Genetic analyses of molybdenum cofactor biology

钼辅助因子生物学的遗传分析

• 批准号: 10676863
• 负责人: Kurt Warnhoff
• 金额: $ 41.5万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676863
• 关键词: Animals; Area; Biochemistry and Cellular Biology; Biological Availability; Biology; Caenorhabditis elegans; Cells; Combined molybdoflavoprotein enzyme deficiency; Dedications; Disease; Enzymes; Genes; Genetic; Goals; Health; Homeostasis; Human; Inborn Errors of Metabolism; Life; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Neonatal; Pathway interactions; Prosthesis; Proteins; Purines; Regulatory Pathway; Research; Sulfur Amino Acids; Sulfur Metabolism Pathway; Work; XDH gene; chemical reaction; cofactor; coping; dalton; dietary; functional genomics; genetic analysis; genetic approach; insight; interdisciplinary approach; loss of function mutation; model organism; molybdenum cofactor; novel therapeutic intervention; programs; purine metabolism; rare genetic disorder; sulfite oxidase; uptake

PROJECT SUMMARY/ABSTRACT Molybdenum cofactor (Moco) is a 520-dalton prosthetic group that is required for animal life. Moco was present in the last universal common ancestor and its synthesis persists in all domains of life. Loss-of-function mutations in the genes encoding Moco-biosynthetic enzymes cause human Moco deficiency, a rare and lethal inborn error of metabolism. In animals, Moco supports the activity of 4 enzymes including sulfite oxidase and xanthine dehydrogenase. These enzymes catalyze critical steps in the metabolism of sulfur amino acids and purines respectively, essential pathways that cause disease when perturbed. Thus, understanding Moco biology and the far-reaching metabolic consequences of Moco deficiency is an important goal of human health. The long-term goal of my research is to i) discover new mechanisms employed by animals to maintain Moco homeostasis and ii) identify and characterize genetic pathways that regulate Moco-mediated metabolism. We employ an interdisciplinary approach using unbiased genetic strategies in the model organism Caenorhabditis elegans in combination with functional genomics, biochemistry, and cellular biology to explore previously intractable areas of Moco biology. This proposal builds on our recent discovery that dietary Moco is bioavailable to C. elegans. Our work reveals a previously unimagined pathway for Moco transport in an animal. The first goal of the current proposal is to define the network of proteins necessary for the stable uptake and distribution of Moco in C. elegans. The second goal of this proposal is to identify regulatory pathways that control sulfur amino acid and purine metabolism; essential metabolic pathways governed by Moco-requiring enzymes. The proposed research program will define fundamental pathways that govern Moco biology and may suggest new therapeutic strategies to treat rare and common diseases where Moco and Moco-mediated metabolism are disturbed.

项目总结/摘要 钼辅因子（Moco）是动物生命所需的520-道尔顿辅基。莫科当时在场 在最后一个普遍的共同祖先和它的合成坚持在所有领域的生活。功能丧失突变 在编码Moco生物合成酶的基因中， 新陈代谢的过程。在动物中，Moco支持4种酶的活性，包括亚硫酸盐氧化酶和黄嘌呤 脱氢酶。这些酶催化含硫氨基酸和嘌呤代谢的关键步骤 分别是受到干扰时导致疾病的重要途径。因此，了解莫科生物学和 Moco缺乏症的深远代谢后果是人类健康的重要目标。长期 我的研究目标是i）发现动物维持Moco稳态的新机制， ii）鉴定和表征调节Moco介导的代谢的遗传途径。我们雇用一名 在模式生物秀丽隐杆线虫中使用无偏遗传策略的跨学科方法 与功能基因组学、生物化学和细胞生物学相结合，探索以前难以解决的领域 莫科生物学这一建议建立在我们最近的发现，膳食莫科是生物利用的C。优美的 我们的工作揭示了一种以前无法想象的动物Moco运输途径。当前的第一个目标 建议是确定蛋白质的网络所需的稳定摄取和分布的莫科在C。 优雅的该提案的第二个目标是确定控制含硫氨基酸的调节途径， 嘌呤代谢;由需要Moco的酶控制的基本代谢途径。拟议研究 该计划将确定管理Moco生物学的基本途径，并可能提出新的治疗策略 用于治疗Moco和Moco介导的代谢紊乱的罕见和常见疾病。