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Gluconeogenesis : Molecular Biochemistry I
Gluconeogenesis : Molecular Biochemistry I
Gluconeogenesis;
Regulation of Glycolysis & Gluconeogenesis
H 4 3 OH H 4 3 OH
Pi H2O
OH H OH H
fructose-6-phosphate fructose-1,6-bisphosphate
Fructose-1,6-biosphosphatase
biotin NH
carboxybiotin NH
red. phosphoenolpyruvate
CO2 + GDP
PEP Carboxykinase
Glycolysis enzyme GTP
names in blue. oxaloacetate
Pi + ADP
Pyruvate Carboxylase
HCO3 + ATP
pyruvate Gluconeogenesis
glucose Gluconeogenesis
Pi
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)
Glycolysis & Gluconeogenesis are both spontaneous.
If both pathways were simultaneously active in a cell, it
would constitute a "futile cycle" that would waste energy.
Glycolysis:
glucose + 2 NAD+ + 2 ADP + 2 Pi
2 pyruvate + 2 NADH + 2 ATP
Gluconeogenesis:
2 pyruvate + 2 NADH + 4 ATP + 2 GTP
glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi
Questions:
1. Glycolysis yields how many ~P ? 2
2. Gluconeogenesis expends how many ~P ? 6
3. A futile cycle of both pathways would waste how many
~P per cycle ? 4
Phosphofructokinase
6 CH OPO 2 1CH2OH 6 CH OPO 2 1CH2OPO32
2 3 2 3
O ATP ADP O
5 H HO 2 5 H HO 2
H 4 3 OH H 4 3 OH
Pi H2O
OH H OH H
fructose-6-phosphate fructose-1,6-bisphosphate
Fructose-1,6-biosphosphatase
60
50 low [ATP]
Sigmoidal PFK Activity
40
dependence of
reaction rate on 30
high [ATP]
[fructose-6- 20
phosphate] is 10
observed at 0
high [ATP]. 0 0.5 1 1.5 2
[Fructose-6-phosphate] mM
60
50 low [ATP]
PFK activity in
the presence of the
PFK Activity
40
globally controlled 30
allosteric regulator 20
high [ATP]
fructose-2,6- 10
bisphosphate is 0
similar to that at 0 0.5 1 1.5 2
[Fructose-6-phosphate] mM
low ATP.
PFK-2
domain
The allosteric regulator
fructose-2,6-bisphosphate
is synthesized & degraded
by a bi-functional enzyme FBPase-2
domain
that includes 2 catalytic with bound
domains: fructose-6-P
in active site
PFK-2
domain
FBPase-2
domain
with bound
fructose-6-P
in active site
Adjacent to the PFK-2 domain in each copy of the liver
enzyme is a regulatory domain subject to
phosphorylation by cAMP-dependent Protein Kinase.
Which catalytic domains of the enzyme are active depends
on whether the regulatory domains are phosphorylated.
(active as Phosphofructokinase-2)
Enz-OH
ATP ADP
fructose-6-P fructose-2,6-bisP
Pi View an
Enz-O-PO32 animation.
(active as Fructose-Bisphosphatase-2)
fructose-6-P fructose-2,6-bisP
Downstream
effects of Pi
the cAMP Enz-O-PO32
cascade: (active as Fructose-Bisphosphatase-2)
X Gluconeogenesis
Glycolysis
Pathway
Glucose Glucose
2 NAD+ 2 NAD+
2 NADH 2 NADH
6 ~P 2 ~P
2 Pyruvate 2 Pyruvate
2 NADH 2 NADH
2 NAD+ 2 NAD+
2 Lactate 2 Lactate
Glucose Glucose
2 NAD+ 2 NAD+
2 NADH 2 NADH
6 ~P 2 ~P
2 Pyruvate 2 Pyruvate
2 NADH 2 NADH
2 NAD+ 2 NAD+
2 Lactate 2 Lactate
Glucose Glucose
2 NAD+ 2 NAD+
2 NADH 2 NADH
6 ~P 2 ~P
2 Pyruvate 2 Pyruvate
2 NADH 2 NADH
2 NAD+ 2 NAD+
2 Lactate 2 Lactate