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Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells

Red blood cells (RBC) have the special challenge of a large amount of reactive oxygen species (from their substantial iron load and Fenton reactions) combined with the inability to synthesize new gene products. Considerable progress has been made in elucidating the multiple pathways by which RBC neu...

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Autores principales: D’Alessandro, Angelo, Hay, Ariel, Dzieciatkowska, Monika, Brown, Benjamin C., Morrison, Evan J, Hansen, Kirk C., Zimring, James C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485689/
https://www.ncbi.nlm.nih.gov/pubmed/33054131
http://dx.doi.org/10.3324/haematol.2020.266676
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author D’Alessandro, Angelo
Hay, Ariel
Dzieciatkowska, Monika
Brown, Benjamin C.
Morrison, Evan J
Hansen, Kirk C.
Zimring, James C
author_facet D’Alessandro, Angelo
Hay, Ariel
Dzieciatkowska, Monika
Brown, Benjamin C.
Morrison, Evan J
Hansen, Kirk C.
Zimring, James C
author_sort D’Alessandro, Angelo
collection PubMed
description Red blood cells (RBC) have the special challenge of a large amount of reactive oxygen species (from their substantial iron load and Fenton reactions) combined with the inability to synthesize new gene products. Considerable progress has been made in elucidating the multiple pathways by which RBC neutralize reactive oxygen species via NADPH driven redox reactions. However, far less is known about how RBC repair the inevitable damage that does occur when reactive oxygen species break through anti-oxidant defenses. When structural and functional proteins become oxidized, the only remedy available to RBC is direct repair of the damaged molecules, as RBC cannot synthesize new proteins. Amongst the most common amino acid targets of oxidative damage is the conversion of asparagine and aspartate side chains into a succinimidyl group through deamidation or dehydration, respectively. RBC express an L-isoaspartyl methyltransferase (PIMT, gene name PCMT1) that can convert succinimidyl groups back to an aspartate. Herein, we report that deletion of PCMT1 significantly alters RBC metabolism in a healthy state, but does not impair the circulatory lifespan of RBC. Through a combination of genetic ablation, bone marrow transplantation and oxidant stimulation with phenylhydrazine in vivo or blood storage ex vivo, we use omics approaches to show that, when animals are exposed to oxidative stress, RBC from PCMT1 knockout undergo significant metabolic reprogramming and increased hemolysis. This is the first report of an essential role of PCMT1 for normal RBC circulation during oxidative stress.
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spelling pubmed-84856892021-10-18 Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells D’Alessandro, Angelo Hay, Ariel Dzieciatkowska, Monika Brown, Benjamin C. Morrison, Evan J Hansen, Kirk C. Zimring, James C Haematologica Article Red blood cells (RBC) have the special challenge of a large amount of reactive oxygen species (from their substantial iron load and Fenton reactions) combined with the inability to synthesize new gene products. Considerable progress has been made in elucidating the multiple pathways by which RBC neutralize reactive oxygen species via NADPH driven redox reactions. However, far less is known about how RBC repair the inevitable damage that does occur when reactive oxygen species break through anti-oxidant defenses. When structural and functional proteins become oxidized, the only remedy available to RBC is direct repair of the damaged molecules, as RBC cannot synthesize new proteins. Amongst the most common amino acid targets of oxidative damage is the conversion of asparagine and aspartate side chains into a succinimidyl group through deamidation or dehydration, respectively. RBC express an L-isoaspartyl methyltransferase (PIMT, gene name PCMT1) that can convert succinimidyl groups back to an aspartate. Herein, we report that deletion of PCMT1 significantly alters RBC metabolism in a healthy state, but does not impair the circulatory lifespan of RBC. Through a combination of genetic ablation, bone marrow transplantation and oxidant stimulation with phenylhydrazine in vivo or blood storage ex vivo, we use omics approaches to show that, when animals are exposed to oxidative stress, RBC from PCMT1 knockout undergo significant metabolic reprogramming and increased hemolysis. This is the first report of an essential role of PCMT1 for normal RBC circulation during oxidative stress. Fondazione Ferrata Storti 2020-09-10 /pmc/articles/PMC8485689/ /pubmed/33054131 http://dx.doi.org/10.3324/haematol.2020.266676 Text en Copyright© 2021 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
D’Alessandro, Angelo
Hay, Ariel
Dzieciatkowska, Monika
Brown, Benjamin C.
Morrison, Evan J
Hansen, Kirk C.
Zimring, James C
Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells
title Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells
title_full Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells
title_fullStr Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells
title_full_unstemmed Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells
title_short Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells
title_sort protein-l-isoaspartate o-methyltransferase is required for in vivo control of oxidative damage in red blood cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485689/
https://www.ncbi.nlm.nih.gov/pubmed/33054131
http://dx.doi.org/10.3324/haematol.2020.266676
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