Genetic analyses of molybdenum cofactor biology

钼辅因子（Moco）是动物生命所需的520-道尔顿辅基。莫科存在于最后一个普遍的共同祖先中，它的合成存在于生命的所有领域。基因编码的功能丧失突变 Moco生物合成酶导致人类Moco缺乏症，这是一种罕见且致命的先天性代谢缺陷。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。这些酶分别催化含硫氨基酸和嘌呤代谢中的关键步骤，当受到干扰时，这些关键途径会导致疾病。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。我的研究的长期目标是i）发现动物维持Moco稳态的新机制，ii）识别和表征调节Moco介导的代谢的遗传途径。我们采用跨学科的方法，在模式生物秀丽隐杆线虫与功能基因组学，生物化学和细胞生物学相结合，探索以前棘手的领域莫科生物学无偏遗传策略。这一建议建立在我们最近意外发现的基础上，即膳食Moco对C.优雅我们的工作揭示了一种以前无法想象的动物Moco运输途径。目前的建议的第一个目标是确定蛋白质的网络所需的稳定摄取和分布的莫科在C。优雅该提案的第二个目标是确定控制含硫氨基酸和嘌呤代谢的调节途径;由Moco需要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.