Journal article
Hypoxia drives the assembly of the multienzyme purinosome complex
The Journal of biological chemistry, Vol.295(28), pp.9551-9566
07/10/2020
DOI: 10.1074/jbc.RA119.012175
PMCID: PMC7363121
PMID: 32439803
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 mitochondrion-derived 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.
Details
- Title: Subtitle
- Hypoxia drives the assembly of the multienzyme purinosome complex
- Creators
- Cyrielle Doigneaux - University of SouthamptonAnthony M. Pedley - Pennsylvania State UniversityIshna N. Mistry - University of SouthamptonMonika Papayova - University of SouthamptonStephen J. Benkovic - Pennsylvania State UniversityAli Tavassoli - University of Southampton
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.295(28), pp.9551-9566
- DOI
- 10.1074/jbc.RA119.012175
- PMID
- 32439803
- PMCID
- PMC7363121
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Number of pages
- 16
- Language
- English
- Date published
- 07/10/2020
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984772260302771
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