Pentose Phosphate Pathway (Oxidative and Non-oxidative phases)

1. 1

   Glucose-6-phosphate + NADP+ → 6-phosphoglucono-delta-lactone + NADPH + H+

   Glucose-6-phosphate dehydrogenase (G6PD) 1.1.1.49 ST-0040 Irreversible rate-limiting NADP+ NADPH
   In Glucose-6-phosphate NADP+

   Out 6-Phosphoglucono-delta-lactone NADPH H+
   › Notes

   Glucose-6-phosphate dehydrogenase (G6PD) uses NADP+ and is the first, rate-limiting, committed, and irreversible oxidative PPP reaction. It generates the first NADPH and is stimulated by a high NADP+/NADPH ratio.

2. 2

   6-Phosphoglucono-delta-lactone + H2O → 6-phosphogluconate

   6-Phosphogluconolactonase 3.1.1.31 ST-0041 Irreversible H2O
   In 6-Phosphoglucono-delta-lactone H2O

   Out 6-Phosphogluconate
   › Notes

   6-Phosphogluconolactonase hydrolyzes the lactone using water. This reaction is not a redox step and is effectively irreversible under cellular conditions.

3. 3

   6-Phosphogluconate + NADP+ → ribulose-5-phosphate + CO2 + NADPH + H+

   6-Phosphogluconate dehydrogenase 1.1.1.44 ST-0042 Irreversible NADP+ NADPH Mg2+ Mn2+
   In 6-Phosphogluconate NADP+

   Out Ribulose-5-phosphate CO2 NADPH H+
   › Notes

   6-Phosphogluconate dehydrogenase requires NADP+ and a divalent cation such as Mg2+ or Mn2+. Oxidative decarboxylation yields the second NADPH; this is the second irreversible reaction of the oxidative phase.

4. 4

   Ribulose-5-phosphate ↔ ribose-5-phosphate

   Ribose-5-phosphate isomerase ST-0043 Reversible
   In Ribulose-5-phosphate

   Out Ribose-5-phosphate
   › Notes

   Ribose-5-phosphate isomerase reversibly converts the ketopentose to the aldopentose needed for phosphoribosyl pyrophosphate and nucleotide synthesis. No nucleotide cofactor is used.

5. 5

   Ribulose-5-phosphate ↔ xylulose-5-phosphate

   Ribulose-5-phosphate 3-epimerase ST-0044 Reversible
   In Ribulose-5-phosphate

   Out Xylulose-5-phosphate
   › Notes

   Ribulose-5-phosphate 3-epimerase reversibly epimerizes carbon 3 to form xylulose-5-phosphate. A divalent metal ion is required.

6. 6

   Xylulose-5-phosphate + ribose-5-phosphate → glyceraldehyde-3-phosphate + sedoheptulose-7-phosphate

   Transketolase 2.2.1.1 ST-0045 Reversible TPP (B1) Mg2+
   In Xylulose-5-phosphate Ribose-5-phosphate

   Out Glyceraldehyde-3-phosphate Sedoheptulose-7-phosphate
   › Notes

   Transketolase transfers a two-carbon glycolaldehyde unit and requires thiamine pyrophosphate (TPP) and Mg2+. This reversible non-oxidative reaction forms a three-carbon and a seven-carbon sugar phosphate.

7. 7

   Sedoheptulose-7-phosphate + glyceraldehyde-3-phosphate → fructose-6-phosphate + erythrose-4-phosphate

   Transaldolase 2.2.1.2 ST-0046 Reversible TPP (B1)
   In Sedoheptulose-7-phosphate Glyceraldehyde-3-phosphate

   Out Fructose-6-phosphate Erythrose-4-phosphate
   › Notes

   Transaldolase transfers a three-carbon dihydroxyacetone unit through a Schiff-base lysine intermediate; no TPP is required. This reversible reaction yields a glycolytic hexose phosphate and a tetrose phosphate.

8. 8

   Xylulose-5-phosphate + erythrose-4-phosphate → glyceraldehyde-3-phosphate + fructose-6-phosphate

   Transketolase 2.2.1.1 ST-0047 Reversible TPP (B1) Mg2+
   In Xylulose-5-phosphate Erythrose-4-phosphate

   Out Glyceraldehyde-3-phosphate Fructose-6-phosphate
   › Notes

   A second transketolase reaction, again requiring TPP and Mg2+, transfers two carbons to form another fructose-6-phosphate and glyceraldehyde-3-phosphate. The reversible non-oxidative phase therefore converts three pentose phosphates into two fructose-6-phosphate and one glyceraldehyde-3-phosphate.

Showing all 8 steps.

Overview

The pentose phosphate pathway (PPP; hexose monophosphate shunt) diverts glucose-6-phosphate to generate NADPH and pentose phosphates. Its oxidative phase is irreversible and produces NADPH; its non-oxidative phase reversibly rearranges carbon skeletons to connect pentoses with glycolytic intermediates. NADPH supports reductive biosynthesis and antioxidant defense, whereas ribose-5-phosphate is required for nucleotide and nucleic-acid synthesis.

Cellular location

All PPP reactions occur in the cytosol. Flux is high in liver, adipose tissue, lactating mammary gland, adrenal cortex, gonads, and other tissues undertaking fatty-acid, cholesterol, or steroid synthesis, as well as in erythrocytes where NADPH maintains reduced glutathione. The pathway is also active in proliferating cells that need ribose-5-phosphate.

Net energetics

The oxidative phase per glucose-6-phosphate is: glucose-6-phosphate + 2 NADP+ + H2O → ribulose-5-phosphate + CO2 + 2 NADPH + 2 H+. It produces 2 NADPH, releases one CO2, and neither consumes nor produces ATP, NADH, FADH2, or GTP. The non-oxidative phase produces no net redox equivalents or ATP; for three pentose phosphates, its net rearrangement is 3 pentose-5-phosphate ↔ 2 fructose-6-phosphate + glyceraldehyde-3-phosphate.

Clinical significance

NADPH is needed for fatty-acid synthesis, cholesterol/steroid synthesis, cytochrome P450 reactions, nitric-oxide synthesis, phagocyte respiratory burst, and maintenance of reduced glutathione by glutathione reductase. Erythrocytes depend strongly on PPP-derived NADPH because they have no mitochondria and must neutralize oxidants through the glutathione system. G6PD deficiency, the most common human enzyme deficiency, predisposes to episodic hemolytic anemia after oxidant drugs, infection, or fava-bean exposure; transketolase activity is reduced in thiamine deficiency and may contribute to neurologic complications of alcohol-use disorder.