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Metabolic reprogramming plays a pivotal role in the development and progression of tumors. Tumor cells rely on glycolysis as their primary energy production pathway and effectively utilize biomolecules generated by the pentose phosphate pathway (PPP) for efficient biosynthesis. However, the role of 6-phosphogluconate dehydrogenase (6PGD), a crucial enzyme in the PPP, remains unexplored in esophageal squamous cell carcinoma (ESCC). In this study, we observed a significant upregulation of 6PGD expression in ESCC tissues, which correlated with an unfavorable prognosis among patients. The experiments demonstrated that knockdown of 6PGD induces oxidative stress and suppresses ESCC cell proliferation. Mechanistically, this is achieved through AMPK activation and subsequent inhibition of downstream mTOR phosphorylation. Moreover, physcion has been found to inhibit 6PGD activity and exert its anti-ESCC effect via the AMPK/mTOR pathway. Subsequently, we conducted both in vitro and in vivo experiments to validate the anticancer efficacy of combining metformin, an AMPK activator, with physcion. The results demonstrated a significantly enhanced inhibition of ESCC growth. This study elucidates the impact of 6PGD on ESCC cell proliferation along with its underlying molecular mechanisms, highlighting its potential as a therapeutic target for ESCC. Furthermore, we investigated a novel approach for improved anti-tumor therapy involving physcion and metformin. These findings will contribute new insights to clinical treatment strategies for ESCC while providing a theoretical foundation for developing molecular targeted therapies.

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 (SLC7A11high) 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 SLC7A11high 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 SLC7A11high cancer cells and suppress SLC7A11high 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 SLC7A11high cancers.Liu et al. show that cancer cells with high levels of SLC7A11 have increased dependency on the pentose phosphate pathway and consequently accumulate disulfide, and can be therapeutically targeted by limiting glucose supply.

The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes. Myeloid derived suppressor cells (MDSC) use different metabolic mechanisms to adapt to the tumour microenvironment. Here the authors show that 6-phosphogluconate dehydrogenase (6PGD) is important for MSDC function and that blockade of 6PGD impaired MDSC function and suppresses tumour growth leading to metabolic and functional changes in the MDSC and a more pro-inflammatory phenotype.

The rapid emergence of drug resistant Staphylococcus aureus ( S. aureus ) poses a serious threat to public health globally. Silver (Ag)-based antimicrobials are promising to combat antibiotic resistant S. aureus , yet their molecular targets are largely elusive. Herein, we separate and identify 38 authentic Ag + -binding proteins in S. aureus at the whole-cell scale. We then capture the molecular snapshot on the dynamic action of Ag + against S. aureus and further validate that Ag + could inhibit a key target 6-phosphogluconate dehydrogenase through binding to catalytic His185 by X-ray crystallography. Significantly, the multi-target mode of action of Ag + (and nanosilver) endows its sustainable antimicrobial efficacy, leading to enhanced efficacy of conventional antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance. Silver (Ag) has been used as an antimicrobial agent since a long time, but its molecular mechanism of action was not elucidated due to technical challenges. Here, the authors develop a mass spectrometric approach to identify the Ag-proteome in Staphylococcus aureus , and capture a molecular snapshot of the dynamic bactericidal mode of action of Ag through targeting multiple biological pathways.

Targeting the enzymes of Pentose Phosphate Pathway (PPP) has been emerged as a novel strategy for treatment of cancer. 6-phosphogluconate dehydrogenase (6PGD) is third enzyme of PPP and converts 6-phosphogluconate (6-PG) into ribulose 5-phosphate (R-5-P) and produces NADPH. The overexpression of 6PGD has been reported in many human cancers especially in breast cancer and is emerged as the potential anti-cancer drug target. The current study is focused to screen an already established library of plant extracts against 6PGD, among which Pomegranate peel extract showed significant 6PGD inhibitory activity with IC50 value = 0.090 μg/mL. Pomegranate peel competitively inhibited NADP+ and 6‐phosphogluconate to 6PGD enzyme having Ki constant value = 12.72 ± 5.54 ng/mL. Moreover, anti-breast cancer activity against MCF-7 cells determined Pomegranate peel as the potent inhibitor of cancerous cells with IC50 value = 3.138 μg/mL. Toxicity profiling of pomegranate peel extract (2000mg/kg) did not show any adverse effect on mice. Moreover, Ont the base of literature a library of known compounds of pomegranate was prepared and established and screened against 6PGD for the identification of actual responsible phytochemicals of 6PGD activity by using molecular docking. Computational tools were used to evaluate selected potent hits. Out of 26 compounds, three potent phytochemicals (Procyanidin, Delphinidin and Cyanidin) exhibited the best binding affinities with 6PGD. In addition, these phytochemicals displayed the best favorable hydrogen bonding, binding energy, and protein–ligand interactions as compare to 3PG. Molecular dynamics simulation suggested that these hits form a stable binding complex with the active site of 6PGD. These findings suggest that Pomegranate peel and its secondary metabolites as the potent inhibitors of 6PGD and the best drug candidate for treatment of breast cancer.

Engineering the coenzyme specificity of redox enzymes plays an important role in metabolic engineering, synthetic biology, and biocatalysis, but it has rarely been applied to bioelectrochemistry. Here we develop a rational design strategy to change the coenzyme specificity of 6-phosphogluconate dehydrogenase (6PGDH) from a hyperthermophilic bacterium Thermotoga maritima from its natural coenzyme NADP + to NAD + . Through amino acid-sequence alignment of NADP + - and NAD + -preferred 6PGDH enzymes and computer-aided substrate-coenzyme docking, the key amino acid residues responsible for binding the phosphate group of NADP + were identified. Four mutants were obtained via site-directed mutagenesis. The best mutant N32E/R33I/T34I exhibited a ~6.4 × 10 4 -fold reversal of the coenzyme selectivity from NADP + to NAD + . The maximum power density and current density of the biobattery catalyzed by the mutant were 0.135 mW cm −2 and 0.255 mA cm −2 , ~25% higher than those obtained from the wide-type 6PGDH-based biobattery at the room temperature. By using this 6PGDH mutant, the optimal temperature of running the biobattery was as high as 65 °C, leading to a high power density of 1.75 mW cm −2 . This study demonstrates coenzyme engineering of a hyperthermophilic 6PGDH and its application to high-temperature biobatteries.

Genetic polymorphism in key metabolic genes plays a pivotal role in shaping phenotypes and adapting to varying environments. Polymorphism in the metabolic gene 6-phosphogluconate dehydrogenase (6Pgdh) in bulb mites, Rhizoglyphus robini is characterized by two alleles, S and F, that differ by a single amino acid substitution and correlate with male reproductive fitness. The S-bearing males demonstrate a reproductive advantage. Although the S allele rapidly fixes in laboratory settings, the persistence of polymorphic populations in the wild is noteworthy. This study examines the prevalence and stability of 6Pgdh polymorphism in natural populations across Poland, investigating potential environmental influences and seasonal variations. We found widespread 6Pgdh polymorphism in natural populations, with allele frequencies varying across locations and sampling dates but without clear geographical or seasonal clines. This widespread polymorphism and spatio-temporal variability may be attributed to population demography and gene flow between local populations. We found some correlation between soil properties, particularly cation content (Na, K, Ca, and Mg) and 6Pgdh allele frequencies, showcasing the connection between mite physiology and soil characteristics and highlighting the presence of environment-dependent balancing selection. We conducted experimental fitness assays to determine whether the allele providing the advantage in male–male competition has antagonistic effects on life-history traits and if these effects are temperature-dependent. We found that temperature does not differentially influence development time or juvenile survival in different 6Pgdh genotypes. This study reveals the relationship between genetic variation, environmental factors, and reproductive fitness in natural bulb mite populations, shedding light on the dynamic mechanisms governing 6Pgdh polymorphism.

Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes. Distant metastases from pancreatic cancer patients were previously reported by the authors to be dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Here the authors report a novel metabolic adaptation that that stably activates PGD to reprogram metastatic chromatin.

6-Phosphogluconate dehydrogenase (6PGD) is a key enzyme that converts 6-phosphogluconate into ribulose-5-phosphate with NADP + as cofactor in the pentose phosphate pathway (PPP). 6PGD is commonly upregulated and plays important roles in many human cancers, while the mechanism underlying such roles of 6PGD remains elusive. Here we show that upon EGFR activation, 6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP + and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. Abrogating 6PGD Y481 phosphorylation (pY481) dramatically attenuates EGF-promoted glioma cell proliferation, tumor growth and resistance to ionizing radiation. In addition, 6PGD pY481 is associated with Fyn expression, the malignancy and prognosis of human glioblastoma. These findings establish a critical role of Fyn-dependent 6PGD phosphorylation in EGF-promoted tumor growth and radiation resistance. 6-phosphogluconate dehydrogenase is commonly upregulated in cancers. Here, the authors show that activation of EGFR induces phosphorylation of this enzyme at Y481 to activate the pentose phosphate pathway, which consequently reduces ROS and accelerates DNA synthesis to promote tumor growth and radioresistance.

Relieving the feedback inhibition of key enzymes in a metabolic pathway is frequently the first step of producer-strain construction by genetic engineering. However, the strict feedback regulation exercised by microorganisms in methionine biosynthesis often makes it difficult to produce methionine at a high level. In this study, Corynebacterium glutamicum ATCC 13032 was metabolically engineered for methionine production. First, the metD gene encoding the methionine uptake system was deleted to achieve extracellular accumulation of methionine. Then, random mutagenesis was performed to remove feedback inhibition by metabolic end-products. The resulting strain C. glutamicum ENM-16 was further engineered to block or decrease competitive branch pathways by deleting the thrB gene and changing the start codon of the dapA gene, followed by point mutations of lysC (C932T) and pyc (G1A, C1372T) to increase methionine precursor supply. To enrich the NADPH pool, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in the pentose phosphate pathway were mutated to reduce their sensitivity to inhibition by intracellular metabolites. The resultant strain C. glutamicum LY-5 produced 6.85 ± 0.23 g methionine l −1 with substrate-specific yield ( Y P/S ) of 0.08 mol per mol of glucose after 72 h fed-batch fermentation. The strategies described here will be useful for construction of methionine engineering strains.