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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
lysine
H
oxaloacetate C H2C CH O
O O S (CH2)4 C NH R
View an oxaloacetate
animation.
Pyruvate Glucose-6-phosphatase
glucose-6-P glucose
Carboxylase
(pyruvate Gluconeogenesis Glycolysis
oxaloactate) pyruvate
is allosterically fatty acids
activated by acetyl CoA ketone bodies
acetyl CoA.
oxaloacetate citrate
[Oxaloacetate]
tends to be
Krebs Cycle
limiting for
Krebs cycle.
When gluconeogenesis is active in liver, oxaloacetate is
diverted to form glucose. Oxaloacetate depletion hinders
acetyl CoA entry into Krebs Cycle. The increase in [acetyl
CoA] activates Pyruvate Carboxylase to make oxaloacetate.
Avidin, a protein in egg whites with a b
barrel structure, tightly binds biotin.
Excess consumption of raw eggs can
cause nutritional deficiency of biotin.
The strong avidin-to-biotin affinity is avidin
used by biochemists as a specific "glue." with bound biotin
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
PFK Activity
the presence of the 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
The allosteric regulator domain
fructose-2,6-bisphosphate
is synthesized & degraded
by a bi-functional enzyme FBPase-2
that includes 2 catalytic domain
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