Genetic analyses of molybdenum cofactor biology

钼辅因子(MoCO)是一种520道尔顿的假体，是动物生活所必需的。MOCO存在于最后一个宇宙共同祖先中，它的合成持续存在于生命的所有领域。编码基因的功能丧失突变 MOCO生物合成酶导致人类MOCO缺乏症，这是一种罕见的、致命的先天代谢错误。在动物体内，MOCO支持亚硫酸盐氧化酶和黄嘌呤脱氢酶等4种酶的活性。这些酶分别催化硫代谢氨基酸和嘌呤代谢的关键步骤，这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。我研究的长期目标是i)发现动物用来维持MOCO稳态的新机制，以及ii)识别和表征调控MOCO介导的新陈代谢的遗传途径。我们采用跨学科的方法，在模式生物秀丽线虫中使用无偏见的遗传策略，结合功能基因组学、生物化学和细胞生物学来探索以前难以解决的MOCO生物学领域。这一建议建立在我们最近意外发现的基础上，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。目前提案的第一个目标是确定线虫稳定摄取和分布MOCO所需的蛋白质网络。这项提议的第二个目标是确定控制硫、氨基酸和嘌呤代谢的调控途径，即由MOCO需要的酶控制的基本代谢途径。拟议的研究计划将定义管理MOCO生物学的基本途径，并可能提出新的治疗策略，以治疗MOCO和MOCO介导的新陈代谢受到干扰的罕见和常见疾病。

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 unexpected 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.