更新于：2024-11-01

NUDT5

更新于：2024-11-01

基本信息

别名

8-oxo-dGDP phosphatase、ADP-sugar pyrophosphatase、hNUDT5

+ [8]

简介

Enzyme that can either act as an ADP-sugar pyrophosphatase in absence of diphosphate or catalyze the synthesis of ATP in presence of diphosphate (PubMed:27257257). In absence of diphosphate, hydrolyzes with similar activities various modified nucleoside diphosphates such as ADP-ribose, ADP-mannose, ADP-glucose, 8-oxo-GDP and 8-oxo-dGDP (PubMed:10567213, PubMed:10722730, PubMed:19699693, PubMed:21389046, PubMed:17052728). Can also hydrolyze other nucleotide sugars with low activity (PubMed:19699693, PubMed:21389046). In presence of diphosphate, mediates the synthesis of ATP in the nucleus by catalyzing the conversion of ADP-ribose to ATP and ribose 5-phosphate. Nuclear ATP synthesis takes place when dephosphorylated at Thr-45 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257). Does not play a role in U8 snoRNA decapping activity (By similarity). Binds U8 snoRNA (By similarity).

关联

靶点

NUDT14 x NUDT5

作用机制

NUDT14 拮抗剂 [+1]

在研机构

University of Oxford

原研机构

University of Oxford

在研适应症

乳腺癌

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

TH-5427

靶点

NUDT5

作用机制

NUDT5 拮抗剂

在研机构

University of Oxford

原研机构

University of Oxford

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

CBH-004

靶点

NUDT5

作用机制

NUDT5 拮抗剂

在研机构

University of Oxford

原研机构

University of Oxford

在研适应症

乳腺癌

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NUDT5 相关的临床结果

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100 项与 NUDT5 相关的转化医学

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0 项与 NUDT5 相关的专利（医药）

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186

项与 NUDT5 相关的文献（医药）

2024-12-01·Molecular Biology Reports

Ataxia telangiectasia and Rad3-related (ATR) inhibition by VE-822 potently reversed 5-flourouracil resistance in colorectal cancer cells through targeting DNA damage response

Article

作者: Mihanfar, Ainaz ; Asghari, Faezeh ; Majidinia, Maryam

BACKGROUNDVE-822 is a novel inhibitor of ATR, a key kinase involved in the DNA damage response pathway. The role of ATR inhibition in reversing drug resistance in various cancer types has been investigated. Therefore, this study investigated the effects of ATR inhibition by VE-822 on reversing 5-fluorouracil (5-FU) resistance in colorectal cancer cell line (Caco-2).METHODSCaco-2 and 5-FU resistance Caco-2 (Caco-2/5-FU) cells were treated with 5-FU and VE-822, alone and in combination. Cell proliferation and viability were assessed by MTT assay and Trypan Blue staining. P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) activities were measured by Rhodamine123 accumulation and uptake assay. The mRNA levels of P-gp, MRP-1, ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) were measured by qRT-PCR. Western blot was used to measure the protein levels of P-gp, MRP-1, γ-H2AX, ATR and CHK1 in cells. 8-Oxo-2'-deoxyguanosine (8-oxo-dG) levels were determined via ELISA. Apoptosis was evaluated by ELISA death assay, DAPI staining and lactate dehydrogenase (LDH) assay.RESULTSThe Caco-2/5-FU cells showed lower levels of 5-FU mediated proliferation inhibition in comparison to Caco-2 cells. VE-822 decreased the IC50 value of 5-FU on resistant cells. In addition, the expression levels and activity of P-gp and MRP-1 were significantly decreased in resistant cells treated with VE-822 (P < 0.05). The combination of 5-FU and VE-822 increased apoptosis in Caco-2/5-FU cells by downregulating CHK1 and ATR and upregulating γ-H2AX and 8-oxo-dG.CONCLUSIONThe simultaneous treatment of resistant colorectal cancer cells with 5-FU and ATR inhibitor, VE-822, was demonstrated to be effective in reversing drug resistance and potentiating 5-FU mediated anticancer effects via targeting DNA damage.

2024-10-01·The FEBS Journal

Kinetic and structural characterization of NUDT15 and NUDT18 as catalysts of isoprene pyrophosphate hydrolysis

Article

作者: Stenmark, Pål ; Jemth, Ann‐Sofie ; Koolmeister, Tobias ; Helleday, Thomas ; Kapsitidou, Despina ; Tsuber, Viktoriia ; Vallin, Karl S. ; Almlöf, Ingrid ; Unterlass, Judith E. ; Scaletti, Emma R.

Isoprene pyrophosphates play a crucial role in the synthesis of a diverse array of essential nonsterol and sterol biomolecules and serve as substrates for posttranslational isoprenylation of proteins, enabling specific anchoring to cellular membranes. Hydrolysis of isoprene pyrophosphates would be a means to modulate their levels, downstream products, and protein isoprenylation. While NUDIX hydrolases from plants have been described to catalyze the hydrolysis of isoprene pyrophosphates, homologous enzymes with this function in animals have not yet been reported. In this study, we screened an extensive panel of human NUDIX hydrolases for activity in hydrolyzing isoprene pyrophosphates. We found that human nucleotide triphosphate diphosphatase NUDT15 and 8‐oxo‐dGDP phosphatase NUDT18 efficiently catalyze the hydrolysis of several physiologically relevant isoprene pyrophosphates. Notably, we demonstrate that geranyl pyrophosphate is an excellent substrate for NUDT18, with a catalytic efficiency of 2.1 × 105 m−1·s−1, thus making it the best substrate identified for NUDT18 to date. Similarly, geranyl pyrophosphate proved to be the best isoprene pyrophosphate substrate for NUDT15, with a catalytic efficiency of 4.0 × 104 M−1·s−1. LC–MS analysis of NUDT15 and NUDT18 catalyzed isoprene pyrophosphate hydrolysis revealed the generation of the corresponding monophosphates and inorganic phosphate. Furthermore, we solved the crystal structure of NUDT15 in complex with the hydrolysis product geranyl phosphate at a resolution of 1.70 Å. This structure revealed that the active site nicely accommodates the hydrophobic isoprenoid moiety and helped identify key binding residues. Our findings imply that isoprene pyrophosphates are endogenous substrates of NUDT15 and NUDT18, suggesting they are involved in animal isoprene pyrophosphate metabolism.

2024-09-01·Yi chuan = Hereditas

CRISPR/Gal4BD-Cas donor adapting systems based on miniaturized Cas proteins for improved gene editing.

Article

作者: Wei, Ze-Hui ; Zhang, Xiao-Jun ; Zhang, Zhi-Ying ; Yang, Sen ; Ma, Bao-Xia ; Wang, Jian-Gang ; Qian, Hong-Run ; Xu, Kun ; Cui, Jie-Yu ; Li, Li-da

在哺乳动物细胞中，利用同源引导修复(homology-directed repair，HDR)机制的基因编辑策略能够实现精准的点编辑和敲入，但是HDR的低效性严重制约了该策略在精准医疗和分子设计育种中的应用。鉴于HDR机制所需的供体DNA模板不能自主募集到基因组双链断裂(double-stranded break，DSB)处，本课题组提出了供体适配系统(donor adapting system，DAS)的概念并开发出CRISPR/SpCas9-Gal4BD供体适配基因编辑系统。由于SpCas9蛋白分子较大，与Gal4BD适配器结合不利于表达、病毒载体包装及活体递送等过程，因此本研究进一步采用两种小型化Cas蛋白——路邓葡萄球菌(Staphylococcus lugdunensis)源SlugCas9变体SlugCas9-HF与氨基酸球菌(Acidaminococcus sp.)源AsCas12a，开发了新型的CRISPR/Gal4BD-SlugCas9和CRISPR/Gal4BD-AsCas12a供体适配基因编辑系统。通过SSA活性报告实验初步证明了Gal4BD与SlugCas9、AsCas12a N-端融合对其打靶活性影响较小。通过HDR效率报告实验进行功能验证并优化供体设计方案，结果表明：对于CRISPR/Gal4BD-AsCas12a DAS，适配器结合序列(binding sequence，BS)与供体5′-端融合(BS-dsDNA)效果较好；对于CRISPR/Gal4BD-SlugCas9 DAS，则BS与供体3′-端融合(dsDNA-BS)较佳。最终，利用CRISPR/Gal4BD-SlugCas9 DAS对HEK293T细胞中的EMX1、NUDT5、AAVS1三个基因位点分别实现了24%、37%、31%的精准编辑，相比对照组得到了显著提高。本研究为供体适配基因编辑系统的进一步优化提供了参考和借鉴，为后续动物分子设计育种应用研究提供了新的基因编辑工具。.