Hypoxia drives the assembly of the multienzyme purinosome complex

Cyrielle Doigneaux, Anthony M. Pedley, Ishna N. Mistry, Monika Papayova, Stephen J. Benkovic, Ali Tavassoli

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The purinosome is a dynamic metabolic complex composed of enzymes responsible for de novo purine biosynthesis, whose formation has been associated with elevated purine demand. However, the physiological conditions that govern purinosome formation in cells remain unknown. Here, we report that purinosome formation is up-regulated in cells in response to a low-oxygen microenvironment (hypoxia). We demonstrate that increased purinosome assembly in hypoxic human cells requires the activation of hypoxia inducible factor 1 (HIF-1) and not HIF-2. Hypoxia-driven purinosome assembly was inhibited in cells lacking 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a single enzyme in de novo purine biosynthesis, and in cells treated with a small molecule inhibitor of ATIC homodimerization. However, despite the increase in purinosome assembly in hypoxia, we observed no associated increase in de novo purine biosynthesis in cells. Our results indicate that this was likely due to a reduction in mitochondrial one-carbon metabolism, resulting in reduced mitochondrionderived one-carbon units needed for de novo purine biosynthesis. The findings of our study further clarify and deepen our understanding of purinosome formation by revealing that this process does not solely depend on cellular purine demand.

Original languageEnglish (US)
Pages (from-to)9551-9566
Number of pages16
JournalJournal of Biological Chemistry
Volume295
Issue number28
DOIs
StatePublished - Jul 10 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Hypoxia drives the assembly of the multienzyme purinosome complex'. Together they form a unique fingerprint.

Cite this