Biochemical Intersections
The case of Glucose-6-PO4
Its not uncommon for biochemical pathways to
intersect and have multiple enzymes competing for the
same substrate. Glucose-6-PO4 (G6P) in glycolysis is one
such intersection. In this tutorial you will see how one
metabolite can be at the hub of at least 4 major pathways.
What you should consider is what controls the carbon
flow into each.
Talk about a traffic jam, glucose-6-PO4 (G6P) is at the crossroads of at least 4 biochemical
pathways (click 1). Converting G6P to fructose-6-PO4 commits the molecule to glycolysis (click 1). On
the other hand G6P can enter the glycogen synthesis pathway by being converted to glucose-1-PO4 (click
1). In liver G6P is the source of blood glucose (click 1). Finally, by an oxidation reaction G6P is converted
into 6-phosphoglucono-d-lactone and enters the pentose phosphate pathway (click 1). The steady-state
concentration of G6P depends on all these reactions plus those that form G6P. Click 1 to go on.
Pentose Phosphate
6-phosphoglucono-d-lactone
CH2OPO3
Blood
Glucose
=
Glycogen
O
OH
Glucose
HO
OH
OH
Fructose-6-PO4
Glycolysis
Glucose-1-PO4
The steady-state concentration of G6P depends on reactions that form this molecule and those that
use it. These reactions are catalyzed by enzymes (click 1). G6P is made from F6P via a reverse of the
phosphoglucose isomerase reaction (click 1) and from glucose-1-PO4 by reversing the phosphoglucomutase
reaction (click 1). The glucose-6-phosphatase (click 1) and glucose-6-PO4 dehydrognease reactions (click 1)
are not reversible (click 1). Hexokinase (click 1) is needed to form G6P from glucose in a reaction that is not
reversible (click 1). Thus, G6P levels are controlled by 5 different enzymes, 3 or which catalyze irreversible
reactions. Click 1 to go on.
6-phosphoglucono-d-lactone
Glucose-6-PO4 dehydrogenase
CH2OPO3=
Glucose-6-phosphatase
O
OH
Glucose
HO
Hexokinase
OH
OH
Glucose-1-PO4
Phosphoglucomutase
Phosphoglucoisomerase
Fructose-6-PO4
Finally, we must decide why some reactions of glucose-6-PO4 are not reversible (click 1). The answer
will be found in the DGo' for the reaction. Recall, a large negative DGo' indicates the forward direction is favored. To
reverse the reaction an equivalent amount of energy must be available. For example, when ATP is hydrolyzed to ADP
+ PO4 , 30.5 kJ of energy per mole are released. Thus 30.5 kJ input is needed to make ATP from ADP + PO 4. To be
reversed, the hexokinase reaction (click 1) must use the hydrolysis of a phosphate ester (DGo'=-13.8 kJ) to form a
bond that requires an input of 30.5 kJ. This can't be done (click 1). On the other hand breaking and making a
phosphate ester bond as the phosphoglucomutase is practically neutral in energy (click 1) as is rearranging C-1 and C2 in the phosphoglucose isomerase reaction (DGo'= 1.7 kJ/mol) (click 1). That's why the isomerase and mutase
reactions are freely reversible and hexokinase is not.
Hexokinase
(-16.7 kJ/mole
Glucose
ATP ADP
HO
CH2OPO3=
O
OH
Phosphoglucomutase
(7.3 kJ/mole)
OH
OH
Glucose-1-PO4
Phosphoglucoisomerase
(-1.7 kJ/mol)
Fructose-6-PO4
What have you learned ?
1. Glucose-6-PO4 is clearly a molecule that has many metabolic fates. Can you
think of a molecule in glycolysis that has only one? (click 1 for answer)
Glucose. Glucose has only one fate and that is to be converted into glucose-6-PO4.
One must consider, however, that glucose is generally found outside the cell, blood
glucose, for example.
2. How much energy is required to reverse the glucose-6-phosphatase reaction?
A phosphate group must bind directly to the -OH group in the 6th position on the glucose
molecule, replacing a water molecule. The energy requirement of that reaction is DGo’=13.8 kJ/mol
3. Is the phosphorylation of glucose by ATP an anabolic or catabolic reaction?
Catabolic. It catabolic because it results in the release of a substantial amount of free energy, i.e.,
exergonic. Similarly, the reaction takes place in a catabolic pathway. But, one could also argue that
ATP hydrolysis is required and that is consistent with an anabolic reaction.
4. Would an increase in the concentration of glucose-6-PO4 favor all the forward reactions
where this molecule is a substrate?
It might. But one must be mindful that glucose-6-PO4 is also a regulator of enzyme activity and an
increase in G6P could result in the shut down of enzymes more forward in the pathways. We’ll see
allosteric effects later.