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更新于：2025-05-07

DAOA

更新于：2025-05-07

基本信息

别名

D-amino acid oxidase activator、DAOA、G72

+ [1]

简介

May suppress DAO (D-amino acid oxidase) and SOD1 activity and promote their degradation (PubMed:18544534, PubMed:20521334, PubMed:21679769, PubMed:30037290). Has conversely also been suggested to function as a DAO activator (PubMed:12364586, PubMed:24362575, PubMed:29114206). May stimulate the degradation of DDO (D-aspartate oxidase) (PubMed:37805834). May play a role in mitochondrial fission (PubMed:17684499).

关联

100 项与 DAOA 相关的临床结果

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100 项与 DAOA 相关的转化医学

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0 项与 DAOA 相关的专利（医药）

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226

项与 DAOA 相关的文献（医药）

2025-03-12·Journal of the American Chemical Society

Probing the Dynamics of Yersinia Adhesin A (YadA) in Outer Membranes Hints at Requirements for β-Barrel Membrane Insertion

Article

作者: Gumbart, James C. ; Ryoo, David ; Habeck, Michael ; Linke, Dirk ; Orwick-Rydmark, Marcella ; van Rossum, Barth-Jan ; Hofstetter, Albert ; Oschkinat, Hartmut ; Yarava, Jayasubba Reddy

The vast majority of cells are protected and functionalized by a dense surface layer of glycans, proteoglycans, and glycolipids. This surface represents an underexplored space in structural biology that is exceedingly challenging to recreate in vitro. Here, we investigate β-barrel protein dynamics within an asymmetric outer membrane environment, with the trimeric autotransporter Yersinia adhesin A (YadA) as an example. Magic-angle spinning NMR relaxation data and a model-free approach reveal increased mobility in the second half of strand β2 after the conserved G72, which is responsible for membrane insertion and autotransport, and in the subsequent loop toward β3. In contrast, the protomer-protomer interaction sites (β1_i-β4_i-1) are rigid. Intriguingly, the mobility in the β-strand section following G72 is substantially elevated in the outer membrane and less so in the detergent environment of microcrystals. A possible source is revealed by molecular dynamics simulations that show the formation of a salt bridge involving E79 and R76 in competition with a dynamic interplay of calcium binding by E79 and the phosphate groups of the lipids. An estimation of overall barrel motion in the outer membrane and detergent-containing crystals yields values of around 41 ns for both. The global motion of YadA in the outer membrane has a stronger rotational component orthogonal to the symmetry axis of the trimeric porin than in the detergent-containing crystal. In summary, our investigation shows that the mobility in the second half of β2 and the loop to β3 required for membrane insertion and autotransport is maintained in the final folded form of YadA.

2024-12-01·Biomolecular NMR Assignments

NMR-based solution structure of the Caulobacter crescentus ProXp-ala trans-editing enzyme

Article

作者: Musier-Forsyth, Karin ; Nagy, Alexandra B Kuzmishin ; Ma, Xiao ; Danhart, Eric M ; Duran, Antonia D ; Foster, Mark P

AbstractProXp-ala is a key component of the translational machinery in all three Domains of life. This enzyme helps to maintain the fidelity of proline codon translation through aminoacyl-tRNAPro proofreading. In the first step of tRNA aminoacylation, the cognate aminoacyl-tRNA synthetase (aaRS) binds and activates an amino acid in the enzyme’s synthetic active site. If a non-cognate amino acid passes this first selection step and is charged onto the tRNA, a distinct aaRS editing active site may recognize the mischarged tRNA and deacylate it. Alternatively, this editing reaction may be carried out by a separate enzyme that deacylates the mischarged tRNA in trans. ProXp-ala is responsible for editing Ala mischarged onto tRNAPro. Since trans-editing domains such as ProXp-ala bind their substrates after release from the synthetase, they must recognize not only the mischarged amino acid, but also the specific tRNA. Previous studies showed that Caulobacter crescentus (Cc) ProXp-ala distinguishes tRNAPro from tRNAAla, in part, based on the unique tRNAPro acceptor stem base pair C1:G72. Previous crystallographic and NMR data also revealed a role for conformational selection by the ProXp-ala α2 helix in Ala- versus Pro-tRNAPro substrate discrimination. The α2 helix makes lattice contacts in the crystal, which left some uncertainty as to its position in solution. We report resonance assignments for the substrate-free Cc ProXp-ala and the NMR-derived three-dimensional structure of the protein. These data reveal the position of the α2 helix in solution, with implications for substrate binding and recognition.

2024-10-01·Journal of Psychiatric Research

Plasma G72 protein in schizophrenia: A comparative analysis of drug-naive schizophrenia patients, patients in acute exacerbation and healthy controls

Article

作者: Kaya, Hasan ; Göka, Erol ; Fırat Oğuz, Esra ; Turhan, Turan ; Çiftçi, Hatice ; Aşut, Gonca ; Aydıner Yılmaz, Meltem ; Bayram, Şenol

OBJECTIVESSchizophrenia is a complex psychiatric disorder with an unclear etiopathogenesis. This study investigates the plasma G72 protein levels in drug-naive schizophrenia patients (DNS), those in acute psychotic episodes (AES), and healthy controls (HC). It also examines the correlation between the plasma G72 protein levels and Positive and Negative Syndrome Scale (PANSS) scores.METHODSThe study included 138 schizophrenia patients (84 DNS, 54 AES) and 83 HCs. Plasma G72 protein levels were measured by ELISA. Statistical analyses, including log-transformation and correlation analysis, were conducted.RESULTSSchizophrenia patients had significantly lower plasma G72 levels than HCs (4.39 ± 5.38 vs. 8.06 ± 10.27 ng/mL, p < 0.001), while DNS and AES groups did not differ significantly. Log-transformed data confirmed these differences. Negative correlation was found between plasma G72 levels and age (r = -0.258, p = 0.02), PANSS-G (r = -0.249, p = 0.004), and total PANSS scores (r = -0.226, p = 0.008). ROC analysis showed poor discrimination between schizophrenia patients and controls (AUC: 0.587, p = 0.031).CONCLUSIONSThis study's novel findings reveal that plasma G72 protein levels are significantly lower in schizophrenia patients and inversely correlated with age and symptom severity. However, the poor diagnostic accuracy observed in the ROC analysis suggests that G72 may not be a reliable biomarker for schizophrenia at this stage. These results underscore the need for further research to explore the potential clinical implications of these findings.

项与 DAOA 相关的新闻（医药）

2024-01-13

·生物探索

2024年，西湖大学施一公团队合作再取进展！

U2小核核糖核蛋白(snRNP)对pre-mRNA分支位点(BS)的选择对于剪接前体 (A complex)的组装至关重要。RNA解旋酶PRP5校对BS选择，但其潜在机制尚不清楚。2024年1月9日，西湖大学施一公及中国科学技术大学张晓峰共同通讯在Nature Structural & Molecular Biology 在线发表题为“Structural insights into branch site proofreading by human spliceosome”的研究论文，该研究报告了导致前质体组装的两个顺序复合物的原子结构:人类17S U2 snRNP和跨外显子pre-A复合物。PRP5主要通过酸性环占领SF3B1的RNA通路锚定在17S U2 snRNP上；PRP5的解旋酶结构域与U2 snRNA结合；U2 snRNA与BS相互作用的茎环(BSL)被TAT-SF1屏蔽，无法与BS接合。在pre-A配合物中，形成初始的U2-BS双相;PRP5的易位解旋酶结构域停留在U2 snRNA上，酸性环仍然占据RNA路径。pre-A构象被剪接因子SF1、DNAJC8和SF3A2特别稳定。癌症衍生的SF3B1突变破坏了其与PRP5的关联，损害了BS校对。总之，这些发现揭示了PRP5对剪接前体组装和BS选择或校对的关键见解。另外，2024年1月2日，上海科技大学刘如娟、西湖大学施一公及圣裘德儿童医院Xu Beisi等团队合作在Nucleic Acids Research 在线发表题为“THUMPD2 catalyzes the N2-methylation of U6 snRNA of the spliceosome catalytic center and regulates pre-mRNA splicing and retinal degeneration ”的研究论文，该研究发现一种RNA修饰-N2 -甲基鸟苷(m2G)沉积在U6 snRNA的G72上(剪接体的催化中心)，促进了人类细胞中有效的pre-mRNA剪接活性。这种修饰在脊椎动物中被证实是保守的。通过明确识别U6特异性序列和结构元件，THUMPD2被证明是负责U6 m2G72的甲基转移酶。敲除THUMPD2消除了U6 m2G72，破坏了pre-mRNA剪接活性，导致人类细胞中内源性pre-mRNA的数千个可选剪接事件发生变化。值得注意的是，异常剪接的pre-mRNA群体引发了无义介导的mRNA衰变途径。进一步表明，THUMPD2与年龄相关性黄斑变性和视网膜功能有关。因此，该研究证明了主要剪接体的RNA表观遗传修饰如何调节全局前mRNA剪接并影响生理和疾病。Pre-mRNA的剪接由剪接体执行，这是一种动态的超分子机器。剪接体通过识别内含子的保守元件:5 ' -剪接位点(5 'SS)、BS、聚嘧啶束(PPT)和3 ' -剪接位点(3 'SS)，组装在pre-mRNA上。首先，U1 snRNP、SF1、U2AF2和U2AF1分别识别5'SS、BS、PPT和3'SS，形成E complex。然后，U2 snRNP取代SF1，使U2 snRNA与BS之间形成双工，从而形成A complex。在高等真核生物中，大多数基因通过选择不同的剪接位点进行选择性剪接。因此，选择BS的A complex的形成是剪接调节的焦点。遗憾的是，人们对E-to-A转换背后的步骤知之甚少。RNA解旋酶PRP5(也称为DDX46)在A complex的组装过程中起关键作用。在人类17S U2 snRNP中，U2 snRNA无法与BS配对，因为U2 snRNA的相关序列形成双链BSL。ATP被PRP5水解导致BSL解绕，从而促进U2-BS双相的形成。在酵母中，Prp5可能校对U2-BS双工，因为Prp5突变允许使用隐性BS和3'SS。然而，PRP5调控剪接保真度的机制尚不清楚。17S人U2 snRNP和人pre-A剪接体的冷冻电镜结构（图源自Nature Structural & Molecular Biology ）大多数已知的癌症衍生的RNA剪接失调突变影响SF3B1的HEAT重复序列中的残基。这些突变大部分聚集在SF3B1的RNA通路上。Hsh155基因中的部分相应突变改变了Prp5相互作用和BS选择。尽管有这些诱人的线索，但这些癌症突变如何干扰正常剪接仍然是一个谜。该研究报道了人类17S U2 snRNP的高分辨率冷冻电镜(cryo-EM)结构和剪接抑制剂捕获的交叉外显子pre-A complex。结合结构导向的生化分析，该研究提出了一个校对BS选择和A complex组装的工作模型。总的来说，该研究为理解剪接体的早期组装过程以及分支位点的识别和选择机制提供了重要的结构信息，同时也为与癌症相关的SF3B1突变的致病机制提供了新的见解。参考文献：Zhang X, Zhan X, Bian T, Yang F, et al. Structural insights into branch site proofreading by human spliceosome. Nat Struct Mol Biol. 2024 Jan 9. doi: 10.1038/s41594-023-01188-0. Epub ahead of print. PMID: 38196034.责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

信使RNA

2024-01-04

·生物探索

2024年首篇！刘如娟/施一公等团队合作取得新进展

相对保守的剪接体如何管理人类中发生的大量剪接事件(人类约200000，酵母约300)的机制尚不清楚。2024年1月2日，上海科技大学刘如娟、西湖大学施一公及圣裘德儿童医院Xu Beisi等团队合作在Nucleic Acids Research 在线发表题为“THUMPD2 catalyzes the N²-methylation of U6 snRNA of the spliceosome catalytic center and regulates pre-mRNA splicing and retinal degeneration ”的研究论文，该研究发现一种RNA修饰-N²-甲基鸟苷(m²G)沉积在U6 snRNA的G72上(剪接体的催化中心)，促进了人类细胞中有效的pre-mRNA剪接活性。这种修饰在脊椎动物中被证实是保守的。通过明确识别U6特异性序列和结构元件，THUMPD2被证明是负责U6 m²G72的甲基转移酶。敲除THUMPD2消除了U6 m²G72，破坏了pre-mRNA剪接活性，导致人类细胞中内源性pre-mRNA的数千个可选剪接事件发生变化。值得注意的是，异常剪接的pre-mRNA群体引发了无义介导的mRNA衰变途径。进一步表明，THUMPD2与年龄相关性黄斑变性和视网膜功能有关。因此，该研究证明了主要剪接体的RNA表观遗传修饰如何调节全局前mRNA剪接并影响生理和疾病。pre-mRNA被称为“剪接体”的巨RNA-蛋白复合物剪接成成熟的mRNA，在真核生物中起着关键作用。从酵母到哺乳动物，剪接事件的频率从所有蛋白质编码基因的约5%增加到约98%。在酿酒酵母的约6000个基因中大约有300个基因含有一个内含子，而在人类的约20,000个基因中平均含有8个内含子。有趣的是，大量的生化和结构研究表明，剪接体的整体组织和剪接催化核的结构在人类和酵母之间是非常保守的。因此，在高等真核生物中大量的剪接事件对剪接体的操作能力提出了挑战，但确切的潜在机制尚不清楚。剪接体是一种在pre-mRNA上动态重新形成的蛋白质协调核酶，涉及5种保守的小核RNA(snRNA)：U1, U2, U4, U5和U6，具有多种蛋白质。snRNA催化pre-mRNA剪接，而U6位于剪接体的催化核心。U6的内部茎环(internal stem-loop,ISL)是剪接催化中心的主要组成部分。在pre-mRNA剪接过程中，催化核的核苷酸与两个催化金属离子螯合以完成分支和外显子连接。RNA修饰在各种生物事件中起着关键的调节作用。在高等真核生物中，U6在转录后被大量修饰，在多个位点检测到假尿嘧啶(ψ)和2'-O-甲基化(Nm)，并检测到两个单独的N6-甲基腺苷(m6A，人类U6的核苷43)和N²-甲基鸟苷(m2G，人类U6的核苷72)。U6的ψ和Nm主要分别由Box C/D snoRNP (dyskerin)和Box H/ACA snoRNP(fibrarin)引入，可能增加了U6中的碱基堆叠和碱基配对。最近，发现U6 m6A被METTL16甲基化，对识别5 '剪接位点(5 ' s)至关重要。然而，唯一的另一个碱基甲基化(m2G72)的作用仍然难以捉摸。文章模式图（图源自Nucleic Acids Research）G72是一个保守的催化活性位点，存在于从酵母(G78)到人类的各种生物中。人类主剪接体的结构表明，ISL的G72(酵母中的G78)参与剪接体活化催化中心的形成，并直接与催化金属离子M1结合。在剪接催化的双金属离子模型中，人U6-G72、-U74和pre-mRNA提供Sp磷酸氧结合两个金属离子，与5 ' ss鸟苷的磷酸结合去除内含子。在一些哺乳动物的U6序列中，可以鉴定出G72上的m2G修饰。尽管这种修饰在40年前首次被发现，但其对前mRNA剪接的影响及其生理作用仍不清楚。本研究表明，m2G72存在于斑马鱼、小鼠和人类的U6中，但不存在于U6atac中(U6在次要剪接体中的功能类似物)。利用反向遗传学方法结合RNA-质谱法，该研究发现THUMP结构域蛋白2(THUMPD2)是负责修饰的甲基转移酶。THUMPD2与一个辅助蛋白，一个多功能甲基转移酶亚基TRM112样蛋白(TRMT112)相互作用，催化U6 m2G72。体外pre-mRNA剪接实验表明，U6 m2G72缺失降低了剪接体的剪接活性。THUMPD2的缺失导致数千个选择性剪接(AS)事件的改变，并上调无义介导的mRNA衰变(NMD)途径。最近的全基因组关联研究(GWAS)发现了与年龄相关性黄斑变性(AMD)相关的THUMPD2基因变异。本研究发现，约50个已报道的AMD相关基因和另外30个具有视网膜特异性功能的基因的pre-mRNA是THUMPD2介导的剪接调控的直接靶点，提示THUMPD2在AMD发病机制中的作用。参考文献：Yang WQ, Ge JY, Zhang X, Zhu WY, Lin L, Shi Y, Xu B, Liu RJ. THUMPD2 catalyzes the N²-methylation of U6 snRNA of the spliceosome catalytic center and regulates pre-mRNA splicing and retinal degeneration. Nucleic Acids Res. 2024 Jan 2:gkad1243. doi: 10.1093/nar/gkad1243. Epub ahead of print. PMID: 38165050.责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

信使RNA寡核苷酸

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