Structure, mechanism, and inhibition of AlkB homologues

AlkB 同系物的结构、机制和抑制

• 批准号: 7501393
• 负责人: JOHN Francis HUNT
• 金额: $ 30.13万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501393
• 关键词: Address; Adenine; Alkylation; Attenuated; Binding; Biochemical; Biochemical Reaction; Biochemistry; Biological; Biological Assay; Biological Process; Biology; Biophysics; Cells; Chemical Models; Chemical Structure; Chemicals; Clinical; Clinical Oncology; Complex; Condition; Cytosine; DNA; DNA Damage; DNA Modification Process; DNA Repair; DNA Repair Enzymes; Enzymes; Escherichia coli; Eubacterium; Eukaryota; Eukaryotic Cell; Explosion; Family; Genomics; Homologous Gene; Human; In Vitro; Knowledge; Laboratories; Lesion; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Molecular Biology; Mutation; Nitrogen; Normal Cell; Nucleotides; Oncogenic; Organism; Pharmaceutical Preparations; Physiological; Play; Preparation; Proteins; Publishing; Quantum Mechanics; Rate; Reaction; Relative (related person); Resistance; Role; Screening procedure; Structure; System; Techniques; Therapeutic Agents; Transfer RNA; Translations; Tumor Biology; Universities; Vertebrates; base; cancer therapy; chemical reaction; computational chemistry; environmental mutagens; improved; inhibitor/antagonist; interdisciplinary collaboration; molecular mechanics; mutant; prevent; repaired; research study; simulation; three dimensional structure; virtual

DESCRIPTION (provided by applicant): DNA repair is considered the double-edged sword of tumor biology. While the biochemical machinery that repairs DNA damage plays a central role in maintaining genomic integrity and thereby preventing cancer in normal cells, it also limits the efficacy of the DNA-damaging agents that represent some of the most widely used and successful chemotherapeutic drugs in clinical oncology. Therefore, a detailed understanding of the enzymatic reaction mechanisms and physiological functions of DNA repair enzymes represents essential basic knowledge concerning the function of normal cells and the systems that protect them from oncogenic transformation. However, this knowledge is also practically important in efforts to improve cancer therapy because inhibitors of DNA repair enzymes can potentiate the potency of other therapeutic agents. Recently, there has been an explosion of knowledge concerning the molecular function of the DNA repair enzymes in the AlkB superfamily, which are present in all eubacteria and all higher eukaryotes. These enzymes have been shown to catalyze direct repair of adenine and cytosine bases that have been alkylated on endocyclic ring nitrogen atoms, a toxic DNA modification that is mediated by both endogenous and environmental mutagens. Elucidation of the chemical reaction catalyzed by AlkB has enabled rapid progress to be made in understanding their physiological function, which includes repair of damaged mRNA and tRNA molecules that reduce translation efficiency in addition to repair of mutagenic lesions in DNA. However, numerous features of AlkB superfamily enzymes remain to be characterized, including the structural mechanisms enabling promiscuous recognition of different substrates, the details of their catalytic reaction mechanism, and the biological function of the 8 distinct sequence homologues that are conserved in mammalian organisms. We plan to apply a combination of biophysical, chemical, and molecular biological techniques to answer these fundamental questions concerning the biochemistry of AlkB-family DNA repair enzymes.

描述（由申请人提供）：DNA修复被认为是肿瘤生物学的双刃剑。维修DNA损伤的生化机械在维持基因组完整性中起着核心作用，从而预防正常细胞中的癌症，但它也限制了DNA损害药物的功效，这些功效代表了一些最广泛使用，最成功的化学治疗药物在临床肿瘤学中。因此，对DNA修复酶的酶促反应机制和生理功能的详细理解代表了有关正常细胞功能以及保护它们免受致癌转化的系统的基本知识。但是，这种知识在改善癌症治疗的努力中实际上也很重要，因为DNA修复酶的抑制剂可以增强其他治疗剂的效力。最近，关于ALKB超家族中DNA修复酶的分子功能的知识爆炸，这些酶都存在于所有真菌和所有较高的真核生物中。这些酶已被证明可以催化在内粒环氮原子上已烷基化的腺嘌呤和胞嘧啶碱的直接修复，这是一种由内源性和环境诱变剂介导的有毒DNA修饰。阐明由ALKB催化的化学反应已使得在理解其生理功能方面取得了快速的进步，其中包括修复受损的mRNA和tRNA分子，除了修复DNA中的诱变病变外，还可以降低翻译效率。然而，ALKB超家族酶的许多特征仍有待表征，包括能够对不同底物识别的结构机制，其催化反应机制的细节以及在哺乳动物生物体中保守的8种不同序列同源物的生物学功能。我们计划将生物物理，化学和分子生物学技术的组合结合起来，以回答有关ALKB家庭DNA修复酶生化的这些基本问题。