Adenylosuccinate Lyase activity in the Purine recycling pathway is essential for developmental timing, germline maintenance and muscle integrity in C. elegans.

Abstract

Purine homeostasis is ensured through a metabolic network widely conserved from prokaryotes to humans. Purines can either be synthesized de novo, reused, or produced by interconversion of extant metabolites using the so-called recycling pathway. Although thoroughly characterized in microorganisms, such as yeast or bacteria, little is known about the regulation of this biosynthesis network in metazoans. In humans, several diseases are linked to purine biosynthesis deficiencies through yet poorly understood etiologies. Particularly, the deficiency in Adenylosuccinate Lyase (ADSL), one enzyme involved both in the purine de novo and recycling pathways, causes severe muscular and neuronal symptoms. In order to address the mechanisms underlying this deficiency, we established Caenorhabditis elegans as a metazoan model organism to study purine metabolism, while focusing on ADSL. We show that the purine biosynthesis network is functionally conserved in C. elegans. Moreover, ADSL is required for developmental timing and germline stem cell maintenance, and muscle integrity. Our results allow to ascribe developmental and tissue specific phenotypes to separable steps of the purine metabolic network in an animal model. Particularly, the muscle, germline and developmental defects are linked specifically to the ADSL role in the purine recycling pathway.