预约演示

更新于：2025-05-07

OGFOD2

更新于：2025-05-07

基本信息

别名

2-oxoglutarate and iron dependent oxygenase domain containing 2、2-oxoglutarate and iron-dependent oxygenase domain-containing protein 2、FLJ13491

+ [2]

简介-

关联

项与 OGFOD2 相关的药物

N-oxalylglycine

靶点

OGFOD2

作用机制

OGFOD2 inhibitors

在研机构

University of Oxford [+1]

原研机构

University of Oxford [+1]

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 OGFOD2 相关的临床结果

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100 项与 OGFOD2 相关的转化医学

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0 项与 OGFOD2 相关的专利（医药）

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项与 OGFOD2 相关的文献（医药）

2025-03-07·Neuro-Oncology

Glutamate dehydrogenase 1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism

Article

作者: Wang, Li ; Li, Haibin ; Li, Yanping ; Meng, Zhen ; Wei, Xiaonan ; Zhang, Guanghui ; Yan, Siyuan ; Wang, Shanshan ; Yang, Rui ; Cui, Hongjuan

AbstractBackgroundGlutamine is an important nutrient for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known.MethodsKnockdown and overexpression cells were obtained to explore the functional roles of glutamate dehydrogenase 1 (GDH1) in cell proliferation, tumor formation, and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay, and western blot were performed to verify the regulation of the EGFR-AKT pathway by the GDH1 (also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis.ResultsHere, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3 and then promotes the activation of the PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays an important role in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose conditions dependent on KDM6A-mediated demethylation of H3K27.ConclusionsThese findings suggest a novel function of glutaminolysis in the regulation of signal transduction and metabolism reprogramming and provide further evidence for the unique role of glutaminolysis in GBM progression.

2025-01-09·Journal of Medicinal Chemistry

Discovery of ZG-2305, an Orally Bioavailable Factor Inhibiting HIF Inhibitor for the Treatment of Obesity and Fatty Liver Disease

Article

作者: Zhang, Linjian ; Yang, Fulai ; Yue, Jie ; Schofield, Christopher J. ; Cai, Haiping ; Zhang, Zewei ; Chen, Yafen ; Zhang, Xiaojin ; Song, Zhe ; Li, Xiang ; Yang, Le ; Zhang, Weiqing ; Wu, Yue ; Li, Zhihong ; Corner, Thomas P.

Genetic loss of the 2-oxoglutarate oxygenase factor inhibiting hypoxia-inducible factor (FIH) enhances both glycolysis and aerobic metabolism. FIH is thus a potential target for adiposity control and improving hepatic steatosis. We describe development of a series of novel, potent, and selective FIH inhibitors that occupy both the FIH catalytic site and a recently defined tyrosine conformational-flip pocket. ZG-2305, with a K_i of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-inducible factor (HIF) prolyl hydroxylase PHD2. Oral administration of ZG-2305 in the western-diet induced obesity mouse model results in improved lipid accumulation and recovery from abnormal body weight/hepatic steatosis. Amelioration of nonalcoholic steatohepatitis (NASH) related pathological phenotypes in the HF-CDAA-diet induced NASH mouse model was observed. Preliminary preclinical studies indicate ZG-2305 has good pharmacokinetic properties and an acceptable safety profile. The results imply ZG-2305 is a promising candidate for treatment of obesity and fatty liver disease.

2024-02-01·Biochimica et Biophysica Acta (BBA) - General Subjects

Structural and functional characterization of triketone dioxygenase from Oryza Sativa

Article

作者: White, Tommi ; Haas, Jeff ; Garvey, Graeme ; Zhang, Meiying ; Karunanandaa, Balasulojini ; Varagona, Rita ; Li, Xin ; Zeng, Jiamin ; Mamanella, Patricia ; Jerga, Agoston ; Chittoor, Jaishree ; Zhang, Jun ; Chen, Danqi ; Wang, Yanfei ; Qi, Qungang ; Duda, David ; Tilton, Gregory ; Hall, Erin ; Duff, Stephen M G ; Xiang, Bosong ; Rydel, Timothy ; Taylor, Christina M ; Zinnel, Fred

The transgenic expression of rice triketone dioxygenase (TDO; also known as HIS1) can provide protection from triketone herbicides to susceptible dicot crops such as soybean. Triketones are phytotoxic inhibitors of plant hydroxyphenylpyruvate dioxygenases (HPPD). The TDO gene codes for an iron/2-oxoglutarate-dependent oxidoreductase. We obtained an X-ray crystal structure of TDO using SeMet-SAD phasing to 3.16 Å resolution. The structure reveals that TDO possesses a fold like that of Arabidopsis thaliana 2-oxoglutarate‑iron-dependent oxygenase anthocyanidin synthase (ANS). Unlike ANS, this TDO structure lacks bound metals or cofactors, and we propose this is because the disordered flexible loop over the active site is sterically constrained from folding properly in the crystal lattice. A combination of mass spectrometry, nuclear magnetic resonance, and enzyme activity studies indicate that rice TDO oxidizes mesotrione in a series of steps; first producing 5-hydroxy-mesotrione and then oxy-mesotrione. Evidence suggests that 5-hydroxy-mesotrione is a much weaker inhibitor of HPPD than mesotrione, and oxy-mesotrione has virtually no inhibitory activity. Of the close homologues which have been tested, only corn and rice TDO have enzymatic activity and the ability to protect plants from mesotrione. Correlating sequence and structure has identified four amino acids necessary for TDO activity. Introducing these four amino acids imparts activity to a mesotrione-inactive TDO-like protein from sorghum, which may expand triketone herbicide resistance in new crop species.

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