The pentose phosphate pathway is a metabolic pathway that provides precursors for nucleotide biosynthesis and generates reducing power in the form of NADPH through the oxidation of glucose-6-phosphate. This pathway is also known as the hexose monophosphate pathway or the phosphogluconate pathway. The first committed step of the pentose phosphate pathway is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PDH) which converts glucose-6-phosphate to 6-phosphoglucono-δ-lactone. This reaction is irreversible and is the rate-limiting step of the pathway.
Allosteric regulation of G6PDH activity by NADP+ serves to ensure that the pathway proceeds at an optimal rate. Under conditions of high NADPH demand G6PDH is “activated” by NADP+ which results in increased conversion of glucose-6-phosphate to 6-phosphoglucono-δ-lactone. Conversely under conditions of low NADPH demand G6PDH is “inhibited” by NADP+ which decreases the conversion of glucose-6-phosphate to 6-phosphoglucono-δ-lactone.
The allosteric regulation of G6PDH by NADP+ is mediated by a conformational change in the enzyme that is induced by NADP+ binding. In the “active” conformation G6PDH exists as a homodimer with each subunit containing a catalytic site that is accessible to substrate. In the “inactive” conformation G6PDH exists as a heterotetramer with the catalytic sites sequestered in the interface between subunits. The binding of NADP+ to G6PDH promotes the formation of the active conformation and is required for enzyme activity.
The activity of G6PDH is also regulated by phosphorylation. Phosphorylation of G6PDH by cAMP-dependent protein kinase (PKA) increases enzyme activity while phosphorylation of G6PDH by protein kinase A (PKA) decreases enzyme activity. Phosphorylation of G6PDH by PKA results in a conformational change that is similar to the change induced by NADP+ binding. However the mechanism by which PKA phosphorylation regulates G6PDH activity is not fully understood.
In addition to allosteric regulation and phosphorylation G6PDH activity is also modulated by reversible oxidation. Oxidation of the flavin moiety of G6PDH results in inactivation of the enzyme while reduction of the flavin moiety results in activation of the enzyme. The mechanism by which oxidation and reduction of the flavin affects G6PDH activity is not fully understood but it is thought to be due to a change in the conformation of the enzyme.
The activity of G6PDH is also modulated by small molecules that bind to the enzyme. The most well-characterized of these small molecule inhibitors is flavine which binds to G6PDH and inhibits enzyme activity. Other small molecule inhibitors of G6PDH include metal ions such as zinc and copper as well as quinones such as menadione.
The activity of G6PDH can also be modulated by changes in the redox state of the cell. In general oxidation of G6PDH is associated with increased enzyme activity while reduction of G6PDH is associated with decreased enzyme activity. The mechanism by which the redox state of the cell affects G6PDH activity is not fully understood but it is thought to be due to a change in the conformation of the enzyme.
The allosteric regulation of G6PDH by NADP+ is the primary mechanism by which the activity of the pentose phosphate pathway is controlled. However other mechanisms such as phosphorylation oxidation and small molecule binding also play a role in modulating G6PDH activity.
What is the primary function of the pentose phosphate pathway?
Answer:
The primary function of the pentose phosphate pathway is to generate NADPH which is used to reduce oxidative stress in cells.
How does the pentose phosphate pathway generate NADPH?
Answer:
The pentose phosphate pathway generates NADPH through the reduction of glucose-6-phosphate to 6-phosphogluconolactone.
What is the enzyme that catalyzes the reduction of glucose-6-phosphate to 6-phosphogluconolactone?
Answer:
The enzyme that catalyzes the reduction of glucose-6-phosphate to 6-phosphogluconolactone is glutathione reductase.
What is the coenzyme that is required for the reaction catalyzed by glutathione reductase?
Answer:
The coenzyme that is required for the reaction catalyzed by glutathione reductase is glutathione.
What is the mechanism by which the pentose phosphate pathway generates NADPH?
Answer:
The pentose phosphate pathway generates NADPH through the reduction of glucose-6-phosphate to 6-phosphogluconolactone.
This reaction is catalyzed by glutathione reductase which requires glutathione as a coenzyme.
What is the end product of the pentose phosphate pathway?
Answer:
The end product of the pentose phosphate pathway is 6-phosphogluconolactone.
What is the fate of 6-phosphogluconolactone?
Answer:
6-phosphogluconolactone is converted to 6-phosphogluconate by phosphogluconate dehydrogenase.
What is the enzyme that catalyzes the conversion of 6-phosphogluconolactone to 6-phosphogluconate?
Answer:
The enzyme that catalyzes the conversion of 6-phosphogluconolactone to 6-phosphogluconate is phosphogluconate dehydrogenase.
What is the fate of 6-phosphogluconate?
Answer:
6-phosphogluconate is converted to ribulose-5-phosphate by transketolase.
What is the enzyme that catalyzes the conversion of 6-phosphogluconate to ribulose-5-phosphate?
Answer:
The enzyme that catalyzes the conversion of 6-phosphogluconate to ribulose-5-phosphate is transketolase.
What is the fate of ribulose-5-phosphate?
Answer:
Ribulose-5-phosphate is converted to xylulose-5-phosphate by transketolase.
What is the enzyme that catalyzes the conversion of ribulose-5-phosphate to xylulose-5-phosphate?
Answer:
The enzyme that catalyzes the conversion of ribulose-5-phosphate to xylulose-5-phosphate is transketolase.
What is the fate of xylulose-5-phosphate?
Answer:
Xylulose-5-phosphate is converted to ribose-5-phosphate by aldolase.
What is the enzyme that catalyzes the conversion of xylulose-5-phosphate to ribose-5-phosphate?
Answer:
The enzyme that catalyzes the conversion of xylulose-5-phosphate to ribose-5-phosphate is aldolase.
What is the fate of ribose-5-phosphate?
Answer:
Ribose-5-phosphate is converted to xylulose-5-phosphate by transketolase.
