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Medical University
Biochemistry
Gluconeogenesis
by
Chimuka Mwaanga, PhD
Gluconeogenesis (Outline)
Significance
Gluconeogenesis
Hormonal
Blood
reactions
control
sugar control
Carbohydrate Metabolism
What is
Gluconeogenesis?
Gluconeogenesis
Glycolysis Vs Gluconeogenesis
H
4
OH
H
OH
3
H
2
CH2OH
OH
OH
glucose-6-phosphate
H
H2O
H
OH
+ Pi
H
OH
OH
H
OH
glucose
H
4
OH
6 CH OPO 2
2
3
1CH2OH
ATP
HO
3 OH
fructose-6-phosphate
ADP
Pi
H2O
1CH2OPO32
HO
3 OH
OH
fructose-1,6-bisphosphate
Fructose-1,6-biosphosphatase
PEP Carboxykinase
O
O
ATP ADP + Pi
C
C
CH3
C
O
pyruvate
GTP GDP
CH2
HCO3
O
C
CO2
O
oxaloacetate
C
OPO32
CH2
PEP
Bypass of Pyruvate
Kinase reaction in
the Mitochondrion
and/or Cytosol
Glucose-6-phosphatase
glucose-6-P
glucose
Pyruvate
Carboxylase is
allosterically
activated by
acetyl CoA
Gluconeogenesis
[Oxaloacetate]
tends to be
limiting for
Krebs cycle.
oxaloacetate
Glycolysis
pyruvate
fatty acids
acetyl CoA
ketone bodies
citrate
Krebs Cycle
Phosphofructokinase
6 CH OPO 2
2
3
H
4
OH
6 CH OPO 2
2
3
1CH2OH
ATP
HO
3 OH
fructose-6-phosphate
ADP
Pi
H2O
1CH2OPO32
HO
3 OH
OH
fructose-1,6-bisphosphate
Fructose-1,6-biosphosphatase
inhibition of glycolysis
stimulation of gluconeogenesis,
Fructose-2,6-bisphosphate stimulates
Glycolysis.
Fructose-2,6-bisphosphate allosterically activates
the Glycolysis enzyme Phosphofructokinase.
Fructose-2,6-bisphosphate also activates
transcription of the gene for Glucokinase, the liver
variant of Hexokinase that phosphorylates glucose
to glucose-6-phosphate, the input to Glycolysis.
Fructose-2,6-bisphosphate allosterically
inhibits the gluconeogenesis enzyme
Fructose-1,6-bisphosphatase.
(active as Phosphofructokinase-2)
Enz-OH
ATP
ADP
fructose-6-P
fructose-2,6-bisP
Pi
Enz-O-PO32
(active as Fructose-Bisphosphatase-2)
Downstream
effects of the
cAMP
cascade:
(active as Phosphofructokinase-2)
Enz-OH
ATP
ADP
fructose-6-P
fructose-2,6-bisP
Pi
Enz-O-PO32
(active as Fructose-Bisphosphatase-2)
Glycogen
X
Glucose-1-P
Pyruvate
Gluconeogenesis
Glucose-6-P
Glucose + Pi
Glucose-6-Pase
X
Glycolysis
Pathway
Cori Cycle
Liver
Glucose
2 NAD+
2 NADH
6 ~P
2 Pyruvate
2 NADH
2 NAD+
2 Lactate
Blood
Muscle
Glucose
2 NAD+
2 NADH
2 ~P
2 Pyruvate
2 NADH
2 NAD+
2 Lactate
Cori Cycle
Liver
Glucose
2 NAD+
2 NADH
6 ~P
2 Pyruvate
2 NADH
2 NAD+
2 Lactate
Blood
Muscle
Glucose
2 NAD+
2 NADH
2 ~P
2 Pyruvate
2 NADH
2 NAD+
2 Lactate
glyceraldehyde-3-phosphate
NAD+ + Pi
Glyceraldehyde-3-phosphate
Dehydrogenase
NADH + H+
Summary of
Gluconeogenesis
Pathway:
Gluconeogenesis
enzyme names in
red.
Glycolysis enzyme
names in blue.
1,3-bisphosphoglycerate
ADP
Phosphoglycerate Kinase
ATP
3-phosphoglycerate
Phosphoglycerate Mutase
2-phosphoglycerate
Enolase
H2O
phosphoenolpyruvate
CO2 + GDP
PEP Carboxykinase
GTP
oxaloacetate
Pi + ADP
HCO3 + ATP
pyruvate
Pyruvate Carboxylase
Gluconeogenesis
glucose
Pi
Gluconeogenesis
Glucose-6-phosphatase
H2O
glucose-6-phosphate
Phosphoglucose Isomerase
fructose-6-phosphate
Pi
Fructose-1,6-bisphosphatase
H2O
fructose-1,6-bisphosphate
Aldolase
glyceraldehyde-3-phosphate + dihydroxyacetone-phosphate
Triosephosphate
Isomerase
(continued)