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Eric L Allen, Danielle B Ulanet, David Pirman, Christopher E Mahoney, John Coco, Yaguang Si, Ying Chen, Lingling Huang, Jinmin Ren, Sung Choe, Michelle F Clasquin, Erin Artin, Zi Peng Fan, Giovanni Cianchetta, Joshua Murtie, Marion Dorsch, Shengfang Jin, Gromoslaw A Smolen
Although aberrant metabolism in tumors has been well described, the identification of cancer subsets with particular metabolic vulnerabilities has remained challenging. Here, we conducted an siRNA screen focusing on enzymes involved in the tricarboxylic acid (TCA) cycle and uncovered a striking range of cancer cell dependencies on OGDH, the E1 subunit of the alpha-ketoglutarate dehydrogenase complex. Using an integrative metabolomics approach, we identified differential aspartate utilization, via the malate-aspartate shuttle, as a predictor of whether OGDH is required for proliferation in 3D culture assays and for the growth of xenograft tumors...
October 11, 2016: Cell Reports
Attila Ambrus, Junjie Wang, Reka Mizsei, Zsofia Zambo, Beata Torocsik, Frank Jordan, Vera Adam-Vizi
Pathogenic amino acid substitutions of the common E3 component (hE3) of the human alpha-ketoglutarate dehydrogenase and the pyruvate dehydrogenase complexes lead to severe metabolic diseases (E3 deficiency), which usually manifest themselves in cardiological and/or neurological symptoms and often cause premature death. To date, 14 disease-causing amino acid substitutions of the hE3 component have been reported in the clinical literature. None of the pathogenic protein variants has lent itself to high-resolution structure elucidation by X-ray or NMR...
August 17, 2016: Biochimica et Biophysica Acta
Maria M Bayliak, Maria P Lylyk, Halyna V Shmihel, Oksana M Sorochynska, Oksana V Manyukh, Stefan G Pierzynowski, Volodymyr I Lushchak
Alpha-ketoglutarate (AKG) is an important intermediate in Krebs cycle which bridges the metabolism of amino acids and carbohydrates. Its effects as a dietary supplement on cold tolerance were studied in Drosophila melanogaster Canton S. Two-day-old adult flies fed at larval and adult stages with AKG at moderate concentrations (5-10mM) recovered faster from chill coma (0°C for 15min or 3h) than control ones. The beneficial effect of AKG on chill coma recovery was not found at its higher concentrations, which suggests hormetic like action of this keto acid...
August 2016: Journal of Thermal Biology
Elda M Rueda, Jerry E Johnson, Anand Giddabasappa, Anand Swaroop, Matthew J Brooks, Irena Sigel, Shawnta Y Chaney, Donald A Fox
PURPOSE: The homeostatic regulation of cellular ATP is achieved by the coordinated activity of ATP utilization, synthesis, and buffering. Glucose is the major substrate for ATP synthesis through glycolysis and oxidative phosphorylation (OXPHOS), whereas intermediary metabolism through the tricarboxylic acid (TCA) cycle utilizes non-glucose-derived monocarboxylates, amino acids, and alpha ketoacids to support mitochondrial ATP and GTP synthesis. Cellular ATP is buffered by specialized equilibrium-driven high-energy phosphate (~P) transferring kinases...
2016: Molecular Vision
Sanne A M van Lith, Anna C Navis, Krissie Lenting, Kiek Verrijp, Jan T G Schepens, Wiljan J A J Hendriks, Nil A Schubert, Hanka Venselaar, Ron A Wevers, Arno van Rooij, Pieter Wesseling, Remco J Molenaar, Cornelis J F van Noorden, Stefan Pusch, Bastiaan Tops, William P J Leenders
The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation...
2016: Scientific Reports
Tor-Christian Aase Johannessen, Joydeep Mukherjee, Pavithra Viswanath, Shigeo Ohba, Sabrina M Ronen, Rolf Bjerkvig, Russell O Pieper
: Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of alpha-ketoglutarate (alpha-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. While mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown...
July 18, 2016: Molecular Cancer Research: MCR
Guiwei Kao, Lili Qiu, Qi Peng, Jie Zhang, Jie Li, Fuping Song
OBJECTIVE: The study aimed to determine the appropriate stage for exploring the responseof Bacillus thuringiensis to the alkaline stress, to profile the metabolic pathways under this stress. METHODS: Using semi-quantitative RT-PCR and qRT-PCR, the proper stage was defined by monitoring the transcriptional changes of marker gene pspA, which was known as a responsive gene under the alkaline stress. The total RNA was then extracted to perform the microarray hybridizations for samples under stress and control, respectively...
March 4, 2016: Wei Sheng Wu Xue Bao, Acta Microbiologica Sinica
Alison M Mondul, Stephanie J Weinstein, Demetrius Albanes
PURPOSE: How micronutrients might influence risk of developing adenocarcinoma of the prostate has been the focus of a large body of research (especially regarding vitamins E, A, and D). Metabolomic profiling has the potential to discover molecular species relevant to prostate cancer etiology, early detection, and prevention, and may help elucidate the biologic mechanisms through which vitamins influence prostate cancer risk. METHODS: Prostate cancer risk data related to vitamins E, A, and D and metabolomic profiling from clinical, cohort, and nested case-control studies, along with randomized controlled trials, are examined and summarized, along with recent metabolomic data of the vitamin phenotypes...
June 23, 2016: World Journal of Urology
Barbara Zdzisińska, Aleksandra Żurek, Martyna Kandefer-Szerszeń
Alpha-ketoglutarate (AKG), an endogenous intermediary metabolite in the Krebs cycle, is a molecule involved in multiple metabolic and cellular pathways. It functions as an energy donor, a precursor in the amino acid biosynthesis, a signalling molecule, as well as a regulator of epigenetic processes and cellular signalling via protein binding. AKG is an obligatory co-substrate for 2-oxoglutarate-dependent dioxygenases, which catalyse hydroxylation reactions on various types of substrates. It regulates the activity of prolyl-4 hydroxylase, which controls the biosynthesis of collagen, a component of bone tissue...
June 20, 2016: Archivum Immunologiae et Therapiae Experimentalis
Fei Yang, Wen Xiao, Xiaohua Ma, Ruixue Huang, Ran Yu, Guiyin Li, Xiao Huang, Cuimei Chen, Ping Ding
OBJECTIVES: A novel magnetic targeting anti-tumour drug delivery system (Fe3 O4 /KCTS-CHE) was designed using magnetic Fe3 O4 /chitosan alpha-ketoglutaric acid (Fe3 O4 /KCTS) as carrier and chelerythrine (CHE) as an anti-tumour drug model. Moreover, the anti-tumour activities and mechanisms of Fe3 O4 /KCTS-CHE were investigated. METHODS: The preparation conditions of Fe3 O4 /KCTS-CHE microspheres were optimized by response surface methodology (RSM). The CHE drug release kinetics was evaluated by fitting the experimental data to standard release equations...
August 2016: Journal of Pharmacy and Pharmacology
Huachen Chen, Lai-Sheung Lee, Guanwu Li, Sai-Wah Tsao, Jen-Fu Chiu
Arsenic and benzo[α]pyrene (B[a]P) are common contaminants in developing countries. Many studies have investigated the consequences of arsenic and/or B[a]P-induced cellular transformation, including altered metabolism. In the present study, we show that, in addition to elevated glycolysis, B[a]P/arsenic-induced transformation also stimulates oxidative phosphorylation (OXPHOS). Proteomic data and immunoblot studies demonstrated that enzymatic activities, involved in both glycolysis and OXPHOS, are upregulated in the primary transformed rat lung epithelial cell (TLEC) culture, as well as in subcloned TLEC cell lines (TMCs), indicating that OXPHOS was active and still contributed to energy production...
June 3, 2016: Oncotarget
R P Radzki, M Bieńko, R Filip, S G Pierzynowski
OBJECTIVE: This study investigated the effect of alpha-ketoglutarate sodium salt (AKG) and ipriflavone (IP) treatment on the mineralization of the tibia in male rats during the development and after the establishment of osteopenia. DESIGN: One hundred and twenty eight male rats were randomly selected and submitted to either sham-operation (SHO) or orchidectomy (ORX), after which each group were then randomly divided between the two experiments. In Experiment-1, treatment with AKG or/and IP started after a 7-day recovery period, whereas in Experiment-2, the experimental protocol proceeded after a 60-day period of osteopenia establishment...
2016: Journal of Nutrition, Health & Aging
Xingcai Cai, Canjun Zhu, Yaqiong Xu, Yuanyuan Jing, Yexian Yuan, Lina Wang, Songbo Wang, Xiaotong Zhu, Ping Gao, Yongliang Zhang, Qingyan Jiang, Gang Shu
Skeletal muscle weight loss is accompanied by small fiber size and low protein content. Alpha-ketoglutarate (AKG) participates in protein and nitrogen metabolism. The effect of AKG on skeletal muscle hypertrophy has not yet been tested, and its underlying mechanism is yet to be determined. In this study, we demonstrated that AKG (2%) increased the gastrocnemius muscle weight and fiber diameter in mice. Our in vitro study also confirmed that AKG dose increased protein synthesis in C2C12 myotubes, which could be effectively blocked by the antagonists of Akt and mTOR...
2016: Scientific Reports
Qian Jiang, Liuqin He, Yongqing Hou, Jiashun Chen, Yehui Duan, Dun Deng, Guoyao Wu, Yulong Yin, Kang Yao
Alpha-ketoglutarate (AKG), a key intermediate in the Krebs cycle, has been reported to promote protein synthesis through activating mechanistic targeting of rapamycin (mTOR) in enterocytes. The study tested the hypothesis that AKG may enhance growth and milk protein synthesis in porcine mammary epithelial cells (PMECs). PMECs were cultured for 96 h in Dulbecco's modified Eagle's-F12 Ham medium (DMEM-F12) containing prolactin (2 µg/ml) and AKG (0 or 1.5 mM). At the end of 96-h culture, the abundance of apoptosis-related proteins (caspase-3, caspase-9), milk-specific proteins (α-lactalbumin and β-casein), mTOR signaling proteins (mTOR, p-mTOR, PERK, p-PERK, eIF2a, P70S6K and p-P70S6K), and endoplasmic reticulum stress (ERS)-associated proteins (BiP and CHOP) in PMEC were determined...
September 2016: Amino Acids
Dingfu Xiao, Liming Zeng, Kang Yao, Xiangfeng Kong, Guoyao Wu, Yulong Yin
L-Glutamine is a nutritionally semi-essential amino acid for proper growth in most cells and tissues, and plays an important role in the determination and guarding of the normal metabolic processes of the cells. With the help of transport systems, extracellular L-glutamine crosses the plasma membrane and is converted into alpha-ketoglutarate (AKG) through two pathways, namely, the glutaminase (GLS) I and II pathway. Reversely, AKG can be converted into glutamine by glutamate dehydrogenase (GDH) and glutamine synthetase (GS), or be converted into CO2 via the tricarboxylic acid (TCA) cycle and provide energy for the cells...
September 2016: Amino Acids
Gemma Aragonès, Teresa Auguet, Alba Berlanga, Esther Guiu-Jurado, Salomé Martinez, Sandra Armengol, Fàtima Sabench, Rosa Ras, Mercè Hernandez, Carmen Aguilar, Josep Colom, Joan Josep Sirvent, Daniel Del Castillo, Cristóbal Richart
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, ranging from simple steatosis to cirrhosis. However, simple steatosis (SS) and steatohepatitis (NASH) cannot yet be distinguished by clinical or laboratory features. The aim of this study was to assess the relationship between alpha-ketoglutarate and the degrees of NAFLD in morbidly obese patients. MATERIALS AND METHODS: We used a gas chromatography-quadruple time-of-flight-mass spectrometry analysis to quantify alpha-ketoglutarate in serum from normal-weight subjects (n = 30) and morbidly obese women (n = 97) with or without NAFLD...
2016: PloS One
Joshua C Farris, Phillip M Pifer, Liang Zheng, Eyal Gottlieb, James Denvir, Steven M Frisch
UNLABELLED: Resistance to anoikis is a prerequisite for tumor metastasis. The epithelial-to-mesenchymal transition (EMT) allows tumor cells to evade anoikis. The wound-healing regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses/reverses EMT, accompanied by suppression of the cancer stem cell (CSC) phenotype and by resensitization to anoikis. Here, the effects of GRHL2 upon intracellular metabolism in the context of reversion of the EMT/CSC phenotype, with a view toward understanding how these effects promote anoikis sensitivity, were investigated...
June 2016: Molecular Cancer Research: MCR
João V Sá, Susanne Kleiderman, Catarina Brito, Ursula Sonnewald, Marcel Leist, Ana P Teixeira, Paula M Alves
Proliferation and differentiation of neural stem cells (NSCs) have a crucial role to ensure neurogenesis and gliogenesis in the mammalian brain throughout life. As there is growing evidence for the significance of metabolism in regulating cell fate, knowledge on the metabolic programs in NSCs and how they evolve during differentiation into somatic cells may provide novel therapeutic approaches to address brain diseases. In this work, we applied a quantitative analysis to assess how the central carbon metabolism evolves upon differentiation of NSCs into astrocytes...
April 12, 2016: Neurochemical Research
Alexandra Maertens, Mounir Bouhifd, Liang Zhao, Shelly Odwin-DaCosta, Andre Kleensang, James D Yager, Thomas Hartung
In the context of the Human Toxome project, mass spectroscopy-based metabolomics characterization of estrogen-stimulated MCF-7 cells was studied in order to support the untargeted deduction of pathways of toxicity. A targeted and untargeted approach using overrepresentation analysis (ORA), quantitative enrichment analysis (QEA) and pathway analysis (PA) and a metabolite network approach were compared. Any untargeted approach necessarily has some noise in the data owing to artifacts, outliers and misidentified metabolites...
April 2, 2016: Archives of Toxicology
Liuqin He, Huan Li, Niu Huang, Junquan Tian, Zhiqiang Liu, Xihong Zhou, Kang Yao, Tiejun Li, Yulong Yin
Alpha-ketoglutarate (AKG) plays a vital part in the tricarboxylic acid cycle and is a key intermediate in the oxidation of L-glutamine (Gln). The study was to evaluate effects of AKG on Gln metabolism in vivo and in vitro. A total of twenty-one piglets were weaned at 28 days with a mean body weight (BW) of 6.0 ± 0.2 kg, and randomly divided into 3 groups: corn soybean meal based diet (CON group); the basal diet with 1% alpha-ketoglutarate (AKG treatment group); and the basal diet with 1% L-glutamine (GLN treatment group)...
April 6, 2016: Journal of Agricultural and Food Chemistry
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