7.2: Pentose Phospate Pathway - Biology

7.2: Pentose Phospate Pathway - Biology

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The Pentose Phosphate Pathway (PPP) is one that many students are confused by. Perhaps the reason for this is that it does not really have a single direction in which it proceeds, as will be apparent below.

Portions of the PPP are similar to the Calvin Cycle of plants, also known as the dark reactions of photosynthesis. The primary functions of the PPP are to produce NADPH (for use in anabolic reductions), ribose-5-phosphate (for making nucleotides), and erythrose-4-phosphate (for making aromatic amino acids). Three molecular intermediates of glycolysis can funnel into PPP (or be used as usual in glycolysis). They include G6P, fructose-6-phosphate (in two places), and glyceraldehyde-3-phosphate (also in two places).

A starting point for the pathway (though there are other entry points) is the oxidative phase. It includes two reactions generating NADPH. In the first of these, oxidation of glucose-6-phosphate (catalyzed by glucose-6-phosphate dehydrogenase), produces NADPH and 6-phosphogluconolactone. 6-phosphogluconolactone spontaneously gains water and loses a proton to become 6-phosphogluconate. Oxidation of this produces ribulose-5-phosphate and another NADPH and releases ( ext{CO}_2). The remaining steps of the pathway are known as the non-oxidative phase and involve interconversion of sugar phosphates.

For example, ribulose-5-phosphate is converted to ribose-5-phosphate (R5P) by the enzyme ribulose-5-phosphate isomerase. Alternatively, ribulose-5-phosphate can be converted to xylulose-5-phosphate (Xu5P). R5P and Xu5P (10 carbons total) can be combined and rearranged by transketolase to produce intermediates with 3 and 7 carbons (glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate, respectively). These last two molecules can, in turn be rearranged by transaldolase into 6 and 4 carbon sugars (fructose-6-phosphate and erythrose-4-phosphate, respectively). Further, the erythrose-4-phosphate can swap parts with Xu5P to create glyceraldehyde-3-phosphate and fructose-6-phosphate.

It is important to recognize that the PPP pathway is not a “top-down" pathway, with all the intermediates derived from a starting G6P. All of the reactions are reversible, so that, for example, fructose-6-phosphate and glyceraldehyde-3-phosphate from glycolysis can reverse the last reaction of the previous paragraph to provide a means of synthesizing ribose-5-phosphate non-oxidatively. The pathway also provides a mechanism to cells for metabolizing sugars, such as Xu5P and ribulose-5-phosphate. In the bottom line of the pathway, the direction the pathway goes and the intermediates it produces are determined by the needs of, and intermediates available to, the cell.

As noted above, the pathway connects in three places with glycolysis. In non- plant cells, the PPP pathway occurs in the cytoplasm (along with glycolysis), so considerable “intermingling" of intermediates can and does occur. Erythrose-4-phosphate is an important precursor of aromatic amino acids and ribose-5-phosphate is an essential precursor for making nucleotides.

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11 high ) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11 high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11 high cancer cells and suppress SLC7A11 high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11 high cancers.

Conflict of interest statement

Competing Financial Interests

K.O. and M.V.P. are full-time employees of Kadmon Corporation, LLC. Other authors declare no competing financial interests.


Extended Data Fig. 1. The effect of…

Extended Data Fig. 1. The effect of SLC7A11 overexpression on glutamate, TCA cycle and glycolysis…

Extended Data Fig. 2. G6PD knockdown sensitizes…

Extended Data Fig. 2. G6PD knockdown sensitizes cancer cells to glucose limitation and SLC7A11 expression…

Extended Data Fig. 3. High expression of…

Extended Data Fig. 3. High expression of SLC7A11 promote disulfide stress, deplete NADPH and causes…

Extended Data Fig. 4. Cystine deprivation or…

Extended Data Fig. 4. Cystine deprivation or 2DG reverses redox defects and prevents cell death…

Extended Data Fig. 5. Preventing disulfide but…

Extended Data Fig. 5. Preventing disulfide but not ROS accumulation rescues redox defects and cell…

Extended Data Fig. 6. Cancer cells with…

Extended Data Fig. 6. Cancer cells with high SLC7A11 expression are sensitive to GLUT inhibition

Extended Data Fig. 7. SLC7A11-high tumors are…

Extended Data Fig. 7. SLC7A11-high tumors are sensitive to GLUT inhibitor

Extended Data Fig. 8. The working model…

Extended Data Fig. 8. The working model depicting how SLC7A11 regulates pentose phosphate pathway dependency…

Extended Data Fig. 9. An example for…

Extended Data Fig. 9. An example for the gating strategy of Flow Cytometry

Fig. 1.. SLC7A11 promotes the PPP flux.

Fig. 1.. SLC7A11 promotes the PPP flux.

Fig. 2.. The cross-talk between SLC7A11 and…

Fig. 2.. The cross-talk between SLC7A11 and the PPP in regulating glucose-limitation-induced cell death and…

Fig. 3.. SLC7A11-mediated cystine uptake and subsequent…

Fig. 3.. SLC7A11-mediated cystine uptake and subsequent cystine reduction to cysteine promote disulfide stress, deplete…

Fig. 4.. Preventing disulfide but not ROS…

Fig. 4.. Preventing disulfide but not ROS accumulation rescues redox defects and cell death in…

Fig. 5.. Aberrant expression of SLC7A11 sensitizes…

Fig. 5.. Aberrant expression of SLC7A11 sensitizes cancer cells to GLUT inhibition.

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The Entner–Doudoroff Pathway

The Entner–Doudoroff (ED) pathway is another glycolytic pathway common in aerobic bacterial genera such as Pseudomonas or Rhizobium. In E. coli, the ED pathway appears to play a minor role in glycolysis, though this may be, in part, an artifact of laboratory growth in pure culture (see below). Like the EMP pathway, the ED pathway begins with the concomitant transport and phosphorylation of glucose by PtsG. The G-6-P is then immediately oxidized by an NADP-dependent G-6-P dehydrogenase (zwf gene) to 6-phosphogluconolactone. The next enzyme, 6-phosphogluconolactonase (pgl gene), then adds water to generate the key intermediate of the pathway, gluconate-6-P.

A water molecule is then removed from 6-phosphogluconate by the ED dehydratase (edd gene) to yield 2-keto-3-deoxyketogluconate phosphate (KDGP). KDGP is cleaved by the ED aldolase (eda gene) to yield GAP and pyruvate, thus rejoining the trunk line reactions of the EMP pathway.

The ED pathway differs in two significant ways from the EMP pathway. First, it generates NADPH (not NADH) from the oxidation of G-6-P. This is used in many biosynthetic reactions. Second, only one triose phosphate is generated by the ED aldolase. As a result, only one ATP is generated per mole of glucose rather than the two generated by the EMP pathway. The ED pathway provides a glycolytic route that bypasses the early steps of the EMP pathway that involve fructose derivatives. The ED intermediate, gluconate-6-P, also serves as a starting point for yet another glycolytic pathway that bypasses the step from G-6-P to fructose-6-phosphate. This so-called pentose phosphate shunt involves a complex set of transketolase- and transaldolase-mediated rearrangements that provide the cell with a variety of sugar phosphates that are required for biosynthesis. These include the phosphorylated versions of fructose, ribose, xylose, erythrose, and sedoheptulose. Although the pentose phosphate shunt can function as a glycolytic pathway that produces GAP for energy generation, it appears to be better designed for biosynthesis, especially since its oxidations generate NADPH rather than NADH.


1) Which of the following step is common in glycolysis and pentose phosphate pathway?
a) Conversion of glucose to glucose-6-P
b) Conversion of glucose-6-P to ribose-5-P
c) Conversion of glucose-6-P- to fructose-6-P
d) Conversion of glucose to glucose-1-P

2) Pentose phosphate pathway is responsible for generating NADPH (reducing equivalents in the cell) in the cell. Which of the following enzyme is involved in generating NADPH?
a) Glucose-6-P oxidase
b) Glucose-6-P dehydrogenase
c) Glucose-6-P reductase
d) Glucose-6-P synthetase

3) Which of the following step is the rate-limiting step of the pentose phosphate pathway?
a) Transketolase
b) Glucose-6-P dehydrogenase
c) Transaldolase
d) Phosphogluconate dehydrogenase

4) Insulin activates the pentose phosphate pathway. Which of the following enzyme is activated by insulin action?
a) Transketolase
b) Glucose-6-P dehydrogenase
c) Transaldolase
d) Phosphogluconate dehydrogenase

5) Which of the following enzyme is used for the diagnosis of thiamine deficiency?
a) Transketolase
b) Glucose-6-P dehydrogenase
c) Transaldolase
d) Phosphogluconate dehydrogenase

6) Glucose -6-Phosphate dehydrogenase is allosterically activated by
c) NAD +
d) NADP +

7) Glucose-6-Phosphate dehydrogenase is allosterically inhibited by
a) Acetyl CoA
b) Citrate
c) Glucose
d) Fructose

8) In some individuals, ingesting fava beans leads to hemolytic anemia. Which of the following enzyme may be deficient in these individuals?
a) Glucose-6-Phosphatase
b) Glucose-6-P- dehydrogenase
c) Glucose -6-Phosphate Isomerase
d) Glycogen phosphorylase

9) What is the cause of hemolytic anemia in Glucose-6-phosphate deficiency?
a) Decreased ATP in erythrocytes
b) Decreased free radicals in erythrocytes
c) Increased sodium concentration in erythrocytes
d) Increased free radicals in erythrocytes

10) The glutathione cycle is the conversion of oxidized glutathione to reduced glutathione in the presence of NADPH. Which of the following enzyme catalyzes this reaction
a) Glutathione peroxidase
b) Glutathione dehydrogenase
c) Glutathione reductase
d) Glutathione synthetase


Four isozymes of pyruvate kinase expressed in vertebrates: L (liver), R (erythrocytes), M1 (muscle and brain) and M2 (early fetal tissue and most adult tissues). The L and R isozymes are expressed by the gene PKLR, whereas the M1 and M2 isozymes are expressed by the gene PKM2. The R and L isozymes differ from M1 and M2 in that they are allosterically regulated. Kinetically, the R and L isozymes of pyruvate kinase have two distinct conformation states one with a high substrate affinity and one with a low substrate affinity. The R-state, characterized by high substrate affinity, serves as the activated form of pyruvate kinase and is stabilized by PEP and fructose 1,6-bisphosphate (FBP), promoting the glycolytic pathway. The T-state, characterized by low substrate affinity, serves as the inactivated form of pyruvate kinase, bound and stabilized by ATP and alanine, causing phosphorylation of pyruvate kinase and the inhibition of glycolysis. [3] The M2 isozyme of pyruvate kinase can form tetramers or dimers. Tetramers have a high affinity for PEP, whereas, dimers have a low affinity for PEP. Enzymatic activity can be regulated by phosphorylating highly active tetramers of PKM2 into an inactive dimers. [4]

The PKM gene consists of 12 exons and 11 introns. PKM1 and PKM2 are different splicing products of the M-gene (PKM1 contains exon 9 while PKM2 contains exon 10) and solely differ in 23 amino acids within a 56-amino acid stretch (aa 378-434) at their carboxy terminus. [5] [6] The PKM gene is regulated through heterogenous ribonucleotide proteins like hnRNPA1 and hnRNPA2. [7] Human PKM2 monomer has 531 amino acids and is a single chain divided into A, B and C domains. The difference in amino acid sequence between PKM1 and PKM2 allows PKM2 to be allosterically regulated by FBP and for it to form dimers and tetramers while PKM1 can only form tetramers. [8]

Many Enterobacteriaceae, including E. coli, have two isoforms of pyruvate kinase, PykA and PykF, which are 37% identical in E. coli (Uniprot: PykA, PykF). They catalyze the same reaction as in eukaryotes, namely the generation of ATP from ADP and PEP, the last step in glycolysis, a step that is irreversible under physiological conditions. PykF is allosterically regulated by FBP which reflects the central position of PykF in cellular metabolism. [9] PykF transcription in E. coli is regulated by the global transcriptional regulator, Cra (FruR). [10] [11] [12] PfkB was shown to be inhibited by MgATP at low concentrations of Fru-6P, and this regulation is important for gluconeogenesis. [13]

Glycolysis Edit

There are two steps in the pyruvate kinase reaction in glycolysis. First, PEP transfers a phosphate group to ADP, producing ATP and the enolate of pyruvate. Secondly, a proton must be added to the enolate of pyruvate to produce the functional form of pyruvate that the cell requires. [14] Because the substrate for pyruvate kinase is a simple phospho-sugar, and the product is an ATP, pyruvate kinase is a possible foundation enzyme for the evolution of the glycolysis cycle, and may be one of the most ancient enzymes in all earth-based life. Phosphoenolpyruvate may have been present abiotically, and has been shown to be produced in high yield in a primitive triose glycolysis pathway. [15]

In yeast cells, the interaction of yeast pyruvate kinase (YPK) with PEP and its allosteric effector Fructose 1,6-bisphosphate (FBP,) was found to be enhanced by the presence of Mg 2+ . Therefore, Mg 2+ was concluded to be an important cofactor in the catalysis of PEP into pyruvate by pyruvate kinase. Furthermore, the metal ion Mn 2+ was shown to have a similar, but stronger effect on YPK than Mg 2+ . The binding of metal ions to the metal binding sites on pyruvate kinase enhances the rate of this reaction. [16]

The reaction catalyzed by pyruvate kinase is the final step of glycolysis. It is one of three rate-limiting steps of this pathway. Rate-limiting steps are the slower, regulated steps of a pathway and thus determine the overall rate of the pathway. In glycolysis, the rate-limiting steps are coupled to either the hydrolysis of ATP or the phosphorylation of ADP, causing the pathway to be energetically favorable and essentially irreversible in cells. This final step is highly regulated and deliberately irreversible because pyruvate is a crucial intermediate building block for further metabolic pathways. [17] Once pyruvate is produced, it either enters the TCA cycle for further production of ATP under aerobic conditions, or is converted to lactic acid or ethanol under anaerobic conditions.

Gluconeogenesis: the reverse reaction Edit

Pyruvate kinase also serves as a regulatory enzyme for gluconeogenesis, a biochemical pathway in which the liver generates glucose from pyruvate and other substrates. Gluconeogenesis utilizes noncarbohydrate sources to provide glucose to the brain and red blood cells in times of starvation when direct glucose reserves are exhausted. [17] During fasting state, pyruvate kinase is inhibited, thus preventing the "leak-down" of phosphoenolpyruvate from being converted into pyruvate [17] instead, phosphoenolpyruvate is converted into glucose via a cascade of gluconeogenesis reactions. Although it utilizes similar enzymes, gluconeogenesis is not the reverse of glycolysis. It is instead a pathway that circumvents the irreversible steps of glycolysis. Furthermore, gluconeogenesis and glycolysis do not occur concurrently in the cell at any given moment as they are reciprocally regulated by cell signaling. [17] Once the gluconeogenesis pathway is complete, the glucose produced is expelled from the liver, providing energy for the vital tissues in the fasting state.

Glycolysis is highly regulated at three of its catalytic steps: the phosphorylation of glucose by hexokinase, the phosphorylation of fructose-6-phosphate by phosphofructokinase, and the transfer of phosphate from PEP to ADP by pyruvate kinase. Under wild-type conditions, all three of these reactions are irreversible, have a large negative free energy and are responsible for the regulation of this pathway. [17] Pyruvate kinase activity is most broadly regulated by allosteric effectors, covalent modifiers and hormonal control. However, the most significant pyruvate kinase regulator is fructose-1,6-bisphosphate (FBP), which serves as an allosteric effector for the enzyme.

Allosteric effectors Edit

Allosteric regulation is the binding of an effector to a site on the protein other than the active site, causing a conformational change and altering the activity of that given protein or enzyme. Pyruvate kinase has been found to be allosterically activated by FBP and allosterically inactivated by ATP and alanine. [18] Pyruvate Kinase tetramerization is promoted by FBP and Serine while tetramer dissociation is promoted by L-Cysteine. [19] [20] [21]

Fructose-1,6-bisphosphate Edit

FBP is the most significant source of regulation because it comes from within the glycolysis pathway. FBP is a glycolytic intermediate produced from the phosphorylation of fructose 6-phosphate. FBP binds to the allosteric binding site on domain C of pyruvate kinase and changes the conformation of the enzyme, causing the activation of pyruvate kinase activity. [22] As an intermediate present within the glycolytic pathway, FBP provides feedforward stimulation because the higher the concentration of FBP, the greater the allosteric activation and magnitude of pyruvate kinase activity. Pyruvate kinase is most sensitive to the effects of FBP. As a result, the remainder of the regulatory mechanisms serve as secondary modification. [9] [23]

Covalent modifiers Edit

Covalent modifiers serve as indirect regulators by controlling the phosphorylation, dephosphorylation, acetylation, succinylation and oxidation of enzymes, resulting in the activation and inhibition of enzymatic activity. [24] In the liver, glucagon and epinephrine activate protein kinase A, which serves as a covalent modifier by phosphorylating and deactivating pyruvate kinase. In contrast, the secretion of insulin in response to blood sugar elevation activates phosphoprotein phosphatase I, causing the dephosphorylation and activation of pyruvate kinase to increase glycolysis. The same covalent modification has the opposite effect on gluconeogenesis enzymes. This regulation system is responsible for the avoidance of a futile cycle through the prevention of simultaneous activation of pyruvate kinase and enzymes that catalyze gluconeogenesis. [25]

Carbohydrate response element binding protein (ChREBP) Edit

ChREBP is found to be an essential protein in gene transcription of the L isozyme of pyruvate kinase. The domains of ChREBP are target sites for regulation of pyruvate kinase by glucose and cAMP. Specifically, ChREBP is activated by a high concentration of glucose and inhibited by cAMP. Glucose and cAMP work in opposition with one another through covalent modifier regulation. While cAMP binds to Ser196 and Thr666 binding sites of ChREBP, causing the phosphorylation and inactivation of pyruvate kinase glucose binds to Ser196 and Thr666 binding sites of ChREBP, causing the dephosphorylation and activation of pyruvate kinase. As a result, cAMP and excess carbohydrates are shown to play an indirect role in pyruvate kinase regulation. [26]

Hormonal control Edit

In order to prevent a futile cycle, glycolysis and gluconeogenesis are heavily regulated in order to ensure that they are never operating in the cell at the same time. As a result, the inhibition of pyruvate kinase by glucagon, cyclic AMP and epinephrine, not only shuts down glycolysis, but also stimulates gluconeogenesis. Alternatively, insulin interferes with the effect of glucagon, cyclic AMP and epinephrine, causing pyruvate kinase to function normally and gluconeogenesis to be shut down. Furthermore, glucose was found to inhibit and disrupt gluconeogenesis, leaving pyruvate kinase activity and glycolysis unaffected. Overall, the interaction between hormones plays a key role in the functioning and regulation of glycolysis and gluconeogenesis in the cell. [27]

Inhibitory effect of metformin Edit

Metformin, or dimethylbiguanide, is the primary treatment used for type 2 diabetes. Metformin has been shown to indirectly affect pyruvate kinase through the inhibition of gluconeogenesis. Specifically, the addition of metformin is linked to a marked decrease in glucose flux and increase in lactate/pyruvate flux from various metabolic pathways. Although metformin does not directly affect pyruvate kinase activity, it causes a decrease in the concentration of ATP. Due to the allosteric inhibitory effects of ATP on pyruvate kinase, a decrease in ATP results in diminished inhibition and the subsequent stimulation of pyruvate kinase. Consequently, the increase in pyruvate kinase activity directs metabolic flux through glycolysis rather than gluconeogenesis. [28]

Gene Regulation Edit

Heterogenous ribonucleotide proteins (hnRNPs) can act on the PKM gene to regulate expression of M1 and M2 isoforms. PKM1 and PKM2 isoforms are splice variants of the PKM gene that differ by a single exon. Various types of hnRNPs such as hnRNPA1 and hnRNPA2 enter the nucleus during hypoxia conditions and modulate expression such that PKM2 is up-regulated. [29] Hormones such as insulin up-regulate expression of PKM2 while hormones like tri-iodothyronine (T3) and glucagon aid in down-regulating PKM2. [30]

Deficiency Edit

Genetic defects of this enzyme cause the disease known as pyruvate kinase deficiency. In this condition, a lack of pyruvate kinase slows down the process of glycolysis. This effect is especially devastating in cells that lack mitochondria, because these cells must use anaerobic glycolysis as their sole source of energy because the TCA cycle is not available. For example, red blood cells, which in a state of pyruvate kinase deficiency, rapidly become deficient in ATP and can undergo hemolysis. Therefore, pyruvate kinase deficiency can cause chronic nonspherocytic hemolytic anemia (CNSHA). [31]

PK-LR gene mutation Edit

Pyruvate kinase deficiency is caused by an autosomal recessive trait. Mammals have two pyruvate kinase genes, PK-LR (which encodes for pyruvate kinase isozymes L and R) and PK-M (which encodes for pyruvate kinase isozyme M1), but only PKLR encodes for the red blood isozyme which effects pyruvate kinase deficiency. Over 250 PK-LR gene mutations have been identified and associated with pyruvate kinase deficiency. DNA testing has guided the discovery of the location of PKLR on chromosome 1 and the development of direct gene sequencing tests to molecularly diagnose pyruvate kinase deficiency. [32]

Applications of pyruvate kinase inhibition Edit

Reactive Oxygen Species (ROS) Inhibition Edit

Reactive oxygen species (ROS) are chemically reactive forms of oxygen. In human lung cells, ROS has been shown to inhibit the M2 isozyme of pyruvate kinase (PKM2). ROS achieves this inhibition by oxidizing Cys358 and inactivating PKM2. As a result of PKM2 inactivation, glucose flux is no longer converted into pyruvate, but is instead utilized in the pentose phosphate pathway, resulting in the reduction and detoxification of ROS. In this manner, the harmful effects of ROS are increased and cause greater oxidative stress on the lung cells, leading to potential tumor formation. This inhibitory mechanism is important because it may suggest that the regulatory mechanisms in PKM2 are responsible for aiding cancer cell resistance to oxidative stress and enhanced tumorigenesis. [33] [34]

Phenylalanine inhibition Edit

Phenylalanine is found to function as a competitive inhibitor of pyruvate kinase in the brain. Although the degree of phenylalanine inhibitory activity is similar in both fetal and adult cells, the enzymes in the fetal brain cells are significantly more vulnerable to inhibition than those in adult brain cells. A study of PKM2 in babies with the genetic brain disease phenylketonurics (PKU), showed elevated levels of phenylalanine and decreased effectiveness of PKM2. This inhibitory mechanism provides insight into the role of pyruvate kinase in brain cell damage. [35] [36]

Pyruvate Kinase in Cancer Edit

Cancer cells have characteristically accelerated metabolic machinery and Pyruvate Kinase is believed to have a role in cancer. When compared to healthy cells, cancer cells have elevated levels of the PKM2 isoform, specifically the low activity dimer. Therefore, PKM2 serum levels are used as markers for cancer. The low activity dimer allows for build-up of phosphoenol pyruvate (PEP), leaving large concentrations of glycolytic intermediates for synthesis of biomolecules that will eventually be used by cancer cells. [8] Phosphorylation of PKM2 by Mitogen-activated protein kinase 1 (ERK2) causes conformational changes that allow PKM2 to enter the nucleus and regulate glycolytic gene expression required for tumor development. [37] Some studies state that there is a shift in expression from PKM1 to PKM2 during carcinogenesis. Tumor microenvironments like hypoxia activate transcription factors like the hypoxia-inducible factor to promote the transcription of PKM2, which forms a positive feedback loop to enhance its own transcription. [8]

A reversible enzyme with a similar function, pyruvate phosphate dikinase (PPDK), is found in some bacteria and has been transferred to a number of anaerobic eukaryote groups (for example, Streblomastix, Giardia, Entamoeba, and Trichomonas), it seems via horizontal gene transfer on two or more occasions. In some cases, the same organism will have both pyruvate kinase and PPDK. [38]

Expression of Pentose Phosphate Pathway-Related Proteins in Breast Cancer

Purpose. The purpose of this study was to assess the expression of pentose phosphate pathway- (PPP-) related proteins and their significance in clinicopathologic factors of breast cancer. Methods. Immunohistochemical staining for PPP-related proteins (glucose-6-phosphate dehydrogenase [G6PDH], 6-phosphogluconolactonase [6PGL], 6-phosphogluconate dehydrogenase [6PGDH], and nuclear factor-erythroid 2-related factor 2 [NRF2]) was performed using tissue microarray (TMA) of 348 breast cancers. mRNA levels of these markers in publicly available data from the Cancer Genome Atlas project and Kaplan-Meier plotters were analyzed. Results. Expression of G6PDH and 6PGL was higher in HER-2 type (

, resp.) and lower in luminal A type. 6PGDH expression was detected only in TNBC subtype ( ). G6PDH positivity was associated with ER negativity ( ), PR negativity ( ), and HER-2 positivity ( ), whereas 6PGL positivity was associated with higher T stage (

). The 562 expression profile from the TCGA database revealed increased expression of G6PDH and 6PG in the tumor compared with normal adjacent breast tissue. The expression of G6PDH was highest in HER-2 type. HER-2 and basal-like subtypes showed higher expression of 6PGDH than luminal types. Conclusion. PPP-related proteins are differentially expressed in breast cancer according to molecular subtype, and higher expression of G6PDH and 6PGL was noted in HER-2 subtype.

1. Introduction

The pentose phosphate pathway (PPP) is a major glucose catabolic pathway parallel to glycolysis that is responsible for synthesis of the nucleotide precursor ribose and nicotinamide adenine dinucleotide phosphate (NADPH) required for glucose metabolism. The PPP consists of an oxidative branch and a nonoxidative branch. Glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL), and 6-phosphogluconate dehydrogenase (6PGDH) are major proteins involved in the synthesis of NADPH and ribonucleotide through the oxidative branch. The PPP provides pentose phosphate required for nucleic acid synthesis in rapidly growing cells. In cancers, the PPP supplies not only pentose phosphate but also NADPH, which is important for lipid synthesis and cell survival under stressful circumstances. Thus, the importance of the PPP is highlighted in rapidly growing cancer cells, and previous studies have reported that the expression of PPP-related enzymes is increased in human cancer tissues [1–3].

As breast cancer is a heterogeneous disease in terms of clinical, histologic, and molecular genetic aspects, a lot of effort has focused on classifying the disease into subgroups with similar characteristics. The molecular genetic subtypes of luminal A, luminal B, HER-2, and normal breast-like and basal-like type were identified by gene profiling analysis [4–6]. Separately, breast cancers with a combined negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), which has therapeutic implications, are classified as triple-negative breast cancer (TNBC) [7]. This intrinsic heterogeneity in the molecular genetics of breast cancer gives rise to heterogeneity in histology, clinical features, treatment response, and prognosis as well as metabolic features. Previous studies have reported increased expression of glycolysis-related proteins GLUT-1 and CAIX in the basal-like type and TNBC [8, 9] and increased expression of glutaminolysis-related proteins in the HER-2 type [10], suggesting a relationship between metabolism and molecular subtypes of breast cancer. However, there are a limited number of studies on the expression of pentose phosphate pathway-related proteins in breast cancer. The objective of this study was to assess the expression of pentose phosphate pathway-related proteins according to breast cancer molecular subtype and their biological and clinical implications.

2. Materials and Methods

2.1. Patient Selection and Histologic Evaluation

Breast cancer tissues were obtained form 348 patients, who were diagnosed as invasive ductal carcinoma not otherwise specified and had undergone mastectomy at Severance Hospital (Seoul, Republic of Korea) during the period of January 2001 to December 2006. This study group is selected form previously published study population [11]. Exclusion criteria were preoperative chemotherapy or hormonal therapy.

This study was approved by the Institutional Review Board of Yonsei University Severance Hospital. The IRB waived the need for informed consent from patients. Breast pathologist (Ja Seung, Koo) reviewed the histologic features by using hematoxylin & eosin- (H&E-) stained slides for all cases. Histologic grade was assessed using the Nottingham grading system [12]. Clinicopathologic parameters including patient age at initial diagnosis, lymph node metastasis, tumor recurrence, distant metastasis, were retrieved from electronic medical records of each case.

2.2. Tissue Microarray

A TMA construct of 3 mm diameter cores was generated from the 10% neutrally buffered formalin-fixed, paraffin-embedded tissue blocks of radical prostatectomy specimens using a tissue microarrayer. Two representative cores from different cancer areas were included for each case. Each tissue core was assigned a unique tissue microarray location number that was linked to a database containing deidentified clinicopathologic data.

2.3. Immunohistochemistry

Antibodies used for immunohistochemistry are summarized in Table 1. Briefly, representative paraffin blocks were cut consecutively at 4 μm thickness, and sections were deparaffinized in xylene and treated with 0.3% hydrogen peroxide in methanol for 20 minutes to block any endogenous peroxidase activity. Citrate buffer was used for antigen retrieval. Nonspecific binding was limited by using protein blocking buffer for 10 minutes. The sections were washed in phosphate-buffered saline and then incubated with the primary antibody for 20 minutes at room temperature. The samples were then incubated in secondary antibody (biotinylated) for 10 minutes, followed by incubation with streptavidin-horseradish peroxidase for 10 minutes, and exposed to diaminobenzidine, which was used as a chromogen. All labeled streptavidin-biotin-horseradish peroxidase system chemicals were obtained from Dako Cytomation Corp. (Carpinteria, CA, USA). Counterstaining was performed with Mayer’s hematoxylin. Negative controls were treated similarly with the exception of incubation with the primary antibody (nonspecific staining control).

2.4. Interpretation of Immunohistochemical Staining

All immunohistochemical markers were evaluated twice by two independent investigators blinded to the clinical details. Cutoff value of 1% or more positively stained nuclei was employed to define ER and PR positivity [13]. HER-2 status was analyzed according to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines using the following categories: 0 = no immunostaining 1+ = weak incomplete membranous staining, less than 10% of tumor cells 2+ = complete membranous staining, either uniform or weak in at least 10% of tumor cells and 3+ = uniform intense membranous staining in at least 30% of tumor cells [14]. HER-2 immunostaining was considered positive when strong (3+) membranous staining was observed, whereas cases with 0 to 1+ staining were counted as negative. Cases showing 2+ HER-2 expression were further evaluated for HER-2 amplification by fluorescent in situ hybridization (FISH).

Immunohistochemical markers for G6PDH, 6PGL, 6PGDH, and NRF2 were assessed by a semiquantitative evaluation method as follows [15]: 0: negative or weak immunostaining in <1% of the tumor 1: focal expression in 1–10% of the tumor 2: positive in 11%–50% of the tumor and 3: positive in 51%–100% of the tumor. The evaluation was made for the whole area of the tumor, and cases with a score greater than 2 were classified as positive.

2.5. Tumor Phenotype Classification

We classified each case breast cancer into molecular phenotype by surrogate immunohistochemistry results for ER, PR, HER-2, Ki-67 labeling index (LI), and FISH results for HER-2 as follows [16]: luminal A type, ER or/and PR positive, HER-2 negative, and Ki-67 LI < 14% luminal B type (HER-2 negative), ER or/and PR positive, HER-2 negative, and Ki-67 LI ≥ 14% luminal B type (HER-2 positive), ER or/and PR positive and HER-2 overexpressed or/and amplified HER-2 overexpression type, ER and PR negative and HER-2 overexpressed or/and amplified and TNBC type: ER, PR, and HER-2 negative.

2.6. Validation of Expression of PPP-Related Markers in a Public Database

We obtained clinical information and level 3 normalized gene expression (RSEM) values from RNA sequencing data of breast cancer (BRCA) from the Broad Genome Data Analysis Center (GDAC) Firehose server (version 01-28-2016) and filtered out genes with an expression equal to zero in more than 50% of samples. PAM50 classification information and patient survival information were also retrieved from the GDAC. We normalized the value again with the voom function of the limma package using R software (R version 3.3.1.). Another set of survival analyses was performed using the Kaplan-Meier plotter [17].

2.7. Statistical Analysis

Statistical analyses were performed with SPSS for Windows, Version 23.0 (SPSS Inc., Chicago, IL, USA). Student’s t-test, and Fisher’s exact tests were employed for continuous and categorical variablefor statistical significance. In case of multiple comparisons, an adjusted value with application of the Bonferroni multiple comparison procedure was used. value < 0.05 was considered to be statistically significant. Kaplan-Meier survival curves and log-rank statistics were employed to evaluate time to tumor recurrence and overall survival. Multivariate regression analysis was performed using the Cox proportional hazard model.

3. Results

3.1. Basal Characteristics of Breast Cancer

The 348 subjects of this study comprised 162 luminal A (46.6%), 84 luminal B (24.1), 27 HER-2 type (7.6%), and 75 TNBC (21.6%) subtypes. TNBC showed higher histologic grade ( ) and higher Ki-67 LI ( ) (Table 2).

3.2. Expression of Pentose Phosphate Pathway-Related Proteins in Breast Cancer

The expression of pentose phosphate pathway-related proteins was assessed according to the molecular subtypes of breast cancer (Figure 1). Expression of G6PDH ( ), 6PGL ( ), and 6PGDH ( ) was identified G6PDH and 6PGL showed higher expression in the HER-2 type and lower expression in luminal A type. Expression of 6PGDH was detected only in the TNBC subtype (Table 3).

3.3. Correlation between Expression of Pentose Phosphate Pathway-Related Proteins and Clinicopathologic Factors

The expression of pentose phosphate pathway-related proteins and clinicopathologic parameters was assessed (Figure 2). G6PDG positivity was associated with ER negativity ( ), PR negativity ( ), and HER-2 positivity ( ), and 6PGL positivity was associated with higher T stage ( ).

3.4. The Impact of Expression of Pentose Phosphate Pathway-Related Proteins on Patient Prognosis

Univariate analysis of patient survival did not show statistically significant differences with regard to expression of pentose phosphate pathway-related proteins (Table 4).

3.5. Validation of Expression of PPP-Related Markers in a Public Database

A total of 526 cases were retrieved from the TCGA study. After normalization, the mRNA level of each marker was assessed. G6PDH expression was generally increased in the tumor compared with normal adjacent breast tissue, and expression was highest in the HER-2 type compared with other types. 6PGL expression was generally increased in tumors compared with adjacent normal cells however, differential expression among tumor subtypes was not identified. Higher 6PGDH expression compared to normal tissue was noted in HER-2 and basal-like groups. The HER-2 type and basal-like subtype showed higher expression of 6PGDH than luminal types of tumor. Finally, the expression level of NRF2 was decreased in all tumor subtypes compared with normal tissue. Univariate analysis of patient survival with regard to expression of G6PDG, 6PGL, 6PGDH, and NRF2 did not show statistical significance although there was a tendency toward longer overall survival with lower expression of 6PGL and NRF2 in luminal B subtype (

, Figure 3(b)). In the cohort of the Kaplan-Meier plotter, high expression of G6PD was generally related to longer overall survival and recurrence-free survival (Figure 3(c)).

4. Discussion

Malignant tumors generally show a rapid growth rate and invasive traits, which require metabolic remodeling of cancer cells and stromal cells. As such, the pentose phosphate pathway is an indispensable metabolic pathway in malignant tumors because of the demand for a high rate of nucleic acid synthesis during growth and the NADPH necessary for cell survival during oncogenic cellular stress. In addition, reactive oxygen species resulting from the rapidly increased metabolism may trigger mutation of protooncogenes and promote protumorigenic signaling, all of which aggravate oxidative stress in cancer cells. Thus, a mechanism for activating the oxidative PPP is expected to be present in cancer cells for maintenance of a high enough level of NADPH. It is possible that an AMPK-dependent mechanism also exists given that oxidative PPP is dependent on glucose availability.

We assessed the expression of PPP-related proteins in TMAs of human breast cancer tissues and a TCGA data set and both analyses revealed higher expression in HER-2 type cancers and lower expression in luminal type cancers. A previous study revealed activation of the PPP in breast carcinoma cells compared with normal breast tissue [18, 19] this was confirmed in an analysis of the TCGA data set, which showed increased expression of PPP-related markers in breast cancer tissue compared with normal control.

There are few studies on activation of the PPP in breast cancer. Previous studies on human breast cancer tissue revealed differential expression of proteins related to glycolysis, glutamine metabolism, lipid metabolism, and serine/glycerine metabolism according to molecular subtype [9, 10, 20–22], suggesting unique metabolic properties of each subtype. Generally, subtypes with a high proliferation rate and aggressive biological behaviors, such as HER-2 or TNBC types, show increased expression of metabolic factors [9, 10, 20–22], and comparable results were obtained in this study. A potential mechanism for higher expression of PPP markers in the HER-2 type is the relationship of HER-2 with NRF2. A previous study reported association between NRF2 and HER-2 in the ErbB2/HER-2-positive breast cancer cell line BT-474 [23], with knockdown of NRF2 leading to repression of HER-2 expression. As NRF2 is the key molecule that coordinates the PPP and is known to have a regulatory role in cancer [24], crosstalk between HER-2 and the PPP mediated by NRF2 may exist. A second mechanism involves the fatty acid synthesis pathway in HER-2 type cancer. TP53-mutated breast cancer shows upregulation of PGD, TK, and ribose 5-phosphate isomerase A [25]. Previous studies reported that a high level of transketolase 1 was correlated with HER-2/neu overexpression [26] and that HER-2 overexpression increases the translation of fatty acid synthase and vice versa [27, 28]. Given that NADPH plays a major role in fatty acid synthesis by fatty acid synthase, HER-2 overexpressing tumor cells may use the PPP as a source of NADPH. It is noticeable that resistance to anti-HER-2 therapy can be overcome by blockade of the fatty acid synthesis pathway. Thus, understanding metabolic reprogramming in terms of the PPP seems clinically relevant.

G6PDH is the rate-limiting enzyme in the PPP and is also highlighted in this study of breast cancer. G6PDH reflects oxidative PPP and the equilibrium between glycolysis and the PPP. p53 is a well-known regulator of the PPP through inhibition of the dimerization and activation of G6PDH [29]. This study revealed a difference in the expression of G6PDH among subtypes of breast cancer, and analysis of the TCGA data showed relatively increased G6PDH levels in all subtypes of breast tumor compared with normal breast tissue. Given that expression and activation of G6PDH in cells are tightly regulated, the increased expression of G6PDH in breast cancers may reflect general activation of the PPP. Interestingly, increased expression of G6PDH was most prominent in HER-2 type breast cancers, indicating transcriptionally regulated expression of G6PDH in this specific type of breast cancer.

The role of NRF2 in tumorigenesis is a subject of debate as activation of NRF2 shows both a tumor suppressor role and oncogenic roles [30]. The NRF2 level was downregulated in all types of breast cancers in the TCGA dataset, suggesting a possible role of NRF2 as a tumor suppressor in breast cancer. However, it is also possible that the result of RNA sequencing may not reflect actual activity of NRF2 in cells due to posttranslational regulation by ubiquitination and degradation.

The clinical implication of this study is the identification of the PPP protein as a potential therapeutic target. Previous studies reported that inhibition of PPP proteins resulted in growth inhibition and cell death in leukemia [31], ovary cancer [32], urinary bladder cancer [33], and breast cancer/prostate cancer [34], suggesting that modulation of this pathway may have therapeutic potential in the treatment of cancer.

In conclusion, PPP-related proteins are differentially expressed according to the molecular subtype of breast cancer in particular, G6PDH and 6PGL are highly expressed in HER-2 type breast cancer. Thus, understanding of the role of this pathway in breast cancers and further studies on the effects of targeting this pathway are needed to clarify the clinical implications of PPP in breast cancers.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1420080). This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science ICT and Future Planning (2015R1A1A1A05001209).


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Copyright © 2018 Junjeong Choi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Calvin-Benson Cycle

The Calvin-Benson cycle has three stages. In stage 1, the enzyme RuBisCO incorporates carbon dioxide into an organic molecule, 3-PGA. In stage 2, the organic molecule is reduced using electrons supplied by NADPH. In stage 3, RuBP, the molecule that starts the cycle, is regenerated so that the cycle can continue. Only one carbon dioxide molecule is incorporated at a time, so the cycle must be completed three times to produce a single three-carbon GA3P molecule, and six times to produce a six-carbon glucose molecule.

No. Your supposition is incorrect — the phosphate in glyceraldehyde 3-phosphate has to come from somewhere, and it comes from glucose 6-phosphate. The reason a second ATP is required before you get to the triose phosphate stage in glycolysis is that you are generating two molecules of triose phosphate. In the pentose phosphate pathway (energy-producing non-oxidative branch) you are not generating two molecules of triose-P from one hexose-P, you are generating two hexose-P and one trisose-P from three hexose-P, as shown in my Diagrams 2 and 3 below. (The other three carbon atoms are lost as CO2.)

A good way of approaching this question is to ask “What can be produced by the pentose phosphate pathway that cannot be produced by glycolysis?”.

Glycolysis may be summarized in this context as:

Glucose + NAD + ➝ Pyruvate + NADH + 2ATP

But to allow glycolysis to continue the NADH is reoxidized to NAD + :

So the sole product of glycolysis for the erythrocyte is ATP (primarily for active cation transport to maintain cell shape) lactate passes into the blood for recycling.

The Pentose Phosphate Pathway (the oxidative stage) is shown in Diagram 1, above, and may be summarized in the way done for glycolysis as:

Glucose + ATP + 2NADP + ➝ Ribulose 5-P + CO2 + 2NADPH

Ribulose 5-P has two possible fates, but only one differs from glycolysis, so the two distinguishing products of the pathway are ribose and NADPH.

Ribose is important for nucleic acid synthesis, particularly in dividing cells, explaining the increased activity of the pentose phosphate pathway in those cells. This cannot be the reason for the high activity of the pathway in erythrocytes as they have no nuclei and do not divide. In fact the ribulose 5-P is fed back into glycolysis for generation of ATP as shown in diagrams 2 and 3.

NADPH, then, is the answer in this case. It is the reducing agent used in the cytoplasm for synthetic processes (unlike NADH used particularly for ATP generation in the mitochondria), and so the pentose phosphate pathway is found in cells such as adipose, mammary gland and liver, that synthesize fatty acids, and cells that synthesize steroids. However that is not there is no fatty acid or steroid synthesis in the erythrocyte.

NADPH is important in erythrocytes as it is the specific source of reducing power required to keep the molecule glutathione in a reduced state. This has an important protective role in reducing cellular molecules that have become oxidized by molecular oxygen, a problem that is more acute in erythrocytes than in perhaps any other cells as they are the carriers of molecular oxygen. The cell membrane is particularly prone to oxidative damage. You can read about this online in this chapter in Berg et al.

Why is pentose phosphate pathway important?

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A: Nernst equation is mainly utilized for the cell potential determination which is indicated by Ecell.

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Watch the video: Pentose phosphate pathway (June 2022).