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The pentose phosphate pathway in health and disease

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From Nature Metabolism

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Abstract

The pentose phosphate pathway (PPP) is a glucose-oxidizing pathway that runs in parallel to upper glycolysis to produce ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). Ribose 5-phosphate is used for nucleotide synthesis, while NADPH is involved in redox homoeostasis as well as in promoting biosynthetic processes, such as the synthesis of tetrahydrofolate, deoxyribonucleotides, proline, fatty acids and cholesterol. Through NADPH, the PPP plays a critical role in suppressing oxidative stress, including in certain cancers, in which PPP inhibition may be therapeutically useful. Conversely, PPP-derived NADPH also supports purposeful cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for signalling and pathogen killing. Genetic deficiencies in the PPP occur relatively commonly in the committed pathway enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency typically manifests as haemolytic anaemia due to red cell oxidative damage but, in severe cases, also results in infections due to lack of leucocyte oxidative burst, highlighting the dual redox roles of the pathway in free radical production and detoxification. This Review discusses the PPP in mammals, covering its roles in biochemistry, physiology and disease.

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Fig. 1: The PPP and its modes of operation.
Fig. 2: Major NADPH-consuming pathways.
Fig. 3: Regulation of the PPP.
Fig. 4: G6PD deficiency leads to RBC and immune dysfunction.
Fig. 5: The role of oxPPP-produced NADPH in phagocyte function.
Fig. 6: Oncogenic contexts for targeting the PPP.

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Acknowledgements

This work was funded by NIH R01CA163591, NIH DP1DK113643, Ludwig Cancer Research and Stand Up to Cancer SU2CAACR-DT-20-16 to J.D.R; NIH R35GM147014 to J.F.

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Authors and Affiliations

  1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Tara TeSlaa

  2. Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany

    Markus Ralser

  3. The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    Markus Ralser

  4. Max Planck Institute for Molecular Genetics, Berlin, Germany

    Markus Ralser

  5. Morgride Institute for Research, Madison, WI, USA

    Jing Fan

  6. Department of Nutritional Sciences, University of Wisconsin—Madison, Madison, WI, USA

    Jing Fan

  7. Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

    Joshua D. Rabinowitz

  8. Department of Chemistry, Princeton University, Princeton, NJ, USA

    Joshua D. Rabinowitz

  9. Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA

    Joshua D. Rabinowitz

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  1. Tara TeSlaa
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  4. Joshua D. Rabinowitz
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T.T., M.R., J.F. and J.D.R. wrote the paper. T.T. prepared the figures.

Corresponding authors

Correspondence to Tara TeSlaa or Joshua D. Rabinowitz.

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Competing interests

J.D.R. is an advisor and stockholder in Colorado Research Partners, LEAF Pharmaceuticals, Empress Therapeutics and Bantam Pharmaceutical; a paid consultant of Pfizer and Third Rock Ventures; a founder, director and stockholder of Farber Partners, Raze Therapeutics and Sofro Pharmaceuticals; a cofounder and stockholder in Marea Therapeutics; and a director of the Princeton University–PKU Shenzhen collaboration. All other authors declare no competing interests.

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TeSlaa, T., Ralser, M., Fan, J. et al. The pentose phosphate pathway in health and disease. Nat Metab 5, 1275–1289 (2023). https://doi.org/10.1038/s42255-023-00863-2

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