArdle syndrome)
– Only muscle is affected;
– Weakness and cramping of muscle after exercise
– no increase in [lactate] during exercise
Glycogen Storage Diseases (examples)• II Lysosomes α (1→4) glucosidase ➔ POMP Disease
• Degradation of glycogen in the lysosomes
• ≈ 3% of glycogen is degraded in the lysosomes
• Affects liver, heart and muscle
• Excessive glycogen in abnormal vacuoles in the lysosomes
• Massive cardiomegaly
• Normal blood sugar, normal glycogen structre
• Early death from heart failure.
Energy needed for glycogen synthesis
Glucose + ATP Glucose 6-phosphate + ADP
Glucose 6-phosphate Glucose 1-phosphate
Glucose 1-phosphate + UTP UDP-Glucose + PPi
PPi + H2O 2Pi
UDP-Glucose + Glycogen(n) UDP + Glycogen(n+1)
Glc. + ATP + UTP+Glycogen(n) ADP + UDP +Glycogen(n+1
The net reaction in glycogen synthesis and degradation
Glucose 1-phosphate + UTP UDP-Glucose + PPi
PPi + H2O 2Pi
UDP-Glucose + Glycogen(n) UDP + Glycogen(n+1)
Glc. 1-phosph. + UTP+Glycogen(n) UDP +Glycogen(n+1
Degradation
Glycogen(n) + Pi Glycogen(n-1) +Glc. 1-phosphate
PInhibitor protein
Glc
GLYCOGEN SYNTHESIS IS INHIBITED
cAMP dependent protein kinase A
Phosphorylation at several sites
Inhibition is proportional to the degree of phosphorylation
Allosteric RegulationRapid response to cell’s needsAvailable substate and ATP➔
synthesis
↓↓Glucose and ↓ATP ➔Glycogenolysis
Ca2+-calmodulin activates dephosphorylated Phosphorylase kinase
Calcium Activation of liver phosphorylase Kinase
Next TopicMetabolism of mono and
disaccharides
Uracil
Ribose
Phosphate