Molecular mechanisms and roles of the mammalian 2-oxoglutarate-dependent oxygenases AlkBH1 and AlkBH7

哺乳动物 2-氧化戊二酸依赖性加氧酶 AlkBH1 和 AlkBH7 的分子机制和作用

• 批准号: 442081128
• 负责人: Dr. Sabine Schneider
• 金额: --
• 依托单位: Department Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/442081128?language=en
• 关键词: Molecular; mechanisms; roles; mammalian; oxoglutarate

Independent from the DNA genetic code, gene and protein activity is controlled by epigenetic mechanisms through writing, reading and erasing specific epigenetic marks. These marks include the covalent modifications of histones, DNA and RNA with methyl groups. These methyl groups play an essential role in many cellular processes. Responsible for the spacial and temporal maintenance of these epigenetic marks is carried out by so called "writer" and "eraser" enzymes. Here enzymes belonging to the Fe2+- and 2-oxoglutarate (2OG; = α-ketoglutarate) dependent oxygenase family are particular prominent actors. About 70 members of the Fe(II)/2OG-family across all kingdoms of life are known to date. These enzymes use the cosubstrate 2OG to bind to ferrous iron and to activate molecular oxygen in order to catalyse the transfer of the molecular oxygen onto a methyl group, resulting either in a stable hydroxylated product (=hydroxylases) or demethylation of the substrate via oxidative demethylation (=demethylases). The subfamily this proposal addresses are the AlkB-homologs (AlkBHs), which are found in various organisms such as Escherichia coli, Drosophila melanogaster, Schizosaccharomyces pombe, Cenorhabditis elegans and mammals.In mammals there are nine AlkB-homologs known by now: AlkBH1-8 and the fat mass- and obesity-associated gene product (FTO). The differences in sequence, structural elements and accessory domains account for their remarkably large diversity in substrates and biological roles. For individual mammalian AlkBHs it was shown, that loss-off function as well as their aberrant expression and activities can be linked to various diseases phenotypes, such as obesity, severe sensitivity to inflammation, multiple malformations, infertility and cancer, which emphasizes the importance of these enzymes. However, a direct link between the molecular functions, observed phenotype and the substrate scope for many of the human AlkBHs is still unclear. In the here proposed research project our aim is to elucidate the molecular mechanism of the most elusive human AlkBHs. We want to learn about their substrates and interaction network. Our focus will be the human AlkBH1 and AlkBH7 proteins. The employed methods involve cell biology, mass spectrometry and structural biology.

独立于DNA遗传密码，基因和蛋白质活性通过写作，阅读和擦除特定的表观遗传标记来控制表观遗传机制。这些标记包括组蛋白，DNA和RNA与甲基的共价修饰。这些甲基在许多细胞过程中起着至关重要的作用。负责这些表观遗传标记的空间和临时维护是由所谓的“作者”和“橡皮擦”酶进行的。在这里，属于Fe2+ - 和2-氧化甲酸酯（2og; =α-酮戊二酸）依赖性氧酶家族的酶是特定的重要参与者。迄今为止，大约有70名Fe（II）/2og家族成员遍布所有王国。这些酶使用cosubstrate 2og与亚铁铁结合并激活分子氧，以催化分子氧转移到甲基上，从而导致稳定的羟基化产物（= =羟基酶）或通过氧化二甲基酶通过氧化剂的脱甲基酶（=脱甲基化酶）。该提议讲话的子家庭是ALKB-同源物（ALKBHS），在各种有机体中，例如大肠杆菌，果蝇Melanogaster，schizosacchosacchomyces pombe pombe，cenorhabditis elegrans和ekelelans和哺乳动物。基因产物（FTO）。序列，结构元素和附件域的差异解释了它们在底物和生物学作用方面的巨大多样性。对于单个哺乳动物的ALKBHS，可以证明，损失功能以及它们异常表达和活性可以与各种疾病表型相关，例如肥胖，对感染，多种畸形，不育和癌症的严重敏感性，这强调了这些酶的重要性。但是，许多人AlkBHS的分子函数，观察到的表型和底物范围之间的直接联系仍不清楚。在此处提出的研究项目中，我们的目的是阐明最难以捉摸的人类ALKBH的分子机制。我们想了解他们的基材和交互网络。我们的重点将是人类ALKBH1和ALKBH7蛋白。使用的方法涉及细胞生物学，质谱和结构生物学。