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Alpha-ketoglutarate

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https://www.readbyqxmd.com/read/29769206/targeting-the-idh2-pathway-in-acute-myeloid-leukemia
#1
Maria L Amaya, Daniel A Pollyea
Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. A large percentage of patients succumb to this disease, in spite of aggressive treatments with chemotherapy. Recent advances with mutational analysis led to the discovery of isocitrate dehydrogenase (IDH) mutations in AML. IDH2 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate; its mutated version leads to the accumulation of the oncometabolite (R)-2 hydroxyglutarate, which disrupts several cell processes and leads to a blockage in differentiation...
May 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29750149/the-antioxidative-function-of-alpha-ketoglutarate-and-its-applications
#2
REVIEW
Shaojuan Liu, Liuqin He, Kang Yao
Alpha-ketoglutarate (AKG) is a crucial intermediate of the Krebs cycle and plays a critical role in multiple metabolic processes in animals and humans. Of note, AKG contributes to the oxidation of nutrients (i.e., amino acids, glucose, fatty acids) and then provides energy for cell processes. As a precursor of glutamate and glutamine, AKG acts as an antioxidant agent as it directly reacts with hydrogen peroxide with formation of succinate, water, and carbon dioxide; meanwhile, it discharges plenty of ATP by oxidative decarboxylation...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29746824/reduction-of-2-methoxy-1-4-naphtoquinone-by-mitochondrially-localized-nqo1-yielding-nad-supports-substrate-level-phosphorylation-during-respiratory-inhibition
#3
Dora Ravasz, Gergely Kacso, Viktoria Fodor, Kata Horvath, Vera Adam-Vizi, Christos Chinopoulos
Provision of NAD+ for oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA by the ketoglutarate dehydrogenase complex (KGDHC) is critical for maintained operation of succinyl-CoA ligase yielding high-energy phosphates, a process known as mitochondrial substrate-level phosphorylation (mSLP). We have shown previously that when NADH oxidation by complex I is inhibited by rotenone or anoxia, mitochondrial diaphorases yield NAD+ , provided that suitable quinones are present (Kiss G et al., FASEB J 2014, 28:1682)...
May 7, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29599405/transketolase-regulates-the-metabolic-switch-to-control-breast-cancer-cell-metastasis-via-the-alpha-ketoglutarate-signaling-pathway
#4
Lu-Hai Wang, Chien-Wei Tseng, Wen-Hung Kuo, Shih-Hsuan Chan, Hong-Lin Chan, King-Jen Chang
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival...
March 29, 2018: Cancer Research
https://www.readbyqxmd.com/read/29545147/directed-evolution-of-the-3-hydroxypropionic-acid-production-pathway-by-engineering-aldehyde-dehydrogenase-using-a-synthetic-selection-device
#5
Joo Yeon Seok, Jina Yang, Sang Jin Choi, Hyun Gyu Lim, Un Jong Choi, Kyung-Jin Kim, Sunghoon Park, Tae Hyeon Yoo, Gyoo Yeol Jung
3-Hydroxypropionic acid (3-HP) is an important platform chemical, and biological production of 3-HP from glycerol as a carbon source using glycerol dehydratase (GDHt) and aldehyde dehydrogenase (ALDH) has been revealed to be effective because it involves a relatively simple metabolic pathway and exhibits higher yield and productivity than other biosynthetic pathways. Despite the successful attempts of 3-HP production from glycerol, the biological process suffers from problems arising from low activity and inactivation of the two enzymes...
March 13, 2018: Metabolic Engineering
https://www.readbyqxmd.com/read/29540215/glutaminase-1-regulates-the-release-of-extracellular-vesicles-during-neuroinflammation-through-key-metabolic-intermediate-alpha-ketoglutarate
#6
Beiqing Wu, Jianhui Liu, Runze Zhao, Yuju Li, Justin Peer, Alexander L Braun, Lixia Zhao, Yi Wang, Zenghan Tong, Yunlong Huang, Jialin C Zheng
BACKGROUND: Extracellular vesicles (EVs) are important in the intercellular communication of the central nervous system, and their release is increased during neuroinflammation. Our previous data demonstrated an increased release of EVs during HIV-1 infection and immune activation in glial cells. However, the molecular mechanism by which infection and inflammation increase EV release remains unknown. In the current study, we investigated the role of glutaminase 1 (GLS1)-mediated glutaminolysis and the production of a key metabolic intermediate α-ketoglutarate on EV release...
March 14, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29525347/metabolites-genome-organization-and-cellular-differentiation-gene-programs
#7
REVIEW
Danielle A Chisolm, Amy S Weinmann
The nutrient environment and metabolism play a dynamic role in cellular differentiation and research is elucidating the mechanisms that contribute to this process. Metabolites serve as an effective bridge that helps to translate information about nutrient states into specific interpretations of the genome. Part of this activity relates to the role for metabolites in regulating epigenetic processes as well as a newly appreciated role for metabolites in the regulation of genome organization. In this review, we will highlight recent research that has defined roles for metabolism in the organization and interpretation of the genome and how this influences cellular differentiation decisions...
April 2018: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29412702/%C3%AE-ketoglutarate-stimulates-pendrin-dependent-cl-absorption-in-the-mouse-ccd-through-protein-kinase-c
#8
Yoskaly Lazo-Fernandez, Paul A Welling, Susan M Wall
Alpha-ketoglutarate (αKG) is a citric acid cycle intermediate and a glutamine catabolism product. It is also the natural ligand of OXGR1, a Gq-protein coupled receptor expressed on the apical membrane of intercalated cells. In the CCD, Cl- /HCO3 - exchange increases upon αKG binding to the OXGR1. To determine the signaling pathway(s) by which αKG stimulates Cl- absorption, we examined αKG-stimulated Cl- absorption in isolated perfused mouse CCDs. αKG increased electroneutral Cl- absorption in CCDs from wild type mice, but had no effect on Cl- absorption in pendrin KO mice...
February 7, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29363081/analysis-of-metabolites-from-the-tricarboxylic-acid-cycle-for-yeast-and-bacteria-samples-using-gas-chromatography-mass-spectrometry
#9
Reza Maleki Seifar, Angela Ten Pierick, Patricia T N van Dam
We here explain step by step the implementation of gas chromatography coupled with tandem mass spectrometry for the quantitative analysis of intracellular metabolites from the tricarboxylic acid (TCA) cycle such as citrate, isocitrate, alpha-ketoglutarate, succinate, malate, and fumarate. Isotope dilution is used to correct for potential metabolite losses during sample processing, matrix effects, incomplete derivatization, and liner contamination. All measurements are performed in selected reaction monitoring (SRM) mode...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29305935/hedgehog-yap-signaling-pathway-regulates-glutaminolysis-to-control-activation-of-hepatic-stellate-cells
#10
Kuo Du, Jeongeun Hyun, Richard T Premont, Steve S Choi, Gregory A Michelotti, Marzena Swiderska-Syn, George D Dalton, Eric Thelen, Bahar Salimian Rizi, Youngmi Jung, Anna Mae Diehl
BACKGROUND & AIMS: Cirrhosis results from accumulation of myofibroblasts derived from quiescent hepatic stellate cells (Q-HSCs); it regresses when myofibroblastic HSCs are depleted. Hedgehog signaling promotes transdifferentiation of HSCs by activating Yes-associated protein 1 (YAP1 or YAP) and inducing aerobic glycolysis. However, increased aerobic glycolysis alone cannot meet the high metabolic demands of myofibroblastic HSCs. Determining the metabolic processes of these cells could lead to strategies to prevent progressive liver fibrosis, so we investigated whether glutaminolysis (conversion of glutamine to alpha-ketoglutarate) sustains energy metabolism and permits anabolism when Q-HSCs become myofibroblastic, and whether this is controlled by hedgehog signaling to YAP...
April 2018: Gastroenterology
https://www.readbyqxmd.com/read/29289682/l-ascorbic-acid-a-true-substrate-for-hif-prolyl-hydroxylase
#11
Andrey I Osipyants, Andrey A Poloznikov, Natalya A Smirnova, Dmitry M Hushpulian, Anna Yu Khristichenko, Tatiana A Chubar, Arpenik A Zakhariants, Manuj Ahuja, Irina N Gaisina, Bobby Thomas, Abe M Brown, Irina G Gazaryan, Vladimir I Tishkov
L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif...
April 2018: Biochimie
https://www.readbyqxmd.com/read/29281828/the-krebs-cycle-enzyme-isocitrate-dehydrogenase-3a-couples-mitochondrial-metabolism-to-synaptic-transmission
#12
Berrak Ugur, Huan Bao, Michal Stawarski, Lita R Duraine, Zhongyuan Zuo, Yong Qi Lin, G Gregory Neely, Gregory T Macleod, Edwin R Chapman, Hugo J Bellen
Neurotransmission is a tightly regulated Ca2+ -dependent process. Upon Ca2+ influx, Synaptotagmin1 (Syt1) promotes fusion of synaptic vesicles (SVs) with the plasma membrane. This requires regulation at multiple levels, but the role of metabolites in SV release is unclear. Here, we uncover a role for isocitrate dehydrogenase 3a (idh3a), a Krebs cycle enzyme, in neurotransmission. Loss of idh3a leads to a reduction of the metabolite, alpha-ketoglutarate (αKG), causing defects in synaptic transmission similar to the loss of syt1...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29277775/novel-metabolically-stable-pca-1-alkbh3-inhibitor-has-potent-antiproliferative-effects-on-du145-cells-in-vivo
#13
Masahiro Ueda, Tadashi Shimizu, Miyuki Mabuchi, Kota Horiike, Kaori Kitae, Hiroaki Hase, Yuko Ueda, Kazutake Tsujikawa, Akito Tanaka
Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA-1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects...
January 2018: Anticancer Research
https://www.readbyqxmd.com/read/29230593/effects-of-alpha-ketoglutarate-akg-on-growth-performance-and-non-specific-immunity-of-juvenile-red-drum-fed-diets-with-low-or-adequate-phosphorus-levels
#14
Qiyou Xu, Delbert M Gatlin
This study evaluated the effects of α-ketoglutarate (AKG) on the growth performance, body, and skeletal composition, as well as non-specific immunity of juvenile red drum (Sciaenops ocellatus) fed adequate or low-phosphorus diets. A 2 × 2 factorial design was arranged with two levels of total phosphorus (1.0 or 1.6%) and two levels (0 or 1%) of AKG. Each diet was fed to red drum in four replicate 110-L aquaria (15 fish/aquarium) twice daily for 7 weeks. The results indicated that the low-P diets significantly (P < 0...
December 11, 2017: Fish Physiology and Biochemistry
https://www.readbyqxmd.com/read/29223816/cortex-and-hippocampus-dna-epigenetic-response-to-a-long-term-arsenic-exposure-via-drinking-water
#15
Xiaoyan Du, Meiping Tian, Xiaoxue Wang, Jie Zhang, Qingyu Huang, Liangpo Liu, Heqing Shen
The neurotoxicity of arsenic is a serious health problem, especially for children. DNA epigenetic change may be an important pathogenic mechanism, but the molecular pathway remains obscure. In this study, the weaned male Sprague-Dawly (SD) rats were treated with arsenic trioxide via drinking water for 6 months, simulating real developmental exposure situation of children. Arsenic exposure impaired the cognitive abilities, and altered the expression of neuronal activity-regulated genes. Total arsenic concentrations of cortex and hippocampus tissues were significantly increased in a dose-dependent manner...
March 2018: Environmental Pollution
https://www.readbyqxmd.com/read/29222329/glutaminolysis-is-required-for-transforming-growth-factor-%C3%AE-1-induced-myofibroblast-differentiation-and-activation
#16
Karen Bernard, Naomi J Logsdon, Gloria A Benavides, Yan Sanders, Jianhua Zhang, Victor M Darley-Usmar, Victor J Thannickal
Myofibroblasts participate in physiological wound healing and pathological fibrosis. Myofibroblast differentiation is characterized by the expression of α-smooth muscle actin and extracellular matrix proteins and is dependent on metabolic reprogramming. In this study, we explored the role of glutaminolysis and metabolites of TCA in supporting myofibroblast differentiation. Glutaminolysis converts Gln into α-ketoglutarate (α-KG), a critical intermediate in the TCA cycle. Increases in the steady-state concentrations of TCA cycle metabolites including α-KG, succinate, fumarate, malate, and citrate were observed in TGF-β1-differentiated myofibroblasts...
January 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29214991/pseudomonas-aeruginosa-zinc-uptake-in-chelating-environment-is-primarily-mediated-by-the-metallophore-pseudopaline
#17
Sébastien Lhospice, Nicolas Oswaldo Gomez, Laurent Ouerdane, Catherine Brutesco, Ghassan Ghssein, Christine Hajjar, Ahmed Liratni, Shuanglong Wang, Pierre Richaud, Sophie Bleves, Geneviève Ball, Elise Borezée-Durant, Ryszard Lobinski, David Pignol, Pascal Arnoux, Romé Voulhoux
Metal uptake is vital for all living organisms. In metal scarce conditions a common bacterial strategy consists in the biosynthesis of metallophores, their export in the extracellular medium and the recovery of a metal-metallophore complex through dedicated membrane transporters. Staphylopine is a recently described metallophore distantly related to plant nicotianamine that contributes to the broad-spectrum metal uptake capabilities of Staphylococcus aureus. Here we characterize a four-gene operon (PA4837-PA4834) in Pseudomonas aeruginosa involved in the biosynthesis and trafficking of a staphylopine-like metallophore named pseudopaline...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29191830/lipoic-acid-metabolism-and-mitochondrial-redox-regulation
#18
Ashley D Solmonson, Ralph J DeBerardinis
Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multi-enzyme complexes...
November 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29190890/administration-of-alpha-ketoglutarate-improves-epithelial-restitution-under-stress-injury-in-early-weaning-piglets
#19
Liuqin He, Xihong Zhou, Niu Huang, Huan Li, Zhijie Cui, Junquan Tian, Qian Jiang, Shaojuan Liu, Jian Wu, Tiejun Li, Kang Yao, Yulong Yin
Alpha-ketoglutarate (AKG) is an important cellular metabolite that participates in energy production and amino acid metabolism. However, the protective effects and mechanism of AKG on mucosal lesions have not been well understood. This study was conducted to investigate the effects of dietary AKG supplementation on epithelial restitution in early-weaning piglets under Escherichia coli lipopolysaccharide (LPS) induction. A total of 32 weaned piglets were used in a 2 × 2 factorial design; the major factors were dietary treatment (basal diet or AKG diet) and inflammatory challenge (LPS or saline)...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29181198/effects-of-long-term-cultivation-on-medium-with-alpha-ketoglutarate-supplementation-on-metabolic-processes-of-saccharomyces-cerevisiae
#20
Nadia Burdyliuk, Maria Bayliak
During last years, alpha-ketoglutarate (AKG), an important intermediate in the Krebs cycle, has been intensively studied as a dietary supplement with stress-protective and potential antiaging effects. Here, we examined the effects of exogenous AKG on metabolic processes and survival of yeast Saccharomyces cerevisiae during long-term cultivation. Growth on AKG had no effect on the total cell number but increased the number of reproductively active cells at the late days of cultivation (from day 7 to day 15)...
2017: Journal of Aging Research
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