Regulation of the pentose phosphate pathway in cancer

Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phos- phate pathway （PPP） is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxi- dative branch and produces a reduced form of nico- tinamide adenine dinucleotide phosphate （NADPH）, an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell pro- liferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous fac- tors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.

Terahertz time-domain spectroscopy of some pentoses

The well-resolved absorption spectra of D-xylose, D-ribose, D-arabinose, D-lyxose and other related substances in the spectral region between 0.3 and 2.0 THz are measured using tera- hertz time-domain spectroscopy (THz-TDS) at 295 K. Comparing the absorption spectra of different chemicals, we can distinguish the samples easily. Thus THz-TDS is demonstrated to be a power and characteristic spectral tool, which is highly sensitive to the minor changes of the molecular structures and can be applied to detect and analyze similar materials.

Respiratory Response of Dormant Nectarine Floral Buds on Chilling Deficiency

Changes in main biochemical respiratory pathways in dormant nectarine floral buds were studied with nectarine trees （Prunus persica.var, nectariana cv. Shuguang） in order to determine the function of respiration in dormancy release. Oxygen-electrode system and respiratory inhibitors were used to measure total respiratory rates and rates of respiratory pathways. Results showed that chilling deficiency blocked the transition of respiratory mode, and made buds stay in a state of high level pentose phosphate pathway （PPP） and low level tricarboxylie acid cycle （TCA）. The decline of PPP and activation of TCA occurred synchronously with the release of dormancy. In addition, the inhibition of PPP stimulated a respiration increase related with TCA. It could be concluded that the function of PPP activation in dormancy release might be limited and PPP declination inducing TCA activation might be part of respiration mode transition mechanism during bud sprouting.

Xylose: absorption, fermentation, and post-absorptive metabolism in the pig

Xylose, as β-1,4-linked xylan, makes up much of the hemicel ulose in cel wal s of cereal carbohydrates fed to pigs. As inclusion of fibrous ingredients in swine diets continues to increase, supplementation of carbohydrases, such as xylanase,is of interest. However, much progress is warranted to achieve consistent enzyme efficacy, including an improved understanding of the utilization and energetic contribution of xylanase hydrolysis product（i.e. xylooligosaccharides or monomeric xylose）. This review examines reports on xylose absorption and metabolism in the pig and identifies gaps in this knowledge that are essential to understanding the value of carbohydrase hydrolysis products in the nutrition of the pig. Xylose research in pigs was first reported in 1954, with only sporadic contributions since. Therefore, this review also discusses relevant xylose research in other monogastric species, including humans. In both pigs and poultry, increasing purified D-xylose inclusion general y results in linear decreases in performance, efficiency, and diet digestibility. However,supplementation levels studied thus far have ranged from 5% to 40%, while theoretical xylose release due to xylanase supplementation would be less than 4%. More than 95% of ingested D-xylose disappears before the terminal ileum but mechanisms of absorption have yet to be ful y elucidated. Some data support the hypothesis that mechanisms exist to handle low xylose concentrations but become overwhelmed as luminal concentrations increase. Very little is known about xylose metabolic utilization in vertebrates but it is wel recognized that a large proportion of dietary xylose appears in the urine and significantly decreases the metabolizable energy available from the diet. Nevertheless, evidence of labeled D-xylose-1-^（14）C appearing as expired^（14）CO_2 in both humans and guinea pigs suggests that there is potential,although small, for xylose oxidation. It is yet to be determined if pigs develop increased xylose metabolic capacity with increased adaptation time to diets supplemented with xylose or xylanase. Overall, xylose appears to be poorly utilized by the pig, but it is important to consider that only one study has been reported which supplemented D-xylose dietary concentrations lower than 5%. Thus, more comprehensive studies testing xylose metabolic effects at dietary concentrations more relevant to swine nutrition are warranted.

Effects of GA3 and ABA on the respiratory pathways during the secondary bud burst in black currants

The effects of exogenous gibberellic acid (GA(3)) and abscisic acid (ABA) on the total respiratory rate, percentages of total respiratory rate contributed by respiratory pathways [Embden-Meyerhof- Parnas Pathway (EMP), Pentose Phosphate Pathway (PPP), and Tricarboxylic Acid Cycle (TCA)], and conversion of starch to soluble sugars in the buds of black currants during secondary bud burst were investigated to determine the relationship between respiratory rates and secondary bud burst. 'Adelinia', a black currant cultivar that is prone to secondary bud burst after the first harvest, was used in this study. Mature bushes of Adelinia were sprayed with 30 mg/L GA(3) and 50 mg/L ABA to manipulate bud burst. The results showed that exogenous applications of GA(3) and ABA had opposite effects on bud respiratory rate. Generally, GA(3) treatment increased the total respiratory rate and respiratory rate of the TCA and PPP, and the respiratory rates after GA(3) treatment were higher than those of control. While ABA treatment mostly decreased the total respiratory rate and the respiratory rate of TCA and PPP in buds in comparison to control. In terms of the percentage of the three respiratory rates in comparison to the total respiratory rate, GA(3) treatment significantly increased the percentage of TCA and PPP respiratory rate in comparison to the control (P < 0.01), whereas ABA decreased the rates. GA(3) significantly increased the content of soluble sugars and decreased the starch content, while the starch content in buds after ABA treatment was significantly higher than that of the control. All results showed that PPP is a critical process for the second bud burst in black currants. While the EMP-TCA pathway is still dominant in bud respiration, provides a series of basic materials and energy (ATP). The conversion of starch to soluble sugars is essential for bud burst. Thus, we conclude that an energy shortage is a main contributor in ABA inhibition of the secondary bud burst of black currants.

Carbon utilization profile of a thermophilic fungus, <i>Thermomyces lanuginosus</i>using phenotypic microarray

The thermophilic filamentous fungus, Thermomyces lanuginosus produces the largest amount of xylanase reported. In addition to this, it expresses large amount of other enzymes that have been used industrially or have academic interest. Thus, this fungus has a potential to be applied for biomass conversion to produce biofuel or other applications. In this study, the Biolog system was used to characterize the utilisation and growth of T. lanuginosus on 95 carbon sources. The carbohydrates based compounds, both single sugars and oligosaccharide, showed the best utilisation profile, with the pentose sugar xylose inducing the highest growth, followed by trehelose, raffinose, D-mannose turanose fructose and glucose. Among oligosaccharides, sucrose had the highest mycelium formation followed by stachyose, maltose, maltotriose, glycogen and dextrin. Interestingly the fungus also grew well on cellobiose suggesting that this fungus can produce cellulose hydrolysing proteins. D-alanine was the best amino acid to promote fungal growth while the effect of other amino acids tested was similar to the control. These results demonstrate the ability of this fungus to grow relatively well on most plant based compounds thus making this fungus a possible candidate for plant biomass conversion which can be applied to a number of biotechnological applications including biofuel production.

Nicotinamide adenine dinucleotide phosphate promote the rapid growth of the tumor

Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase is the main source of ROS(intracellular reactive oxygen species), ROS plays an important role in a variety of tumor, the ROS mediated by NADPH oxidase increase the expression of hypoxia inducing factor alpha(HIF-α) through multiple signaling pathways in tumor, and HIFcould be regulated and controlled by downstream multiple targeted genes such as vascular endothelial growth factor(VEGF), glucose transporter(GLUT) to promote tumor angiogenesis, cell energy metabolism reprogram and tumor metastasis.HIF-α, meanwhile, also can regulate the expression of NADPH oxidase by ROS, thus further promote development of tumor.In this review, we will summarize the functions of NADPH in tumorigenesis and discuss their potential implications in cancer therapy.

PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism

Metabolic reprogramming is a hallmark of cancer,including lung cancer.However,the exact underlying mechanism and therapeutic potential are largely unknown.Here we report that protein arginine methyltransferase 6(PRMT6)is highly expressed in lung cancer and is required for cell metabolism,tumorigenicity,and cisplatin response of lung cancer.PRMT6 regulated the oxidative pentose phosphate pathway(PPP)flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phosphogluconate dehydrogenase(6PGD)and a-enolase(ENO1).Furthermore,PRMT6 methylated R324 of 6PGD to enhancing its activity;while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate(2-PG)binding to ENO1,respectively.Lastly,targeting PRMT6 blocked the oxidative PPP flux,glycolysis pathway,and tumor growth,as well as enhanced the antitumor effects of cisplatin in lung cancer.Together,this study demonstrates that PRMT6 acts as a posttranslational modification(PTM)regulator of glucose metabolism,which leads to the pathogenesis of lung cancer.It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer

Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of chemotherapy.However,limitations exist in current strategies including chemoresistance for instance.Tumor initiation and progression is driven by reprogramming of metabolism,in particular during HCC development.Recently,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment.In this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical intervention.We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment.Furthermore,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

The 6-phosphogluconate Dehydrogenase Genes Are Responsive to Abiotic Stresses in Rice

Glucose-6-phosphate dehydrogenase （G6PDH, E.C. 1.1.1.49） and 6-phosphogluconate dehydrogenase （6PGDH, EC 1.1.1.44） are both key enzymes of the pentose phosphate pathway （PPP）. The OsG6PDH1 and Os6PGDH1 genes encoding cytosolic G6PDH and cytosolic 6PGDH were Isolated from rice （Oryza sativa L.）. We have shown that Os6PGDH1 gene was up-regulated by salt stress. Here we reported the isolation and characterization of Os6PGDH2 from rice, which encode the plastidic counterpart of 6PGDH. Genomic organization analysis indicated that OsG6PDH1 and OsG6PDH2 genes contain multiple introns, whereas two Os6PGDH1 and Os6PGDH2 genes have no introns in their translated regions. In a step towards understanding the functions of the pentose phosphate pathway in plants in response to various abiotic stresses, the expressions of four genes in the rice seedlings treated by drought, cold, high salinity and abscisic acid （ABA） were investigated. The results show that OsG6PDH1 and OsG6PDH2 are not markedly regulated by the abiotic stresses detected. However, the transcript levels of both Os6PGDH1 and Os6PGDH2 are up-regulated in rice seedlings under drought, cold, high salinity and ABA treatments. Meanwhile, the enzyme activities of G6PDH and 6PGDH in the rice seedlings treated by various abiotic stresses were Investigated. Like the mRNA expression patterns, G6PDH activity remains constant but the 6PGDH Increases steadily during the treatments. Taken together, we suggest that the pentose phosphate pathway may play an important role in rice responses to abiotic stresses and the second key enzyme of PPP, 6PGDH, may function as a regulator controlling the efficiency of the pathway under abiotic stresses.

NADPH debt drives redox bankruptcy:SLC7A11/xCT-mediated cystine uptake as a double-edged sword in cellular redox regulation

Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell survival under oxidative stress conditions.Recent studies showed that,to prevent toxic buildup of highly insoluble cystine inside cells,cancer cells with high expression of SLC7A11(SLC7A11high)are forced to quickly reduce cystine to more soluble cysteine,which requires substantial NADPH supply from the glucose-pentose phosphate pathway(PPP)route,thereby inducing glucose-and PPP-dependency in SLC7A11high cancer cells.Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH“debt”,redox“bankruptcy”,and subsequent cell death.This review summarizes our current understanding of NADPH-generating and-consuming pathways,discusses the opposing role of SLC7A11 in protecting cells from oxidative stresseinduced cell death such as ferroptosis but promoting glucose starvationeinduced cell death,and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation.A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.

Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver

Mitochondria-associated endoplasmic reticulum membranes(MAM)play a key role in mitochondrial dynamics and function and in hepatic insulin action.Whereas mitochondria are important regulators of energy metabolism,the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown.In this study,we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver.Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity both in vitro and in vivo.Glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A(PP-PP2A)pathway,induced mitochondria fission,and impaired respiration.Blocking MAM reduction counteracted glucose-induced mitochondrial alterations.Furthermore,disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function.This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice,both characterized by chronic disruption of MAM integrity,mitochondrial fission,and altered mitochondrial respiration.These data indicate that MAM contribute to the hepatic glucose-sensing system,allowing regulation of mitochondria dynamics and function during nutritional transition.Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance.

Arginine methylation of ribose-5-phosphate isomerase A senses glucose to promote human colorectal cancer cell survival

Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway(PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribose. How cancer cells modulate PPP activity in response to glucose supply remains unclear. Here we show that ribose-5-phosphate isomerase A(RPIA), an enzyme in PPP, directly interacts with co-activator associated arginine methyltransferase 1(CARM1) and is methylated at arginine 42(R42). R42 methylation up-regulates the catalytic activity of RPIA. Furthermore, glucose deprivation strengthens the binding of CARM1 with RPIA to induce R42 hypermethylation. Insufficient glucose supply links to RPIA hypermethylation at R42, which increases oxidative PPP flux. RPIA methylation supports ROS clearance by enhancing NADPH production and fuels nucleic acid synthesis by increasing ribose supply. Importantly, RPIA methylation at R42 significantly potentiates colorectal cancer cell survival under glucose starvation. Collectively, RPIA methylation connects glucose availability to nucleotide synthesis and redox homeostasis.

Modules for in vitro metabolic engineering:Pathway assembly for biobased production of value-added chemicals

Bio-based chemical production has drawn attention regarding the realization of a sustainable society.In vitro metabolic engineering is one of the methods used for the bio-based production of value-added chemicals.This method involves the reconstitution of natural or artificial metabolic pathways by assembling purified/semi-purified enzymes in vitro.Enzymes from distinct sources can be combined to construct desired reaction cascades with fewer biological constraints in one vessel,enabling easier pathway design with high modularity.Multiple modules have been designed,built,tested,and improved by different groups for different purpose.In this review,we focus on these in vitro metabolic engineering modules,especially focusing on the carbon metabolism,and present an overview of input modules,output modules,and other modules related to cofactor management.

Glycolytic Shunts Replenish the Calvin-Benson-Bassham Cycle as Anaplerotic Reactions in Cyanobacteria

The recent discovery of the Entner-Doudoroff(ED)pathway as a third glycolytic route beside Embden-Meyerhof-Parnas(EMP)and oxidative pentose phosphate(OPP)pathway in oxygenic photoautotrophs requires a revision of their central carbohydrate metabolism.In this study,unexpectedly,we observed that deletion of the ED pathway alone,and even more pronounced in combination with other glycolytic routes,diminished photoautotrophic growth in continuous light in the cyanobacterium Synechocystis sp.PCC 6803.Furthermore,we found that the ED pathway is required for optimal glycogen catabolism in parallel to an operating Calvin-Benson-Bassham(CBB)cycle.It is counter-intuitive that glycolytic routes,which are a reverse to the CBB cycle and do not provide any additional biosynthetic intermediates,are important under photoautotrophic conditions.However,observations on the ability to reactivate an arrested CBB cycle revealed that they form glycolytic shunts that tap the cellular carbohydrate reservoir to replenish the cycle.Taken together,our results suggest that the classical view of the CBB cycle as an autocatalytic,completely autonomous cycle that exclusively relies on its own enzymes and C02 fixation to regenerate ribulose-1,5-bisphosphate for Rubisco is an oversimplification.We propose that in common with other known autocatalytic cycles,the CBB cycle likewise relies on anaplerotic reactions to compensate for the depletion of intermediates,particularly in transition states and under fluctuating light conditions that are common in nature.

Cancer metabolism in gastrointestinal cancer

Cancer cells exhibit altered glucose metabolism,mitochondrial dysfunction,anaerobic glycolysis and upregulation of the pentose phosphate pathway(PPP).Recent genetic and metabolic analyses have provided insights into the molecular mechanisms of genes that are involved in the alteration of cancer metabolism and tumorigenesis.Hypoxic induced factor 1 regulates the reciprocal relationship between glycolysis and oxidative phosphorylation,and p53 also modulates the balance between the glycolytic pathway and oxidative phosphorylation.Mitochondria function in cancer differs from that in normal cells owing to mutations of mitochondrial DNA and alterations of metabolism.Overexpression of transcription factors,metabolite transporters and glycolytic enzymes is observed and associated with poor prognosis,and it may be associated with chemoradiotherapy resistance in multiple cancer cell types.The PPP plays a critical role in regulating cancer cell growth by supplying cells with ribose-5-phosphate and nicotinamide adenine dinucleotide phosphate for detoxifi cation of intra-cellular reactive oxygen species(ROS),reductive biosynthesis and ribose biogenesis.ROS levels increase during carcinogenesis owing to metabolic aberrations.This review discusses alterations of mitochondrial metabolism,anaerobic glycolysis,the PPP and control of ROS levels by the endogenous anti-oxidant system in cancer,as well as the novel small molecules targeting these enzymes or transporters that exert anti-proliferative effects.

Ethanol production by a filamentous fungal strain Byssochlamys fulva AM130 under alternating aerobic and oxygen-limited conditions

Byssochlamys fulva AM130,a novel strain of filamentous fungus,could produce ethanol from glucose,xylose,and alkali pretreated rice straw(PRS),while the efficiencies were very low with PRS.Ethanol production of 11.84 g/L was attained by the fungus when grown in glucose,indicating that the limitations while growing on PRS were related to low hydrolytic efficiency.Enzyme profiling of the fungus showed 365 IU/ml of beta-glucosidase and 89 IU/ml of xylanase activity,while endoglucanase and filter paper activity were negligible,which accounts for the low hydrolytic efficiency.The fungus could survive for extended periods under oxygen-limited conditions and produce ethanol.The fungal mycelia could also be used for repeated cycles of anaerobic fermentation,wherein the ethanol yield improved with each consecutive cycle.