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Pentose Phosphate Pathway

Dongxin Zhao, Mehmet G Badur, Jens Luebeck, Jose H Magaña, Amanda Birmingham, Roman Sasik, Christopher S Ahn, Trey Ideker, Christian M Metallo, Prashant Mali
The metabolic pathways fueling tumor growth have been well characterized, but the specific impact of transforming events on network topology and enzyme essentiality remains poorly understood. To this end, we performed combinatorial CRISPR-Cas9 screens on a set of 51 carbohydrate metabolism genes that represent glycolysis and the pentose phosphate pathway (PPP). This high-throughput methodology enabled systems-level interrogation of metabolic gene dispensability, interactions, and compensation across multiple cell types...
February 15, 2018: Molecular Cell
Weipeng Hong, Peiheng Cai, Chuncao Xu, Di Cao, Weibang Yu, Zhongxiang Zhao, Min Huang, Jing Jin
The pentose phosphate pathway (PPP), which branches from glycolysis, is correlated with cancer cell proliferation, survival and senescence. In this study, differences in the metabolic profile of the PPP and the redox status of human lung carcinoma A549 cells and cisplatin-induced multidrug-resistant A549/DDP cells were analyzed and evaluated. The results showed that A549/DDP cells exhibited differential PPP-derived metabolic features and redox-related molecules. A549/DDP cells exhibited increased expression and enzymatic activity of PPP enzyme glucose-6-phosphate dehydrogenase (G6PD)...
2018: Frontiers in Pharmacology
Ammaji Rajala, Yuhong Wang, Richard S Brush, Kristine Tsantilas, Connor S R Jankowski, Ken J Lindsay, Jonathan D Linton, James B Hurley, Robert E Anderson, Raju V S Rajala
Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that is expressed in cancer cells. Its role in tumor metabolism is not definitively established, but investigators have suggested that regulation of PKM2 activity can cause accumulation of glycolytic intermediates and increase flux through the pentose phosphate pathway. Recent evidence suggests that PKM2 also may have non-metabolic functions, including as a transcriptional co-activator in gene regulation. We reported previously that PKM2 is abundant in photoreceptor cells in mouse retinas...
February 14, 2018: Cell Death & Disease
Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F Xiao-Feng Qin, Bo Huang
Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models...
February 12, 2018: Journal of Clinical Investigation
Wenqi Xu, Jingwen Peng, Dongmei Li, Clement K M Tsui, Zhimin Long, Qiong Wang, Huan Mei, Weida Liu
Mucormycosis is one of the most invasive mycosis and has caused global concern in public health. Cutaneous mucormycosis caused by Mucor irregularis (formerly Rhizomucor variabilis) is an emerging disease in China. To survive in the human body, M. irregularis must overcome the hypoxic (low oxygen) host microenvironment. However, the exact molecular mechanism of its pathogenicity and adaptation to low oxygen stress environment is relatively unexplored. In this study, we used Illumina HiSeq technology (RNA-Seq) to determine and compare the transcriptome profile of M...
October 9, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Ioannis Papapetridis, Maaike Goudriaan, María Vázquez Vitali, Nikita A de Keijzer, Marcel van den Broek, Antonius J A van Maris, Jack T Pronk
Background: Reduction or elimination of by-product formation is of immediate economic relevance in fermentation processes for industrial bioethanol production with the yeast Saccharomyces cerevisiae. Anaerobic cultures of wild-type S. cerevisiae require formation of glycerol to maintain the intracellular NADH/NAD+ balance. Previously, functional expression of the Calvin-cycle enzymes ribulose-1,5-bisphosphate carboxylase (RuBisCO) and phosphoribulokinase (PRK) in S. cerevisiae was shown to enable reoxidation of NADH with CO2 as electron acceptor...
2018: Biotechnology for Biofuels
Ee-Been Goh, Yan Chen, Christopher J Petzold, Jay D Keasling, Harry R Beller
We previously engineered E. coli to overproduce medium- to long-chain saturated and monounsaturated methyl ketones, which could potentially be applied as diesel fuel blending agents or in the flavor and fragrance industry. Recent efforts at strain optimization have focused on cofactor balance, as fatty acid-derived pathways face the systematic metabolic challenge of net NADPH consumption [in large part, resulting from the key fatty acid biosynthetic enzyme FabG (β-ketoacyl-ACP reductase)] and net NADH production...
February 7, 2018: Biotechnology and Bioengineering
Ilya R Akberdin, Merlin Thompson, Richard Hamilton, Nalini Desai, Danny Alexander, Calvin A Henard, Michael T Guarnieri, Marina G Kalyuzhnaya
Biological methane utilization, one of the main sinks of the greenhouse gas in nature, represents an attractive platform for production of fuels and value-added chemicals. Despite the progress made in our understanding of the individual parts of methane utilization, our knowledge of how the whole-cell metabolic network is organized and coordinated is limited. Attractive growth and methane-conversion rates, a complete and expert-annotated genome sequence, as well as large enzymatic, 13C-labeling, and transcriptomic datasets make Methylomicrobium alcaliphilum 20ZR an exceptional model system for investigating methane utilization networks...
February 6, 2018: Scientific Reports
Zia Fatma, Hassan Hartman, Mark G Poolman, David A Fell, Shireesh Srivastava, Tabinda Shakeel, Syed Shams Yazdani
Biologically-derived hydrocarbons are considered to have great potential as next-generation biofuels owing to the similarity of their chemical properties to contemporary diesel and jet fuels. However, the low yield of these hydrocarbons in biotechnological production is a major obstacle for commercialization. Several genetic and process engineering approaches have been adopted to increase the yield of hydrocarbon, but a model driven approach has not been implemented so far. Here, we applied a constraint-based metabolic modeling approach in which a variable demand for alkane biosynthesis was imposed, and co-varying reactions were considered as potential targets for further engineering of an E...
February 3, 2018: Metabolic Engineering
Nelson Alencar, Irene Sola, María Linares, Jordi Juárez-Jiménez, Caterina Pont, Antonio Viayna, David Vílchez, Cristina Sampedro, Paloma Abad, Susana Pérez-Benavente, Jerónimo Lameira, José M Bautista, Diego Muñoz-Torrero, F Javier Luque
In Plasmodium falciparum the bifunctional enzyme glucose-6-phosphate dehydrogenase‒6-phosphogluconolactonase (PfG6PD‒6PGL) is involved in the catalysis of the first reaction of the pentose phosphate pathway. Since this enzyme has a key role in parasite development, its unique structure represents a potential target for the discovery of antimalarial drugs. Here we describe the first 3D structural model of the G6PD domain of PfG6PD‒6PGL. Compared to the human enzyme (hG6PD), the 3D model has enabled the identification of a key difference in the substrate-binding site, which involves the replacement of Arg365 in hG6PD by Asp750 in PfG6PD...
February 1, 2018: European Journal of Medicinal Chemistry
Katja Weckmann, Philip Diefenthäler, Marius W Baeken, Kamran Yusifli, Christoph W Turck, John M Asara, Christian Behl, Parvana Hajieva
The ability of cells to rearrange their metabolism plays an important role in compensating the energy shortage and may provide cell survival. Our study focuses on identifing the important adaptational changes under the conditions of oxygen and glucose reduction. Employing mass spectrometry-based metabolomics in combination with biochemistry and microscopy techniques we identified metabolites, proteins and biomolecular pathways alterations in primary human IMR90 fibroblasts upon energy deficits. Multivariate statistical analyses revealed significant treatment-specific metabolite level and ratio alterations as well as major energy metabolism pathways like 'glycolysis', 'pentose phosphate pathway', 'mitochondrial electron transport chain' and 'protein biosynthesis (amino acids)' indicating an activation of catabolism and reduction of anabolism as important mechanisms of adaptation towards a bioenergetic demand...
February 5, 2018: Scientific Reports
Annapoorna Sreedhar, Yunfeng Zhao
Tumor cells carry various genetic and metabolic alterations, which directly contribute to their growth and malignancy. Links between metabolism and cancer are multifaceted. Metabolic reprogramming, such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid (TCA) cycle metabolic enzymes, and dependence on lipid and glutamine metabolism are key characteristics of cancer cells. Understanding these metabolic alterations is crucial for development of novel anti-cancer therapeutic strategies. In the present review, the broad importance of metabolism in tumor biology is discussed, and the current knowledge on dysregulated metabolic enzymes involved in the vital regulatory steps of glycolysis, the TCA cycle, the pentose phosphate pathway, and lipid, amino acid, and mitochondrial metabolism pathways are reviewed...
January 2018: Biomedical Reports
William J Roesler, Kristine Dreaver-Charles
Successful learning of biochemistry requires students to engage with the material. In the past this often involved students writing out pathways by hand, and more recently directing students to online resources such as videos, songs, and animated slide presentations. However, even these latter resources do not really provide students an opportunity to engage with the material in an active fashion. As part of an online introductory metabolism course that was developed at our university, we created a series of twelve online interactive activities using Adobe Captivate 9...
February 1, 2018: Biochemistry and Molecular Biology Education
Catherine J Libby, Anh Nhat Tran, Sarah E Scott, Corinne Griguer, Anita B Hjelmeland
De-regulated cellular energetics is an emerging hallmark of cancer with alterations to glycolysis, oxidative phosphorylation, the pentose phosphate pathway, lipid oxidation and synthesis and amino acid metabolism. Understanding and targeting of metabolic reprogramming in cancers may yield new treatment options, but metabolic heterogeneity and plasticity complicate this strategy. One highly heterogeneous cancer for which current treatments ultimately fail is the deadly brain tumor glioblastoma. Therapeutic resistance, within glioblastoma and other solid tumors, is thought to be linked to subsets of tumor initiating cells, also known as cancer stem cells...
January 26, 2018: Biochimica et Biophysica Acta
Na Jiao, Susan S Baker, Colleen A Nugent, Maria Tsompana, Liting Cai, Yong Wang, Michael J Buck, Robert J Genco, Robert D Baker, Ruixin Zhu, Lixin Zhu
BACKGROUND: A number of studies have associated obesity with altered gut microbiota, although results are discordant regarding compositional changes in the gut microbiota of obese animals. Herein we aimed to obtain an unbiased evaluation of structural and functional changes of the gut microbiota in diet-induced obese rodents using a meta-analysis. METHODS: The raw sequencing data of nine studies generated with high-fat diet (HFD)-induced obese rodent models were processed with QIIME to obtain gut microbiota compositions...
January 26, 2018: Physiological Genomics
Zhichao Gu, Huafeng Zhang, Yong Li, Susu Shen, Xiaonan Yin, Wei Zhang, Ruimin Cheng, Yong Zhang, Xiaoyan Zhang, Hui Chen, Bo Huang, Yuchun Cao
Metabolic reprogramming allows tumor cells to thrive in the typically hypoxic tumor microenvironment. Using immunodetection and clinical data analyses, we demonstrate here that fumarylacetoacetate hydrolase (FAH) is highly expressed in melanoma and correlates with poor survival. FAH knockdown inhibits proliferation and migration, while promoting apoptosis in melanoma cells, result in prolonged survival in tumor-bearing mice. Molecular analyses using real time RT-PCR, western blot, and 13C tracing showed that these changes are driven by strong stimulation of anaplerotic reactions through the TCA cycle and the pentose-phosphate pathway, resulting in increased fatty acid and nucleotide synthesis...
December 26, 2017: Oncotarget
Andres García, Pau Ferrer, Joan Albiol, Tania Castillo, Daniel Segura, Carlos Peña
BACKGROUND: Azotobacter vinelandii is a bacterium that produces alginate and polyhydroxybutyrate (P3HB); however, the role of NAD(P)H/NAD(P)+ ratios on the metabolic fluxes through biosynthesis pathways of these biopolymers remains unknown. The aim of this study was to evaluate the NAD(P)H/NAD(P) + ratios and the metabolic fluxes involved in alginate and P3HB biosynthesis, under oxygen-limiting and non-limiting oxygen conditions. RESULTS: The results reveal that changes in the oxygen availability have an important effect on the metabolic fluxes and intracellular NADPH/NADP+ ratio, showing that at the lowest OTR (2...
January 22, 2018: Microbial Cell Factories
Aude Sadet, Emmanuelle Weber, Aditya Jhajharia, Dennis Kurzbach, Geoffrey Bodenhausen, Emeric Miclet, Daniel Abergel
The isomerisation of 6-phosphogluconolactones and their hydrolyses into 6-phosphogluconic acid form a non enzymatic side cycle of the pentose-phosphate pathway (PPP) in cells. We show that dissolution dynamic nuclear polarization can be used for determining its kinetic rates in real time. It is found that the hydrolysis of both lactones is significantly slower than the isomeration process, thereby shedding new light onto this subtle and puzzling chemical process.
January 22, 2018: Chemistry: a European Journal
Dezhuo Pan, Lingxia Wang, Fanglin Tan, Si Lu, Xiaojie Lv, Madiha Zaynab, Chi-Lien Cheng, Yakubu Saddeeq Abubakar, Shipin Chen, Wei Chen
The mangrove Kandelia candel (L.) Druce experiences daily flooding cycles. To explore the molecular mechanism underlying the physiological adaptation of K. candel to flooding, the potential role of protein phosphorylation in flooding responses was investigated by a large-scale quantitative phosphoproteomic analysis using isobaric tag for relative and absolute quantitation. Total 2141 unique phosphopeptides and 2603 non-redundant phosphorylation sites were identified from 1516 phosphoproteins in K. candel leaves...
January 15, 2018: Journal of Proteomics
Eunsook S Jin, Min Hee Lee, Rebecca E Murphy, Craig R Malloy
The pentose phosphate pathway (PPP) is widely assumed to play a key role in both reductive biosynthesis and protection from oxidative stress because it is the major source of NADPH. However, little is known about the activity of the PPP in fatty liver which is characterized by both oxidative stress and lipogenesis. This study was designed to test whether the PPP is active in parallel with lipogenesis and antioxidant processes in the fatty liver of whole animals. Eight- and 16-week old, obese Zucker diabetic fatty rats and their lean littermates received [U-13C3]glycerol, and 13C labeling patterns of glucose and triglycerides were analyzed for the assessment of hepatic PPP activity and the potentially-related processes simultaneously...
January 9, 2018: American Journal of Physiology. Endocrinology and Metabolism
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