pubmed.ncbi.nlm.nih.gov

The return of metabolism: biochemistry and physiology of the pentose phosphate pathway - PubMed

Review

The return of metabolism: biochemistry and physiology of the pentose phosphate pathway

Anna Stincone et al. Biol Rev Camb Philos Soc. 2015 Aug.

Abstract

The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares reactions with the Entner-Doudoroff pathway and Calvin cycle and divides into an oxidative and non-oxidative branch. The oxidative branch is highly active in most eukaryotes and converts glucose 6-phosphate into carbon dioxide, ribulose 5-phosphate and NADPH. The latter function is critical to maintain redox balance under stress situations, when cells proliferate rapidly, in ageing, and for the 'Warburg effect' of cancer cells. The non-oxidative branch instead is virtually ubiquitous, and metabolizes the glycolytic intermediates fructose 6-phosphate and glyceraldehyde 3-phosphate as well as sedoheptulose sugars, yielding ribose 5-phosphate for the synthesis of nucleic acids and sugar phosphate precursors for the synthesis of amino acids. Whereas the oxidative PPP is considered unidirectional, the non-oxidative branch can supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand. These functions require dynamic regulation of the PPP pathway that is achieved through hierarchical interactions between transcriptome, proteome and metabolome. Consequently, the biochemistry and regulation of this pathway, while still unresolved in many cases, are archetypal for the dynamics of the metabolic network of the cell. In this comprehensive article we review seminal work that led to the discovery and description of the pathway that date back now for 80 years, and address recent results about genetic and metabolic mechanisms that regulate its activity. These biochemical principles are discussed in the context of PPP deficiencies causing metabolic disease and the role of this pathway in biotechnology, bacterial and parasite infections, neurons, stem cell potency and cancer metabolism.

Keywords: NADPH; cancer; glucose 6‐phosphate dehydrogenase; glycolysis; host–pathogen interactions; inherited metabolic disease; metabolic engineering; metabolism of infection; metabolomics; oxidative stress; parasitic protozoa; pentose phosphate pathway; stem cells.

© 2014 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1

Schematic representation of the pentose phosphate pathway (PPP, left) and glycolysis (canonical topology of the Embden-Meyerhof-Parnas pathway) (right). The enzymatic reactions constituting both pathways are represented by double or single arrows, according to the reversibility of the reactions. The oxidative and non-oxidative branches of the PPP are highlighted by background coloring. Sedoheptulose conversion enzymes found in *bacteria; **fungi (S. cerevisiae) and plants, ***mammals. Abbreviations are defined in Table 1; FBA, fructose bisphosphate aldolase; HK, hexokinase; PFK, phosphofructokinase; PK, pyruvate kinase; SH17BP, SH17BPase.

Fig. 2
Fig. 2

The light-independent reactions of carbon fixation in the Calvin cycle share enzymes and reactions with the pentose phosphate pathway (PPP) and glycolysis. Abbreviations are defined in Table 1; PGK, phosphoglycerate kinase; PRK, phosphoribulokinase, TK, transketolase; FBA, fructose-bisphosphate aldolase.

Fig. 3
Fig. 3

Induction of the glycolysis/pentose phosphate pathway (PPP) transition during oxidative stress. The PPP plays a pivotal role in counteracting oxidative stress and is implicated in (i) maintaining metabolic and redox homeostasis via NADP+ to NADPH reduction, (ii) by synthesizing ribose 5-phosphate used in nucleotide biosynthesis (increased synthesis is required upon DNA damage stress), and (iii) an important role in activating stress-responsive gene expression. In a stress situation, activity of the PPP is increased through orchestrated allosteric/post-translational (=metabolic) and transcriptional regulation, but these are not necessarily acting at the same time. The fastest response (~seconds timescale) is made possible through oxidative inhibition of glycolytic enzymes represented by the arrow moving from glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (illustrated as a crystallographic structure), which acts as one of the metabolic switches, while the PPP remains active. This process is supported by post-translational modifications that increase glucose 6-phosphate dehydrogenase (G6PDH) activity. The comparatively slower (=minutes) process of altering transcript and protein levels allows for cellular adaptation to stress in the long(er)-term response. The GAPDH crystallographic structure was obtained from RCSB-PDB (

www.rcsb.org

). PDB ID 3PYM: (DOI:10.2210/pdb3pym/pdb).

Fig. 4
Fig. 4

Inherited metabolic disease caused by pentose phosphate pathway (PPP) deficiencies, including two glycolytic enzymopathies with effects on the PPP. PPP enzymopathies are caused either by complete or partial deficiency of PPP and glycolytic enzymes. Abbreviations are defined in Table 1, H6PDH, hexose 6-phosphate dehydrogenase.

Fig. 5
Fig. 5

The pentose phosphate pathway (PPP) in parasitic protozoa (left) and bacterial infection (right). In kinetoplastids (A), PPP enzymes are localised in the cytosol and glycosomes (*). Plasmodia (B) have a bifunctional enzyme (glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase; GluPho) that has the activity of glucose 6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconolactonase (6PGL). Entamoeba histolytica lacks G6PDH and transaldolase (TAL), however has developed an alternative hexose–pentose interconversion pathway (C) in which the enzymes transketolase (TKL), fructose-bisphopshate aldolase (FBA) and pyrophosphate dependent-phosphofructokinase [(PPi)PFK] are involved. The activity of the PPP pathway is modulated by metabolites that respond to oxidants (i.e. H2O2 or paraquat); oxidant-responsive enzymes; or by the glutathione/glutathione disulfide (GSH/GSSG) ratio. 6PGDH, 6-phosphogluconate dehydrogenase. During bacterial lipopolysaccharide (LPS) infection of the mammalian intestine, sedoheptulokinase (SHPK) is of reduced activity in the host (D) and leads to macrophage M1 polarization. In bacteria (E), sedoheptulose 7-phosphate isomerase (SHI) and arabinose 5-phosphate isomerase (API) enzymes can increase LPS production. O2−: superoxide.

Fig. 6
Fig. 6

The pentose phosphate pathway (PPP) is associated with several cancer- and cell-proliferation-related signalling cascades. The p53 pathway can stimulate the PPP by inhibiting phosphofructokinase 1 (PFK1) through TP53-induced glycolysis and apoptosis regulator (TIGAR), and by inhibiting glucose 6-phosphate dehydrogenase (G6PDH). This enzyme is also targeted by the ataxia telangiectasia mutated (ATM) kinase, which increases G6PDH activity by phosphorylating heat shock protein 27 (HSP27), and an NAD-dependent deacetylase (SirT2), which acts on this enzyme directly by de-acetylation. All three mechanisms activate the oxidative branch of the PPP, which is also controlled by the mammalian target of rapamycin complex 1 (mTOR) pathway. Cancer signalling mechanisms operate alongside allosteric and metabolic regulation. For instance, reduced pyruvate kinase PKM2 activity leading to triosephosphate isomerase (TPI) inhibition increases the carbohydrate flux towards the PPP, achieving a metabolic self-regulation that counteracts oxidative stress. The activity of the PPP itself has an influence on cancer signalling pathways. The antioxidant capacity of the PPP modulates proto-oncogene k-ras-driven tumourigenesis; concurrently, reactive oxygen species (ROS) can potentiate the oncogenic activity of k-ras (the two opposing regulations are highlighted). The PPP has also been associated with drug resistance and hypoxia. Depending on the sensitivity to imatinib, chronic myeloid leukaemia (CML) cells can either exhibit reduced (sensitive cells) or increased (resistant cells) transketolase (TKL) activity after hypoxia-inducible transcription factor 1 (HIF-1) activation. F 2,6-BP, fructose 2,6-biphosphatase; P13K (Phosphatidylinositol-3-kinase), Akt (protein kinase B); PEP, phosphoenolpyruvate.

Fig. 7
Fig. 7

The pentose phosphate pathway (PPP) in neuronal energy metabolism. Schematic representation of glucose metabolism in neurons (left) and astrocytes (right). Metabolic regulators differentially expressed between neurons and astrocytes are highlighted. Summarized is evidence that astrocytes ferment glucose to lactate which is secreted aside GSH into the intracellular space. Neurons then uptake lactate and GSH; lactate is then converted to pyruvate and enters the tricarboxylic acid cycle to generate ATP over the respiratory chain. Abbreviations: as in Table 1; GSH, glutathione; GSSG, glutathione disulfide; GLUT, glucose transporters; GR, glutathione reductase; GPx, glutathione peroxidase; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter.

Similar articles

Cited by

References

    1. Achcar F, Kerkhoven EJ, Bakker BM, Barrett MP, Breitling R. Dynamic modelling under uncertainty: the case of Trypanosoma brucei energy metabolism. PLoS Computational Biology. 2012;8:e1002352. - PMC - PubMed
    1. Akache B, Wu K, Turcotte B. Phenotypic analysis of genes encoding yeast zinc cluster proteins. Nucleic Acids Research. 2001;29:2181–2190. - PMC - PubMed
    1. Albert MA, Haanstra JR, Hannaert V, Van Roy J, Opperdoes FR, Bakker BM, Michels PA. Experimental and in silico analyses of glycolytic flux control in bloodstream form Trypanosoma brucei. The Journal of Biological Chemistry. 2005;280:28306–28315. - PubMed
    1. Alcina A, Ramagopalan SV, Fernández O, Catalá-Rabasa A, Fedetz M, Ndagire D, Leyva L, Arnal C, Delgado C, Lucas M, Izquierdo G, Ebers GC, Matesanz F. Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis. European Journal of Human Genetics. 2010;18:618–620. - PMC - PubMed
    1. Almeida A, Almeida J, Bolaños JP, Moncada S. Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:15294–15299. - PMC - PubMed

Publication types

MeSH terms