Hypoxia drives the assembly of the multienzyme purinosome complex.
J Biol Chem
; 295(28): 9551-9566, 2020 07 10.
Article
in En
| MEDLINE
| ID: mdl-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Purines
/
Hydroxymethyl and Formyl Transferases
/
Hypoxia-Inducible Factor 1
/
Multienzyme Complexes
/
Nucleotide Deaminases
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2020
Type:
Article
Affiliation country:
United kingdom