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The pentose phosphate pathway in health and disease - PubMed

Review

The pentose phosphate pathway in health and disease

Tara TeSlaa et al. Nat Metab. 2023 Aug.

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.

© 2023. Springer Nature Limited.

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Conflict of interest statement

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.

Figures

Fig. 1 |
Fig. 1 |. The PPP and its modes of operation.

a, Overview of the oxPPP, the non-oxPPP and their connections to glycolysis. Each glucose that goes through the PPP can generate two NADPH molecules and one ribose-5-phosphate molecule. Abbreviations: HK, hexokinase; GPI, glucose-6-phosphate isomerase; RPE, ribulose-phosphate 3-epimerase; RPI, ribose-5-phosphate isomerase; FBPase, fructose 1,6-bisphophatase; ALDO, fructose-bisphosphate aldolase. b, Modes of PPP operation. Unmet ribose demand (that is, pentose insufficiency) leads to net non-oxPPP flux toward ribose-5-phosphate synthesis. Higher NADPH demand than ribose demand (after accounting for 2:1 pathway stoichiometry) causes non-oxPPP flux in the opposite direction, from ribose 5-phosphate toward glycolysis (that is, pentose overflow). Very high NADPH demand can lead to pentose cycling, in which the glycolytic enzyme 6-phosphate isomerase runs in reverse to make additional glucose 6-phosphate to feed the oxPPP.

Fig. 2 |
Fig. 2 |. Major NADPH-consuming pathways.

Abbreviations: CoA, coenzyme A; GR, glutathione reductase; GPx, glutathione peroxidase; GSH, glutathione; GSSG, glutathione disulfide; TR, thioredoxin reductase; FASN, fatty acid synthase; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; SQLE, squalene epoxidase; P5CR, pyrroline-5-carboxylate reductase; RNR, ribonucleotide reductase; DHFR, dihydrofolate reductase; TRX, thioredoxin.

Fig. 3 |
Fig. 3 |. Regulation of the PPP.

The PPP and glycolysis compete for carbon flux. Factors that increase oxPPP flux are highlighted in yellow, and those that decrease it are in blue. Names of enzymes induced by NRF2 are in red. E4P, erythrose 4-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose 1,6-biphosphate; F2,6BP, fructose 2,6-biphosphate; G6P, glucose 6-phosphate; 6PG, 6-phosphogluconate; GAP, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; S7P, sedoheptulose 7-phosphate; X5P, xylulose 5-phosphate.

Fig. 4 |
Fig. 4 |. G6PD deficiency leads to RBC and immune dysfunction.

The best-studied mutations in G6PD and their locations within the protein. Mutations are coloured according to their clinical phenotype from most to least severe: class I mutations in red, class II in purple, class III in blue and class IV in beige. The most severe class 1 mutations cluster around the glucose-6-phosphate (G6P) binding site, the dimer interface and the NADP+ structural site that is involved in allosteric activation and homotetramer formation.

Fig. 5 |
Fig. 5 |. The role of oxPPP-produced NADPH in phagocyte function.

a, In phagocytic cell types including macrophages and neutrophils, NADPH production by the oxPPP supports production of superoxide by NOX and nitric oxide by NOS for killing pathogens in the phagosomes and extracellular space. Ru5P, ribulose 5-phosphate. b, In macrophages involved in haem clearance, NADPH supports the breakdown of haem into biliverdin by HMOX with the help of p450 oxoreductase (POR) and biliverdin into bilirubin by biliverdin reductase (BVR).

Fig. 6 |
Fig. 6 |. Oncogenic contexts for targeting the PPP.

a, KEAP1 mutations lead to stabilization of NRF2, which promotes transcription of PPP genes and leads to dependency on their enzyme activity. Ub, ubiquitin. b, Mutations in IDH1 convert IDH from an NADPH producer into a consumer. Therefore, the oxPPP becomes a more important source of NADPH with mutant IDH.

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