Genetic analyses of molybdenum cofactor biology

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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.