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Pentose Phosphate Pathway

Pentose Phosphate Pathway

4 min read Updated Apr 18, 2026

The pentose phosphate pathway (PPP) - also called the hexose monophosphate shunt - runs parallel to glycolysis. It branches off at the first glycolysis intermediate (glucose-6-phosphate) and diverts it away from ATP production toward two different goals: generating NADPH and producing ribose-5-phosphate. The PPP does NOT feed the TCA cycle or ETC directly; it is a side path that produces biosynthetic precursors while glycolysis continues toward pyruvate.

The pentose phosphate pathway

Pathway map
Oxidative half · irreversible Non-oxidative half · fully reversible Glucose-6-P straight off the first step of glycolysis ! G6PD rate-limiting NADPH 6-Phosphogluconolactone lactonase 6-Phosphogluconate 6-phosphogluconate dehydrogenase NADPH CO₂ Ribulose-5-P (5C) NADPH is spent on fat and cholesterol synthesis · keeping glutathione reduced in red cells · the neutrophil respiratory burst Ribose-5-P (5C) DNA · RNA · ATP · NAD⁺ · CoA isomerase TRANSKETOLASE moves 2 carbons · needs thiamine TRANSALDOLASE moves 3 carbons Fructose-6-P + G3P straight back into glycolysis Runs either direction need ribose but not NADPH? go backwards from F6P Per glucose-6-P 2 NADPH 1 CO₂ 1 ribulose-5-P 0 ATP either way G6PD deficiency no NADPH in red cells means no reduced glutathione, so oxidative stress lyses them: Heinz bodies and bite cells.
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G6PD: irreversible and rate-limiting NADPH made Shared with glycolysis Reversible, non-oxidative

Back into glycolysisThe non-oxidative half is fully reversible and its products, fructose-6-P and glyceraldehyde-3-P, are glycolytic intermediates. A cell that needs ribose but not NADPH can therefore run this half backwards from glycolysis and skip the oxidative steps entirely.

What NADPH is forReductive biosynthesis (fatty acids, cholesterol, steroids), keeping glutathione reduced so red cells survive oxidative stress, the respiratory burst in neutrophils, and cytochrome P450 detoxification. NADPH is for building and defending; NADH is for burning.

G6PD deficiencyThe most common enzyme deficiency in humans. Red cells have no nucleus and no other NADPH source, so under oxidative stress (fava beans, sulfa drugs, antimalarials, infection) glutathione cannot be regenerated, hemoglobin precipitates as Heinz bodies, and the cells lyse.

No ATP is made or spent anywhere in this pathway. It exists to produce two things glycolysis cannot: NADPH for building and defending, and ribose-5-phosphate for nucleotides. The cell dials the two halves independently depending on which of them it actually needs.

Why PPP Matters

  • NADPH: needed for fatty acid synthesis, cholesterol synthesis, nucleotide biosynthesis, and regeneration of glutathione (the main cellular antioxidant).
  • Ribose-5-phosphate: the sugar backbone for nucleotides (DNA, RNA, ATP, NAD+, FAD, CoA).

Both products are critical. The PPP can produce just NADPH, just ribose-5-P, or both, depending on cellular needs.

Two Phases

Oxidative Phase (Irreversible)

  1. Glucose-6-P → 6-phosphogluconolactone + NADPH. Enzyme: glucose-6-phosphate dehydrogenase (G6PD). Rate-limiting step.
  2. 6-phosphogluconolactone → 6-phosphogluconate.
  3. 6-phosphogluconate → ribulose-5-phosphate + CO2 + NADPH.

Net: 1 G6P → ribulose-5-P + 2 NADPH + CO2.

Non-Oxidative Phase (Reversible)

Ribulose-5-P can be isomerized to ribose-5-P (for nucleotides) or transketolase/transaldolase enzymes can rearrange sugars to produce glycolytic intermediates (F6P, G3P) if ribose is not needed.

G6PD Deficiency

G6PD is X-linked. Deficiency is the most common human enzyme deficiency worldwide. Without G6PD, the oxidative phase of the PPP is impaired, reducing NADPH production. This is a problem for red blood cells because:

  • RBCs have no nucleus (cannot make new enzymes to replace damaged ones).
  • RBCs are exposed to oxidative stress in blood.
  • RBCs depend on NADPH to regenerate reduced glutathione, which detoxifies reactive oxygen species.

Without NADPH, oxidative damage accumulates, hemoglobin precipitates (forming Heinz bodies), and RBCs lyse. This causes hemolytic anemia. Triggers include fava beans, sulfa drugs, antimalarials (primaquine), and infections.

What are the two main products of the pentose phosphate pathway, and what is each used for?
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(1) NADPH - used for fatty acid synthesis, cholesterol synthesis, nucleotide biosynthesis, and to reduce glutathione for antioxidant defense. (2) Ribose-5-phosphate - used as the sugar for DNA, RNA, ATP, NAD+, FAD, CoA, and other nucleotide-based molecules. The PPP can produce either or both depending on cellular needs.
Why are red blood cells particularly vulnerable to G6PD deficiency?
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RBCs lack a nucleus and cannot synthesize new enzymes to replace damaged ones. Their entire antioxidant defense depends on glutathione, which requires NADPH to be kept in its reduced (active) form. G6PD is the main producer of NADPH in RBCs. Without functional G6PD, RBCs cannot combat oxidative stress; hemoglobin precipitates into Heinz bodies and the cells lyse - hemolytic anemia.
What enzyme catalyzes the rate-limiting step of the pentose phosphate pathway?
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Glucose-6-phosphate dehydrogenase (G6PD). It catalyzes the first oxidative step (glucose-6-phosphate + NADP+ → 6-phosphogluconolactone + NADPH). The enzyme is regulated primarily by the NADP+/NADPH ratio - more NADP+ (less NADPH) means more substrate and increased activity.
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