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Hypoxia drives the assembly of the multi-enzyme purinosome complex

Hypoxia drives the assembly of the multi-enzyme purinosome complex
Hypoxia drives the assembly of the multi-enzyme purinosome complex
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 was observed 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.
purinosome, hypoxia, hypoxia-inducible factor 1, HIF-1, metabolon, de novo purine biosynthesis, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), cellular metabolism
1083-351X
9551-9566
Doigneaux, Cyrielle
9f8adf0b-137e-4642-8cfc-e7e0e556d4b0
Pedley, Anthony
71458542-c517-47fa-838f-39a15740ce2f
Mistry, Ishna N
70e94cae-a95e-44f8-b1f3-3218d6d278cf
Papayova, Monika
64eacb08-da7d-4691-afc8-67ebed9f6ab7
Benkovic, Stephen
3a5a771a-1630-4ee6-8a4c-89e75df107d7
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Doigneaux, Cyrielle
9f8adf0b-137e-4642-8cfc-e7e0e556d4b0
Pedley, Anthony
71458542-c517-47fa-838f-39a15740ce2f
Mistry, Ishna N
70e94cae-a95e-44f8-b1f3-3218d6d278cf
Papayova, Monika
64eacb08-da7d-4691-afc8-67ebed9f6ab7
Benkovic, Stephen
3a5a771a-1630-4ee6-8a4c-89e75df107d7
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Doigneaux, Cyrielle, Pedley, Anthony, Mistry, Ishna N, Papayova, Monika, Benkovic, Stephen and Tavassoli, Ali (2020) Hypoxia drives the assembly of the multi-enzyme purinosome complex. The Journal of Biological Chemistry, 295 (28), 9551-9566. (doi:10.1074/jbc.RA119.012175).

Record type: Article

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 was observed 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.

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Accepted/In Press date: 19 May 2020
e-pub ahead of print date: 21 May 2020
Published date: 10 July 2020
Keywords: purinosome, hypoxia, hypoxia-inducible factor 1, HIF-1, metabolon, de novo purine biosynthesis, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), cellular metabolism

Identifiers

Local EPrints ID: 441089
URI: http://eprints.soton.ac.uk/id/eprint/441089
ISSN: 1083-351X
PURE UUID: 95e75635-6e70-4ca6-aa7e-958cbacf846f
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 01 Jun 2020 16:30
Last modified: 18 Feb 2021 17:07

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Contributors

Author: Cyrielle Doigneaux
Author: Anthony Pedley
Author: Ishna N Mistry
Author: Monika Papayova
Author: Stephen Benkovic
Author: Ali Tavassoli ORCID iD

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