Download Fructose-1,6 - LSU School of Medicine

GLUCONEOGENESIS
Synthesis of glucose from noncarbohydrate precursors
Learning objectives:
List gluconeogenic precursors
List the enzymes and intermediates involved in gluconeogenesis
List the irreversible and regulated steps of gluconeogenesis
Discuss regulation of gluconeogenesis
Gluconeogenic precursors
• 18 amino acids
(diet and degradation of protein)
•
Lactate
(anaerobic glycolysis)
•
Glycerol
(hydrolysis of triacylglycerols)
Notable exception: Fatty acids
Gluconeogenic precursors
Lactate and some amino acids can be converted to pyruvate
Some amino acids can be converted to oxaloacetate
Glycerol can be converted to dihydroxyacetone phosphate
Gluconeogenic pathway describes conversion
of pyruvate to glucose
Main organs producing glucose via the
gluconeogenic pathway are liver and kidney
Gluconeogenic pathway is NOT a simple
reversal of glycolysis
The 3 irreversible steps of glycolysis
Hexokinase/Glucokinase
Phosphofructokinase
Pyruvate kinase
must be circumvented
The 7 reversible steps of glycolysis are
part of gluconeogenesis
All the intermediates of glycolysis are part of
gluconeogenesis
In addition, gluconeogenesis involves
oxaloacetate and (indirectly) malate
O-
O
C
C
C
O
O-
O
O
H C
OH
CH2
CH2
C
C
O-
Oxaloacate
O
O-
Malate
Stoichiometry
2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O →
1 Glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD+
Pyruvate
carboxylase
Pyruvate + CO2 + ATP + H2O
Oxaloacetate + ADP + Pi + 2 H+
This reaction occurs in the mitochondria
It is a regulated step
Biotin is a coenzyme for the reaction
Pyruvate is transported from the cytoplasm to the mitochondria.
In the mitochondria, pyruvate is converted to oxaloacetate by pyruvate carboxylase
Oxaloacetate can not be transported to the cytoplasm.
Oxaloacetate is reduced in the mitochondria to malate:
Oxaloacetate + NADH + H+
Malate dehydrogenase
Malate + NAD+
Malate is transported to the cytoplasm and reoxidized back to oxaloacetate:
Malate dehydrogenase
Malate + NAD+
Oxaloacetate + NADH + H+
Phosphoenolpyruvate
carboxykinase
(PEPCK)
Oxaloacetate + GTP
It is a regulated step
Phosphoenolpyruvate + GDP + CO2
Fructose-1,6bisphosphatase
Fructose 1,6-bisphosphate + H2O
Irreversible
Regulated step
Fructose 6-phosphate + Pi
Glucose-6-phosphatase
Glucose 6-phosphate +
H2 O
Glucose + Pi
Irreversible
Regulated step
Only present in large amount in liver and kidney
Reaction occurs in the endoplasmic reticulum
P
Glucose-6-phosphatase
catalytic subunit
Glucose-6-phosphate
transporter
P
P
Endoplasmic
reticulum
Glycerol kinase
Glycerol phosphate + ADP + H+
Glycerol + ATP
Glycerol
phosphate
dehydrogenase
Glycerol phosphate + NAD+
Dihydroxyacetone phosphate + NADH + H+
Pyruvate
carboxylase
Oxaloacetate + ADP + Pi + 2 H+
Pyruvate + CO2 + ATP + H2O
+
Acetyl CoA
(High energy signal)
LIVER IN THE FASTED STATE
Energy is derived mostly from fatty acids
Pyruvate
dehydrogenase
Acetyl-CoA
Pyruvate
Pyruvate
carboxylase
Fatty acids
+
Oxaloacetate
Phosphoenolpyruvate
carboxykinase
(PEPCK)
Oxaloacetate + GTP
Phosphoenolpyruvate + GDP + CO2
Phosphoenolpyruvate carboxykinase is regulated at the level of
gene transcription
+
-
Glucagon, glucocorticoids (fasted state)
Insulin (fed state)
Fructose-1,6bisphosphatase
Fructose 1,6-bisphosphate + H2O
+
Fructose 6-phosphate + Pi
AMP (low-energy state)
Fructose 2,6-bisphosphate (fed state, high insulin/glucagon ratio)
ATP (high-energy state)
Glucose-6-phosphatase
Glucose 6-phosphate +
H2 O
Glucose + Pi
The catalytic subunit of glucose-6-phosphatase is regulated
at the level of gene transcription
+
+
Glucagon, glucocorticoids (fasted state)
Insulin (fed state)
Glucose (fed state) - “Paradoxical regulation”
Glycolysis
Gluconeogenesis
Glucose
Glucokinase
+
+
Glucose-6-phosphatase
Insulin
Glucose
Glucose-6-phosphate
+
+
Insulin
Glucagon
Glucose
Glycolysis
Gluconeogenesis
Fructose-1,6bisphosphatase
Fructose 6-phosphate
Phosphofructokinase
+
+
ATP
+
ATP
-
Fructose 2,6-bisphosphate
Citrate
H+
Fructose 2,6-bisphosphate
AMP
Fructose 1,6-bisphosphate
AMP
Glycolysis
Gluconeogenesis
Phosphoenolpyruate
Pyruvate kinase
PEPCK
- Glucagon
- ATP
- Alanine
+ Fructose 1,6-bisphosphate
+ Glucose
+
-
Glucagon
Insulin
Pyruvate carboxylase
+
Pyruvate
Acetyl-CoA
Allosteric regulator of glycolysis and gluconeogenesis
Fructose 2,6-bisphosphate
Phosphofructokinase 2
Fructose 6-phosphate + ATP
Fructose 2,6-bisphosphate + ADP
Fructose bisphosphatase 2
Fructose 2,6-bisphosphate + H2O
Fructose 6-phosphate + Pi
G-6-P
F-6-P
PFK 2
FBPase 2
F-2,6-P2
+
FBPase 1
PFK 1
F-1,6-P 2
+
PK
The PFK2 and FBPase 2 activities are located in a single protein:
The bifunctional enzyme
Fasted state:
High Glucagon -> High cAMP -> activation of PKA -> phosphorylation of
bifunctional enzyme -> inhibition of PFK2, activation of FBPase2 ->
decrease in fructose 2,6-bisphosphate -> no stimulation of glycolysis, no
inhibition of gluconeogenesis -> Gluconeogenesis prevails!
Fed state:
Low Glucagon -> No/Low cAMP -> no activation of PKA ->
dephosphorylation of bifunctional enzyme prevails -> activation of PFK2,
inhibition of FBPase2 -> increase in fructose 2,6-bisphosphate ->
stimulation of glycolysis, inhibition of gluconeogenesis -> Glycolysis
prevails!
The Cori cycle
LIVER
Glucose
Gluconeogenesis
Lactate
Bloodstream
MUSCLE
Glucose
Glycolysis
Lactate