Gluconeogenesis - JU Medicine€¦ · •Gluconeogenesis –Sustained synthesis –Slow in...

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