Indeed, fatty acid oxidation is essential for rapid memory T cell responses Interestingly, these fatty acids are not taken up from the surrounding microenvironment, but rather memory T cells use glucose and glycolysis to generate citrate for de novo fatty acid synthesis and the generation and storage of triacylglycerides TAGs 44 , Nonetheless, this seemingly futile cycle of fatty acid synthesis and fatty acid oxidation is important for memory T cell survival 44 , This approach may be taken by memory T cells, for which long term survival is of utmost importance, as glucose levels are stringently controlled in the blood, making glucose a more dependable fuel source than fatty acids, whose levels can vary in different tissues.
Another advantage of this cycle of fatty acid synthesis and oxidation may be that it allows the cell to concurrently engage both glycolysis and OxPhos, thus maintaining the machinery required for rapid induction of metabolic flux through these pathways upon antigen recognition and so facilitating rapid functional responses.
M2 macrophages have roles in tissue repair and secrete anti-inflammatory cytokines, growth factors, and factors involved in tissue remodeling Tregs and M2 macrophages oxidize both glucose and fatty acids in the mitochondria to sustain OxPhos 17 , 49 — It is likely that Tregs and M2 macrophages use glutamine metabolites to sustain cellular biosynthetic processes Fig.
Indeed, M2 macrophages have increased glutamine metabolism when compared with M1 macrophages Additionally, given that M2 macrophages are professional scavengers of apoptotic debris, it is tempting to speculate that M2 macrophages sustain cellular biosynthesis using biomolecules scavenged from the surrounding microenvironment 48 , Controlling the longevity of immune cells is an important aspect of a healthy immune system. In contrast, it is crucial that upon resolution of a viral infection, the large population of CTL undergoes apoptosis as these effector T cells have the potential to cause significant immunopathology Therefore, CTL have a short lifespan of days to weeks.
Similarly, differences in lifespan are apparent in different subsets of macrophages. M1 macrophages are short-lived and are a key component of the innate immune system that forms the first line of defense occurring within hours to days of an immunological challenge.
In contrast, M2 macrophages are longer-lived as they have important roles within the resolution phase and in tissue repair and remodeling. Strikingly, the cellular metabolic signature of an immune cell corresponds to the longevity of the cell; aerobic glycolysis is characteristic of short-lived immune cells, whereas oxidative metabolism is characteristic of long-lived cells Fig. It is perhaps unsurprising that OxPhos is important for longevity in immune cells given the importance of mitochondrial membrane potential in controlling the induction of apoptosis.
Certainly, in activated DC, preserving OxPhos results in an increased cellular lifespan Moreover, in macrophages, switching cellular metabolism from glycolysis to oxidative metabolism promotes a shift from short-lived M1 macrophages to longer-lived M2 macrophages In addition, manipulating glycolytic versus oxidative metabolism impacts upon the formation of long-lived memory T cells; inhibiting glycolysis promotes memory T cell formation, whereas inhibiting fatty acid oxidation-dependent OxPhos represses memory T cell formation 55 , These reports are consistent with a number of other studies that also support the notion that promoting oxidative phosphorylation enhances cell survival and lifespan 57 — On the other hand, there are also numerous reports on a variety of cell types showing that manipulating glycolytic metabolism has profound impacts upon cellular viability 60 — Growth factors that promote elevated levels of cellular glycolysis also have the consequence of making that cell highly dependent on continued growth factor signaling and glycolysis for survival This provides an elegant mechanism for terminating effector T cell responses.
Cellular metabolism is crucial for facilitating immune cell functions, but in addition, there is emerging evidence that metabolic enzymes and regulators can also have a direct role in controlling immune cell functions. This mechanism provides a direct link between rates of glycolysis and the expression of important immunological effector molecules. Intriguingly, it appears that many other metabolic enzymes can bind to mRNA molecules including numerous glycolytic enzymes, Krebs cycle enzymes, and enzymes involved in other metabolic pathways Although the specific mRNA transcripts that these metabolic enzymes bind to still have to be identified, this study highlights the abundant potential for cellular metabolism to directly impact upon cellular functions.
Various metabolic regulators that evolved to control cellular metabolic pathways have since acquired roles in directly controlling immune cell function. AhR promotes Th17 differentiation, while inhibiting Treg differentiation, and is required for the production of the Th17 cytokines IL17 and IL22 74 — The transcription factor sterol regulatory element-binding protein Srebp , a central regulator fatty acid and cholesterol synthesis, has dual roles in controlling T cell metabolism and directly controlling genes required for immune function. Therefore, there is growing evidence that multiple important regulators of cellular metabolism have additional functions in directly controlling immune responses.
Distinct metabolic configurations will result in different levels of metabolites that can directly impact upon cellular function. It has recently been shown that the glycolytic intermediate phosphoenolpyruvate is important in sustaining T cell receptor TCR signaling and T cell effector functions. Mitochondrial reactive oxygen species generated as a side product of OxPhos are also important for optimal TCR signal transduction. T cells that cannot produce mitochondrial reactive oxygen species fail to activate nuclear NFAT, produce IL2, or engage in proliferative expansion Succinate can act as a signaling molecule that acts through the receptor SUCNR1 and can also be used as a substrate for the post-translational modification of proteins that is, succinylation Numerous metabolic enzymes are succinylated on lysine residues, but at present, it is not clear whether this modification impacts upon the regulation of immune responses Citrate levels are also elevated in M1 macrophages, and this metabolite is important for the production of various proinflammatory molecules: Cellular metabolites are also important substrates for various enzymes involved in the epigenetic control of gene expression via covalent modification of DNA and histones.
Given that the distinct metabolic configurations that characterize immune cells result in different levels of these cellular metabolites, it follows that the epigenetic control of gene expression will differ in parallel with differences in metabolism. Jmjd3 has been shown to be of particular importance in controlling gene expression in LPS-stimulated macrophages Acetylation of histones is another post-translational modification that impacts on DNA structure and gene expression. Acetylation of histones by histone acetyl transferases HATs requires acetyl-CoA, which is supplied via the export of mitochondrial citrate Fig.
Indeed, there is evidence in yeast that the concentration of acetyl-CoA is important for histone acetylation Histone acetylation levels are also controlled by the rate of deacetylation. In fact, sirtuins can also deacetylate targets other than histones, which are important in immune regulation. Although there are numerous studies suggesting that cellular metabolism impacts upon epigenetic programming of immune cells to affect immune cell fate and function, the best evidence of this comes from a study of trained immunity in macrophages.
Therefore, it is clear that metabolites can impact directly on immune cell function, and it is likely that further examples of this will be revealed as the field of immunometabolism progresses. Links between cellular metabolism and epigenetic modifications. Methylation of DNA and histones is controlled by the rates of methylation and demethylation. The data now support an important role for cellular metabolism in controlling the function of immune cells. Given that metabolic regulators and pathways are acutely sensitive to external levels of nutrients, oxygen, and growth factors, cellular metabolism represents a means to relay information from the local microenvironment to modulate immune cell function accordingly.
Other nutrients are important for providing the substrates for enzymes that impact upon immune cell function. For example, methionine, which is an essential amino acid and so must be imported into the cell, is used to generate S -adenosylmethionine for epigenetic methylation of DNA and histones.
Although most studies have focused on how activating immune receptors affect cellular metabolism, it is now becoming apparent that ligation of inhibitory receptors also alters metabolic pathways. Recent research has demonstrated that ligation of the inhibitory receptors PD-1 and CTLA-4 expressed on human CD4 T cells has pronounced effects on cellular metabolism, inhibiting aerobic glycolysis, and in the case of PD-1, promoting fatty acid oxidation These data suggest that the inhibitory actions of these receptors may be mediated, at least in part, due to changes in cellular metabolism.
The emerging data now argue that metabolism has duel roles in immune cells to facilitate requirements for energy and biosynthesis and to directly regulate immune cell functions. Basic and Applied Aspects. Essentials of Stem Cell Biology. Cellular Effects of Heavy Metals. Microbial Stress Tolerance for Biofuels. Mechanisms of Gene Regulation. Marine enzymes and specialized metabolism - Part A. Nanostructuring Operations in Nanoscale Science and Engineering. Old Drugs, New Therapeutics. Iron Uptake in Bacteria with Emphasis on E.
Basic and Applied Aspects of Biotechnology. Mechanisms of DNA Repair. Calcium-Binding Proteins in Health and Disease. Advances in Applied Microbiology. Fifty Years of Cytochrome P Research. Natural Products via Enzymatic Reactions. Bergey's Manual of Systematic Bacteriology. DNA Damage and Repair. Plant Cells and their Organelles. Advances in Cancer Research. Gene Transfer and Expression in Mammalian Cells. Methods in Tau Cell Biology. The biology behind the host—parasite relationship, the infection process and in some cases, even to identify drug targets, is highly dependent on parasite metabolism.
Parasite metabolic reconfiguration and mutations in their enzymes may contribute towards resistance to drug treatment as well as parasite evasion of the host innate immune response. One important way the host immune system counteracts parasite infection is via the generation of hydrogen peroxide and other oxidants. Due to its function in maintaining the supply of the antioxidant cofactor NADPH, the PPP is therefore of great importance to the pathology of these parasites, becoming an attractive target for drug design.
Kinetoplastids have a complete and functional PPP. Studies in both T. Most of the canonical PPP enzymes have homologues in these parasites and have been cloned, characterized and crystallized in at least one of the trypanosomatids Fig. However, these PPP enzymes could be important for the infection process. It has been observed that bloodstream forms host stage in T. The pentose phosphate pathway PPP in parasitic protozoa left and bacterial infection right. 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.
The activity of the PPP pathway is modulated by metabolites that respond to oxidants i. 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.
The enzymes of the PPP in these parasites are mainly cytosolic. The role of the PPP enzymes in the glycosome appears to be: In the trypanosome, antioxidant action relies on an alternative molecule, trypanothione [T SH 2 ; N1-N8-bisglutathionylspermidine], an analogue of glutathione. The major part of the antioxidant system in trypanosomatids therefore depends on trypanothione, and its reduction requires NADPH equivalents supplied by the PPP Barrett, Due to the central role of the PPP in antioxidant metabolism, several studies have focused on the regulation of PPP enzymes under oxidative stress.
It has been demonstrated that G6PDH increases its activity fold in metacyclic trypomastigotes of T. These results demonstrate that oxidative stress not only regulates the activity of G6PDH kinetically but also at the protein level. This PPP enzyme appears to be associated with the antioxidant machinery of the parasite T.
The importance of the PPP in the response to oxidative stress in trypanosomes has also been corroborated by dynamic modelling. Recently, a kinetic model of glycolysis in Trypanosoma brucei Albert et al. Both models predicted that the flux through the cytosolic PPP was regulated by oxidative stress. Under low-oxidative-stress conditions the flux through this pathway was very low. After the stress, a steady state was predicted to be reached after 1 min Kerkhoven et al.
The lethal phenotype has been attributed to the accumulation of 6-phosphogluconate inhibiting PGI Barrett, , a result that has been challenged by i the observation that fructose supplementation, which enters glycolysis after PGI, does not rescue the cells from death, and ii a lack of support from dynamic modelling Kerkhoven et al. Mutations in TKL null mutants , by contrast, do not have any effect on cell growth, nor were changes in morphology detected Stoffel et al.
Metabolite analysis of these mutants showed that the substrates ribulose 5-phosphate, ribose 5-phosphate and xylulose 5-phosphate had accumulated 7. Additionally, intracellular concentration of 2,3-bisphosphoglycerate, phosphoenolpyruvate, fructose 6-phosphate and glyceraldehyde 3-phosphate were reduced 2-, 4. Consequently, taken together, these results indicate that a main role of the PPP in trypanosomatids appears to be in defence against oxidative stress.
This has been confirmed through in silico analysis, using transcriptome profiles collected hourly during the intra-erythrocytic cycle of the parasite. Although the parasites have the enzymes isocitrate dehydrogenase and glutamate dehydrogenase, which are also able of supplying NADPH to the cell, the former enzyme generally oxidizes this cofactor and the latter has been demonstrated not to be an NADPH supplier for antioxidant systems Preuss et al. Furthermore, ribose 5-phosphate can be obtained from the uptake and degradation of host purines in contrast to being obtained from the PPP.
Thus, the main role of the PPP in Plasmodium spp. The role of the PPP in P. As discussed in Section VI. Although this resistance is not fully understood, two hypotheses have been proposed: An alternative PPP is found in the parasite, Entamoeba histolytica. When Entamoeba histolytica is exposed to oxidative stress, metabolites of the non-oxidative branch of the PPP, glycerol and chitin biosynthesis are increased, a process attributable to an inhibition of glycolytic enzymes which, in turn, promotes redirection of the carbon flux Husain et al.
Thus, although the oxidative branch is absent from the PPP in this parasite, it seems that the non-oxidative pathway still responds to the presence of oxidative stress. Similar to eukaryotes, the PPP and glycolysis together with overlapping reaction sequences such as the Entner—Doudoroff pathway constitute core carbon metabolism in bacteria Sprenger, An important additional function however concerns the provision of sedoheptulose 7-phosphate for the initiation of lipopolysaccharide LPS biosynthesis Taylor et al.
Moreover, the PPP appears to be the only pathway allowing bacteria to utilize sugars such as 3-xylose, 3-ribose, and 3-arabinose, which cannot be catabolised by other means Wood, ; Sprenger, ; Lin, Here we briefly introduce the role of the PPP in the bacterial infection process and the importance of this pathway for both host and pathogen.
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The invasion of host cells gives rise to the activation of defence mechanisms required for survival and pathogen expulsion. The cellular reprogramming utilizes metabolic adaptation in response to environmental changes. Nevertheless, there is only limited knowledge of the bioenergetic rearrangement that takes place during macrophage activation. Reduced SHPK expression was observed in both in vivo and in vitro experiments and associated with macrophage type 1 M1 polarization. Neutrophil activation characterizes the immune response in the Gram-negative bacterium Helicobacter pylori , the agent causing chronic gastritis and peptic ulcer disease Nielsen et al.
It was suggested that, following H. Moreover, GSH availability, normally high in the stomach, is rapidly depleted after H. The infection process requires rapid adaptation of intracellular and extracellular bacteria, involving reconfiguration of their central carbon metabolism. This is caused predominantly by their newly encountered physical conditions and nutrient availability Eisenreich et al. More precisely, pathogens need to modulate their metabolism and coordinate their life cycle in order to develop specific virulence factors Ray et al.
For example, enterohaemorrhagic EHEC and uropathogenic UPEC Escherichia coli strains causing haemolytic colitis and urinary tract infection, respectively , differ in their ability to cause infection according to their localization i. The mammalian urinary tract is characterized by the presence of amino acids and small peptides, therefore mutations in the genes coding for the PPP and glycolytic enzymes do not affect the pathogenicity of the UPEC E. One of the possible targets for drug discovery is SHI, as characterized in E.
This enzyme converts sedoheptulose 7-phosphate from the PPP into the lipopolysaccharide precursor glycero-manno-heptose 7-phosphate Kneidinger et al. Further investigations on the LPS biosynthetic pathway highlighted another enzyme involved in the pathogenicity of an E. Cell growth necessitates biosynthesis of the required intermediates, such as nucleotides, amino acids, and lipid precursors. Consequently, when proliferation is induced, cells restructure their central carbon metabolism in order to adapt to the rise in metabolic demands.
The PPP playing a crucial, non-redundant role in the supply of building blocks such as ribose 5-phosphate, the molecular backbone of nucleic acids, is consequently of central importance. Indeed, a key feature of the metabolic transformation events accompanying cellular proliferation is the enhancement of biosynthetic capacity. Hence, diverting the energy flux towards the non-oxidative branch of the PPP has the key advantage of enabling the needed nucleotide biosynthesis through the production of ribose 5-phosphate Deberardinis et al.
The central importance of metabolism in reprogramming and self-renewal has recently caught the attention of the stem cell community, with most discoveries dating back to recent years only reviewed in Folmes et al. PSCs exhibit an elevated rate of proliferation and distinct cell cycle features compared to common somatic cells Ruiz et al.
Moreover, PSCs are particularly sensitive to redox imbalance Saretzki et al. Indeed, increased ROS levels have been shown to promote differentiation Yanes et al. The establishment of the proliferative PSC state has been found to be coupled with elevated lactate generation and enhanced glycolytic flux Prigione et al. Moreover, upon glycolysis-activating conditions, such as under hypoxia stimulation or after treatment with small-molecule inducers of the master metabolic regulator hypoxia-inducible transcription factor 1 HIF-1 see section VIIId , the efficiency of somatic cell reprogramming is significantly improved Yoshida et al.
Currently, evidence from altered PPP metabolism in stem cell populations mainly originates from the analysis of their gene expression profiles. Hence, the transcriptional data of PSCs suggest that glycolytic intermediates may be diverted into the PPP, in order to support both the biomass accumulation and redox homeostasis that are associated with the maintenance and derivation of PSCs.
Finally, the importance of the PPP for the maintenance of the pluripotent state is supported by the findings that G6PDH-depleted ESCs proliferate at a reduced rate and, upon oxidant exposure, are incapable of increasing the PPP flux, thus resulting in apoptotic cell death Filosa et al. Furthermore, genetic or small-molecule-based inhibition of the PPP forces PSCs to exit the self-renewal state and start the differentiation process Manganelli et al.
Overall, it appears that promoting the activation of the PPP is functionally critical to support the establishment and the maintenance of the proliferative conditions associated with the undifferentiated PSC state. It is however not clear to which extent the metabolic reconfiguration has an active role in maintaining pluripotency, or whether changes in energy metabolism are causative in driving differentiation. Evidence for an active role of the PPP in supporting cell proliferation has however been found by studying the metabolism of cancer cells.
Rising attention has recently been paid to deregulated cell proliferation when it has been noticed that malignant transformation and metabolic reprogramming may be intimately intertwined. Despite a vast amount of research, cancer still represents the second most common cause of death in the world, beaten to the top only by cardiovascular diseases.
While the last decade has substantially changed the way cancer therapy is performed, the majority of newly approved molecular-targeted drugs e. Inhibition of processes that are absolutely essential and non-redundant for tumour cell proliferation is a promising strategy to improve cancer therapy. Tumour-specific metabolism clearly represents such a process. Despite being recognized nearly a century ago, the fundamental importance of metabolic deregulation for cancer pathogenesis has escaped the appreciation of most cancer researchers for decades.
Recently however, characterization of cancer metabolism has become the focus of a rapidly growing research community, taking advantage of the improved analytical and increasingly also computational methodology to identify fascinating and unexpected interactions Weinberg, While the majority of published work analysed the role of glycolysis, glutaminolysis and mitochondrial activity, the importance of the PPP for malignant transformation remained elusive for quite some time.
Otto Warburg was not only able to identify some of the first enzymes and co-enzymes of central metabolism, but at the same time, was one of the first research pioneers that recognized the importance of altered metabolism for tumour growth. Intriguingly, the elevation in glycolytic flux also occurred under sufficient oxygen supply aerobic glycolysis.
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Based on these results, Warburg concluded that cancer cells must suffer from defects in their respiratory machinery. But why are cancer cells then not fully exploiting this efficient ATP-producing machinery? This observation implies that other factors than ATP production are more limiting for the cancer cell. Recent observations indicate that a balanced redox state, achieved in part by increased PPP activity, is essential for tumourigenesis Anastasiou et al. Although this theory has attractive components, it fails to explain some aspects of the effect; for instance it does not explain why other organisms, like yeast cells, also show Warburg-like metabolic reconfigurations despite not sharing lactate.
First, respiratory activity does not compete with aerobic glycolysis for carbons, as aerobic glycolysis is followed by lactate excretion instead of pyruvate decarboxylation. Thus, Warburg like cells have a negative carbon balance. Oxidative stress is a major cause of damage for macromolecules and can eventually lead to cell death. On the other hand, a certain amount of oxidizing equivalents are certainly necessary for cell physiology, and thus, only situations with constantly or periodically elevated ROS levels can be considered as a risk factor for tumourigenesis.
ROS-induced DNA damage can lead to cancerogenic mutations and genomic instability, and ROS also trigger inflammatory pathways and have a stabilizing effect on HIF-1; a transcription factor highly expressed in cancer cells Gao et al. Therefore, the pool of intracellular ROS must be kept balanced and below a toxic threshold — a drastic shift towards oxidation would cause tumour cell death Gao et al. Thus, dynamic tuning of the metabolic network as well as the antioxidant systems, involving glycolytic metabolite accumulation and PPP activation, is of fundamental importance to keep the production of cellular building blocks, energy and reducing equivalents in check.
Vice versa however, pro-oxidant therapies could prove helpful in inhibiting tumour cell proliferation. Gene and protein expression analyses together with immunohistochemistry are widely applied as surrogate methods to assess the role of specific factors for cancer pathogenesis. However, while these methods are certainly useful and have helped to identify numerous molecules important for cancer biology, a valid and detailed characterization of metabolic pathways cannot be achieved by them.
Metabolic pathways appear mostly regulated by post-translational mechanisms Daran-Lapujade et al. Due to the difficulty in applying these techniques in heterogeneous tumours, it is hence not surprising that published literature is rather scant. Fortunately, G6PDH is an informative exception as its enzyme activity in tumours is well studied and was increased in various human cancer types when compared to the respective benign control tissue, e.
To the best of our knowledge, there is less information available about tumour-specific activities of the non-oxidative PPP, especially for its key enzymes TAL and TKL. Assessment of enzyme activity however points towards modified PPP flux in cancer. Similar results have been obtained in renal cell carcinoma where altered activity of the PPP has been identified as a key metabolic feature of the cancer state Catchpole et al.
In addition, PPP adaptation could be crucial for cancer cells that use glucose alternatives, such as fructose, for their carbohydrate needs. There is evidence that in pancreatic cancer cells, fructose is preferentially metabolized via the non-oxidative PPP supporting tumour growth Liu et al. As an alternative to the classical biochemical approaches, functional imaging is becoming increasingly sophisticated and has shown promise as another more direct method to assess metabolic changes in vivo. A recent study used intravenous infusion of [1,2- 13 C 2 ] glucose, followed by 13 C NMR analysis of the micro-dissected tumour mass and non tumour-bearing surrounding brain, to assess PPP flux relative to glycolytic flux.
The malignant tissue in this study did not show enhanced PPP flux relative to glycolysis, when compared with the surrounding benign brain tissue Marin-Valencia et al. While the latter two studies demonstrate the potential of measurements for the PPP flux, it is clear that additional data are needed from a broad spectrum of tumours for a more comprehensive picture of PPP activity in cancer.
New opportunities arise from the use of hyperpolarized NMR tracers, as these allow non-invasive and real-time assessment of metabolic flux in vivo. The technique has recently been translated to the clinic with a study in prostate cancer Nelson et al. Intriguingly, in studies on E. Such measurements have recently been reported for tumors in vivo , where hyperpolarized [U- 2 H, U- 13 C] glucose and the lactate formed from it were imaged and the resonance previously assigned to 6-phosphogluconate was observed Rodrigues et al.
Different enzymatic switches could be involved in triggering and modulating metabolic reprogramming towards increased PPP flux. Most human tissues are dominated by the expression of one of two mutually exclusive spliceforms of the PKM gene: In most human tissues whether healthy or cancerous, bladder, liver, colon, lung, kidney, thyroid, fibroblasts, epithelial cells , but not in muscle and potentially neurons, PKM2 is the dominantly expressed isoform over PKM1 Bluemlein et al. Hence, the expression level of the PKM gene appears to be an important determinant of total pyruvate kinase activity and is highly dependent on the tissue.
In many cancer cells PKM2 expression is increased when compared to tissue-matched controls Ashrafian et al. Despite the total protein amount being up-regulated, overall PK activity however does not increase accordingly, or it is inhibited, suggesting that the specific PKM activity is lowered in the tumour cells Hitosugi et al. In addition, post-translational modifications can modulate PKM2 activity.
For example, phosphorylation at tyrosine prevents the formation of the more active tetrameric form of PKM2 Hitosugi et al. Disruption of this mechanism can exacerbate oxidative stress and subsequently decrease proliferation in cancer cells Anastasiou et al. What does link decreased PK activity and increased cellular oxidative capacity? The mechanism seems to depend on the glycolytic block and PEP accumulation. The latter can directly lead to increased PPP activity and stress protection. TPI thus might represent a key enzymatic switch for metabolic reprogramming.
The transcription factor p53 represents a tumour suppressor with well-established functions on genomic integrity, apoptosis and cell cycle control Vazquez et al. It became evident in recent years that p53, in addition to the functions outlined above, exerts control over metabolic pathways. The p53 target gene TIGAR was shown to dampen glycolysis by lowering the level of fructose 2,6-bisphosphate which is a powerful allosteric activator of PFK1. As a result the glycolytic intermediates can be diverted to the oxidative or non-oxidative branch of the PPP Fig. In highly proliferative tissues such as the intestine, a lack of TIGAR in vivo leads to decreased regeneration after acute stresses such as ulcerative colitis and irradiation, indicating an important role of TIGAR in proliferation Cheung et al.
Tumour intestinal crypts isolated from these mice showed that the in vitro growth of the TIGAR- deficient tissues can be rescued by the addition of antioxidants and nucleosides, again indicating an important role of TIGAR in increasing PPP during proliferation. Hence, it is possible that a p53 target protein such as TIGAR can become oncogenic when it is not properly regulated by p Recently, it has been shown that TIGAR predominantly functions as phosphoglycolate-independent 2,3-bisphos phoglycerate phosphatase Gerin et al.
In contrast to this activity of a ptarget gene, p53 itself can inhibit G6PDH and regulate its activity; this results in reduced PPP activity and a redirection of the central carbon flux towards increased glycolytic activity Jiang et al. As a result, pdeficient cells display enhanced lipid synthesis as well as reduced sensitivity towards oxidative stress-induced cell death as a functional consequence of higher oxidative PPP activity Jiang et al.
These opposing functions of p53 may reflect the different roles of p53 depending on the severity of the damage to the cell. During transient and mild stress, p53 may act as a pro-survival mediator for repair and regeneration. However, if the damage is too high and persistent, p53 may switch off the pro-survival mode for the proper elimination of irreversibly damaged cells.
In some cases, as a result of p53 activity, the homeostasis and integrity of the tissue as a whole is preserved. Interestingly, p73 a p53 relative was shown to enhance the PPP by activating the expression of G6PDH under conditions where p73 showed tumour-promoting activities Du et al.
While illustrating the complexity of function of the p53 family of proteins, these studies support the general notion that flux through the PPP supports cancer cell growth. The pentose phosphate pathway PPP is associated with several cancer- and cell-proliferation-related signalling cascades. 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.
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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. It phosphorylates the heat shock protein 27 HSP27 which forms a complex with the first enzyme of the oxidative branch of the PPP: Therefore, by connecting genome stability and cell cycle control to PPP activation and metabolic adaptation, ATM represents another crucial hub for cellular homoeostasis during tumourigenesis Cosentino et al.
The proto-oncogene K-ras is found activated in a number of human cancers, in particular adenocarcinomas of the pancreas, lung and colon Downward, The observation that K-ras -transfected murine fibroblasts display enhanced resistance against oxidative stress via NADPH-mediated glutathione recycling first pointed towards a potential importance of the PPP for K-ras -induced transformation Recktenwald et al.
Subsequently, it was found that oxidative stress is induced upon matrix detachment of cells and that resistance against detachment-induced cell death anoikis largely depends on antioxidant capacity Schafer et al. Intriguingly, anoikis resistance, which represents a central hallmark of malignant cells and a fundamental prerequisite for metastatic dissemination, in K-ras -driven human colon and mammary cancer cells, depends on functional integrity of the PPP Weinberg et al.
While these results point towards a functional importance of PPP-mediated antioxidant capacity for K-ras -driven tumourigenesis, ROS generation has shown to be essential for the full oncogenic potential of K-ras Weinberg et al. These apparently contradictory results clearly need further experimental clarification before a clear-cut picture of the interplay between K-ras and the PPP during malignant transformation can be proposed Fig. The hypoxia-inducible transcription factor HIF-1 is found overexpressed in the majority of human cancers and regulates pivotal pro-tumourigenic features such as angiogenesis, glucose uptake and glycolysis as well as resistance towards apoptosis and anoikis Rohwer et al.
Later, experimental evidence supported a critical role of HIFmediated PPP activation in cellular antioxidant capacity of neuroblastoma cells Guo et al. This HIF-1 activation was associated with reduced flux through the oxidative branch of the PPP while the glycolytic rate was significantly enhanced. On the other hand, the non-oxidative PPP branch was found activated in a TKL-dependent manner in cells with stabilized HIF-1, thereby supplying ribose synthesis essential for cellular proliferation Zhao et al.
Chemical inhibition of TKL resulted in enhanced imatinib sensitivity in vitro and in vivo against CML, pointing towards a functional role of HIFdriven non-oxidative PPP in mediating resistance against targeted therapies. These results are especially intriguing as imatinib represents the only targeted therapeutic that was able to result in undisputed and long-lasting clinical benefit of patients with cancer. It became evident in recent years that mTORC1 exerts pro-tumourigenic activity not only via its well-established roles in protein synthesis and autophagy, but also via elaborate control over cellular metabolism.
A genomic approach unravelled that mTORC1 induces a variety of genes that encode for specific metabolic pathways, e. The antioxidant capacity needed to promote survival of tumour cells after detachment from the extracellular matrix depends on PI3K-Akt-induced activation of the oxidative PPP Schafer et al.
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The notion that increased PPP activity is beneficial for cancer cells is also supported by other studies that propose alternative mechanisms of PPP activation in cancer cells. For example, phosphofructokinase 1 PFK1 is inhibited in cancer cells through glycosylation, drives PPP flux and supports cancer cell growth Yi et al. Moreover, a study addressing the plant stilbenoid resveratrol indicates that its suppressive function on human colon cancer cell proliferation is attributable to PPP targeting and talin-focal adhesion kinase talin-FAK signalling pathways as well Vanamala et al.
While the prognosis of certain types of cancers e. We still need to unravel the basic principles that enable malignant transformation, unchecked proliferation, systemic spread and therapy resistance. There is good reason to believe that understanding cancer metabolism might provide an important contribution to these attempts. The study of the PPP could be central, as the pathway is at the crossroads of both oncogenic signalling and biosynthetic pathways.
In this respect, first results are promising: The brain energy demands to maintain its physiological signalling activities are extremely high. Therefore, glycolysis-based metabolism appears of fundamental importance for the energetic needs of active neuronal tissue. Studies of primary cultures of glia and neurons helped to demonstrate the physiological metabolic compartmentalization of the CNS.
In particular, astrocytes are mainly glycolytic and convert glucose into lactate Itoh et al. This model is supported by a cell-type-specific expression pattern of regulatory members of carbon metabolism Lovatt et al. 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. An interesting consequence of the metabolic coupling between astrocytes and neurons is the peculiar neuronal dependence on PPP activity. Due to constant proteasomal degradation, PFKFB3 is absent in neurons and cannot be activated upon inhibition of mitochondrial respiration Almeida et al.
On the contrary, PFKFB3 is expressed in astrocytes was upregulated upon mitochondrial impairment in order to increase the glycolytic rate Herrero-Mendez et al. Therefore, the high neuronal sensitivity to mitochondrial dysfunction may be due to their inability to sustain elevated glycolysis because of their dependence on PPP-based utilization of glucose. A similar mechanism may also be present in cancer cells, where PFKFB3 has been reported to display reduced methylation and enhanced degradation in the proteasome, resulting in the shunt of glucose away from glycolysis and towards the PPP Yamamoto et al.
Neurons are also less capable than astrocytes in utilizing extracellular cysteine, used as precursor of GSH, and thus rely on the uptake of GSH that has been produced and released by the astrocytes Dringen, In accordance, brain PPP activity has been found induced upon experimental brain injury in mice and after traumatic brain injury in humans Bartnik et al. Recent findings suggest a second reason behind the importance of the PPP in brain metabolism. A meta-analysis of glucose and oxygen consumption throughout the human lifespan and among different brain regions suggests that non-oxidative glucose utilization may be important during development to support synaptic remodelling Vaishnavi et al.
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This may imply that the nucleotide biosynthesis derived by PPP activity might be crucial in neurons for synaptic plasticity Magistretti, Accordingly, glycolysis-generated ATP appears of fundamental importance for vesicle motility Zala et al. Therefore, as mitochondria may be unevenly distributed in the neuronal cells, the glycolytic machinery may provide the constant energy needed for fast axonal transport Zala et al. Overall, our understanding of human brain energy metabolism is still limited. This might potentially clarify the role of the PPP in the CNS and the interplay between different human brain cell types in the basal state and under conditions stimulating remodelling of energy flux.
The PPP is a central component of metabolism in the majority of single- and multicellular organisms. Despite the pathway is central and evolutionary ancient, it possesses a high level of flexibility, which renders it an attractive target for biotechnology and medicine. National Center for Biotechnology Information , U. Biol Rev Camb Philos Soc. Author manuscript; available in PMC Mar Keller , 1, 2 Michael Breitenbach , 8 Kevin M. Brindle , 1, 9 Joshua D. K Find articles by Anna Stincone. K Find articles by Kate Campbell. K Find articles by Eric Cheung. K Find articles by Viridiana Olin-Sandoval.
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K Find articles by Mohammad Tauqeer Alam. K Find articles by Markus A. K Find articles by Kevin M. A Find articles by Joshua D. K Find articles by Markus Ralser. Author information Copyright and License information Disclaimer. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. See other articles in PMC that cite the published article. Abstract The pentose phosphate pathway PPP is a fundamental component of cellular metabolism.
Open in a separate window. Table 1 Enzymes of the cytosolic pentose phosphate pathway. PPP metabolites as regulators of the stress response During stress conditions, the PPP seems to have attained another role: In summary The main biochemical function of the PPP is the biosynthesis of nucleic-acid and amino-acid sugar phosphate precursors. The PPP is highly flexible, dynamic, and is adapting to varying nutrient supply and stress conditions.
This coordinates these functions and is required meet cellular metabolic demands in the constantly changing environment. The PPP is important for biotechnology, as its flexibility can be exploited to tune NADPH production, and for medical research, as the PPP activity is altered by bacterial and eukaryotic parasites during the infection process, when stem cells differentiate, when cancer cells maintain redox homeostasis, and in neurons to sustain energy metabolism. Unveiling the complex regulation of the PPP, which despite 80 years of detailed basic and medical research is still not fully understood, appears hence essential for addressing metabolic adaptation and its consequences on cellular and organismic physiology.
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