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Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase

Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific multifunctional enzyme that is responsible for the regulation of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells through its synthase and phosphatase activities; the latter enzymatic function is stimulated by the endogenous activator...

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Autores principales: Aljahdali, Anfal S., Musayev, Faik N., Burgner, John W., Ghatge, Mohini S., Shekar, Vibha, Zhang, Yan, Omar, Abdelsattar M., Safo, Martin K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972806/
https://www.ncbi.nlm.nih.gov/pubmed/35362470
http://dx.doi.org/10.1107/S2059798322001802
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author Aljahdali, Anfal S.
Musayev, Faik N.
Burgner, John W.
Ghatge, Mohini S.
Shekar, Vibha
Zhang, Yan
Omar, Abdelsattar M.
Safo, Martin K.
author_facet Aljahdali, Anfal S.
Musayev, Faik N.
Burgner, John W.
Ghatge, Mohini S.
Shekar, Vibha
Zhang, Yan
Omar, Abdelsattar M.
Safo, Martin K.
author_sort Aljahdali, Anfal S.
collection PubMed
description Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific multifunctional enzyme that is responsible for the regulation of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells through its synthase and phosphatase activities; the latter enzymatic function is stimulated by the endogenous activator 2-phosphoglycolate (2-PG). 2,3-BPG is a natural allosteric effector of hemoglobin (Hb) that is responsible for decreasing the affinity of Hb for oxygen to facilitate tissue oxygenation. Here, crystal structures of BPGM with 2-PG in the presence and absence of 3-phosphoglycerate are reported at 2.25 and 2.48 Å resolution, respectively. Structure analysis revealed a new binding site for 2-PG at the dimer interface for the first time, in addition to the expected active-site binding. Also, conformational non-equivalence of the two active sites was observed as one of the sites was found in an open conformation, with the residues at the active-site entrance, including Arg100, Arg116 and Arg117, and the C-terminus disordered. The kinetic result is consistent with the binding of 2-PG to an allosteric or noncatalytic site as well as the active site. This study paves the way for the rational targeting of BPGM for therapeutic purposes, especially for the treatment of sickle cell disease.
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spelling pubmed-89728062022-04-28 Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase Aljahdali, Anfal S. Musayev, Faik N. Burgner, John W. Ghatge, Mohini S. Shekar, Vibha Zhang, Yan Omar, Abdelsattar M. Safo, Martin K. Acta Crystallogr D Struct Biol Research Papers Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific multifunctional enzyme that is responsible for the regulation of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells through its synthase and phosphatase activities; the latter enzymatic function is stimulated by the endogenous activator 2-phosphoglycolate (2-PG). 2,3-BPG is a natural allosteric effector of hemoglobin (Hb) that is responsible for decreasing the affinity of Hb for oxygen to facilitate tissue oxygenation. Here, crystal structures of BPGM with 2-PG in the presence and absence of 3-phosphoglycerate are reported at 2.25 and 2.48 Å resolution, respectively. Structure analysis revealed a new binding site for 2-PG at the dimer interface for the first time, in addition to the expected active-site binding. Also, conformational non-equivalence of the two active sites was observed as one of the sites was found in an open conformation, with the residues at the active-site entrance, including Arg100, Arg116 and Arg117, and the C-terminus disordered. The kinetic result is consistent with the binding of 2-PG to an allosteric or noncatalytic site as well as the active site. This study paves the way for the rational targeting of BPGM for therapeutic purposes, especially for the treatment of sickle cell disease. International Union of Crystallography 2022-03-11 /pmc/articles/PMC8972806/ /pubmed/35362470 http://dx.doi.org/10.1107/S2059798322001802 Text en © Anfal S. Aljahdali et al. 2022 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Aljahdali, Anfal S.
Musayev, Faik N.
Burgner, John W.
Ghatge, Mohini S.
Shekar, Vibha
Zhang, Yan
Omar, Abdelsattar M.
Safo, Martin K.
Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
title Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
title_full Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
title_fullStr Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
title_full_unstemmed Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
title_short Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
title_sort molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972806/
https://www.ncbi.nlm.nih.gov/pubmed/35362470
http://dx.doi.org/10.1107/S2059798322001802
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