REGULATION OF THE

PENTOSE PHOSPHATE
PATHWAY
Group 3
 Overview
• The pentose phosphate pathway (or, hexose monophosphate shunt) is an
alternative route for the metabolism of glucose in the cytosol that leads to
the formation of mainly Ribose and NADPH.
• The overall reaction:
3G6P + 6NADP+ + 3H2O = 6NADPH + 6H+ + 3CO2 + 2F6P + GAP
•The pentose phosphate pathway involve two phases as follows;
i. The oxidative phase, which generates NADPH
ii. The Nonoxidative Phase,which Generates Ribose Precursors
• NADPH is essential for biosynthetic reactions (e.g., fatty acid synthesis) and
antioxidant defense (e.g., maintaining reduced glutathione levels).
• Ribose-5-phosphate is a precursor for nucleotide synthesis, including DNA and
RNA.
oxidative phase

Non oxidative
phase
Regulation of pentose phosphate pathway
•The Pentose Phosphate pathway is regulated to ensure that cells can
meet their demands for NADPH and ribose-5-phosphate based on
metabolic needs.
• Here are some key regulatory mechanisms:
1.Enzyme Regulation:
• Glucose-6-Phosphate Dehydrogenase (G6PD): This enzyme is the rate-
limiting step(commited) in the oxidative phase of the PPP. It is activated
by its substrate, NADP+, and inhibited by its product, NADPH.
• This feedback inhibition helps regulate the rate of NADPH production
based on the cellular NADPH/NADP+ ratio. High levels of NADPH
inhibit G6PD activity, while low levels stimulate it, ensuring a balance
in NADPH production.
 .
pentose phosphate pathway and nicotinamide adenine dinucleotide phosphate (NADPH)
2. Substrate Availability
• Glucose-6-Phosphate (G6P): The availability of G6P, the substrate
for the PPP, can regulate the pathway.
•High levels of G6P can stimulate the PPP, increasing NADPH and
ribose-5-phosphate production.
3. Redox State.
•NADPH/NADP+ Ratio: The PPP is sensitive to the cellular redox state. A high ratio of
NADPH/NADP+ inhibits G6PD, while a low ratio activates it.
•This mechanism allows cells to regulate NADPH production based on their redox needs. For
example, under oxidative stress, cells may require more NADPH for antioxidant defense, so
the pathway is activated to produce more NADPH.

4. Transcriptional Regulation.
•Transcription factors are proteins that play a crucial role in regulating gene expression by
binding to specific DNA sequences near the genes they control.
•The expression of PPP enzymes can be regulated at the transcriptional level by various
factors, including transcription factors that respond to cellular stress or metabolic signals.
•For example, the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) is
known to regulate the expression of several genes involved in antioxidant defense and
metabolism, including some PPP enzymes. NRF2 is activated in response to oxidative stress
and can upregulate the expression of PPP enzymes like glucose-6-phosphate dehydrogenase
(G6PD) to increase NADPH production for antioxidant defense.
5. Allosteric Regulation.
Allosteric regulation plays a critical role in controlling the activity of key
enzymes, thereby influencing the flow of metabolites through the pathway.
•Transketolase and Transaldolase:
These enzymes, which catalyze reactions in the non-oxidative phase of the PPP,
are also subject to allosteric regulation by various metabolites. For example,
high concentrations of certain sugar phosphates can act as allosteric effectors,
modulating the activity of these enzymes to balance the production of ribose-5-
phosphate and other sugars based on cellular demands.
•Feedback Regulation by Metabolites:
Ribose-5-Phosphate: High levels of ribose-5-phosphate can allosterically inhibit
the enzyme transketolase, which is involved in the non-oxidative phase of the
PPP. This inhibition helps regulate the balance between the production of
ribose-5-phosphate for nucleotide synthesis and the generation of glycolytic
intermediates.
6.Post-translational Modification.
•Phosphorylation: Enzymes in the PPP can be regulated by post-
translational modifications such as phosphorylation. For example;
•Transketolase and Transaldolase: These enzymes, involved in the non-
oxidative phase of the PPP, can also be regulated by phosphorylation.
Phosphorylation can alter the activity of these enzymes, affecting the
interconversion of pentose phosphates and glycolytic intermediates.
•Regulation of Transcription Factors: Phosphorylation can regulate the
activity of transcription factors that control the expression of genes
encoding PPP enzymes. For example, phosphorylation of NRF2 can
enhance its activity, leading to increased expression of PPP enzymes
like G6PD.
7. Energy Status.
•Low ATP/High AMP Levels: A low ATP/high AMP scenario signals an
energy deficit within the cell. Under such conditions, cells might favor
glycolysis over the PPP to generate ATP quickly. AMP can activate AMP-
activated protein kinase (AMPK), which in turn promotes glycolysis and
suppresses pentose phosphate pathway.
•High ATP Levels: When ATP levels are high, indicating sufficient energy,
cells might allocate more glucose-6-phosphate to the PPP for NADPH
and ribose-5-phosphate production rather than glycolysis. High ATP
levels can reduce the activity of glycolytic enzymes like
phosphofructokinase-1 (PFK-1), indirectly favoring the PPP.
 low energy

high
energy
End.