Genetic analyses of molybdenum cofactor biology

项目摘要/摘要 钼辅因子(MoCO)是一种520道尔顿的假体，是动物生活所必需的。莫科也在场 在上一个宇宙中，共同祖先及其合成持续存在于生命的所有领域。功能丧失突变 在编码MOCO生物合成酶的基因中导致人类MOCO缺乏症，这是一种罕见的致命的先天错误 新陈代谢。在动物体内，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。 分别是当受到干扰时导致疾病的基本途径。因此，了解MOCO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。长期的 我的研究目标是：1)发现动物用来维持MOCO动态平衡的新机制 Ii)确定和描述调节MOCO介导的新陈代谢的遗传途径。我们雇佣了一名 在模式生物秀丽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 莫科生物学的。这项建议建立在我们最近的发现之上，即饮食中的MOCO对线虫是生物可利用的。 我们的工作揭示了动物体内Moco运输的一条以前想象不到的途径。当前的第一个目标 建议定义稳定摄取和分布MoCO所需的蛋白质网络。 优雅女装。这项提案的第二个目标是确定控制含硫氨基酸和 嘌呤代谢；由需要MOCO的酶控制的基本代谢途径。拟议的研究 该计划将定义管理MOCO生物学的基本途径，并可能提出新的治疗策略 治疗MOCO及其介导的代谢紊乱的罕见病和常见病。

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.