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Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis
Human carbamoyl phosphate synthetase (CPS1), a 1500-residue multidomain enzyme, catalyzes the first step of ammonia detoxification to urea requiring N-acetyl-L-glutamate (NAG) as essential activator to prevent ammonia/amino acids depletion. Here we present the crystal structures of CPS1 in the absen...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655335/ https://www.ncbi.nlm.nih.gov/pubmed/26592762 http://dx.doi.org/10.1038/srep16950 |
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author | de Cima, Sergio Polo, Luis M. Díez-Fernández, Carmen Martínez, Ana I. Cervera, Javier Fita, Ignacio Rubio, Vicente |
author_facet | de Cima, Sergio Polo, Luis M. Díez-Fernández, Carmen Martínez, Ana I. Cervera, Javier Fita, Ignacio Rubio, Vicente |
author_sort | de Cima, Sergio |
collection | PubMed |
description | Human carbamoyl phosphate synthetase (CPS1), a 1500-residue multidomain enzyme, catalyzes the first step of ammonia detoxification to urea requiring N-acetyl-L-glutamate (NAG) as essential activator to prevent ammonia/amino acids depletion. Here we present the crystal structures of CPS1 in the absence and in the presence of NAG, clarifying the on/off-switching of the urea cycle by NAG. By binding at the C-terminal domain of CPS1, NAG triggers long-range conformational changes affecting the two distant phosphorylation domains. These changes, concerted with the binding of nucleotides, result in a dramatic remodeling that stabilizes the catalytically competent conformation and the building of the ~35 Å-long tunnel that allows migration of the carbamate intermediate from its site of formation to the second phosphorylation site, where carbamoyl phosphate is produced. These structures allow rationalizing the effects of mutations found in patients with CPS1 deficiency (presenting hyperammonemia, mental retardation and even death), as exemplified here for some mutations. |
format | Online Article Text |
id | pubmed-4655335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46553352015-11-27 Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis de Cima, Sergio Polo, Luis M. Díez-Fernández, Carmen Martínez, Ana I. Cervera, Javier Fita, Ignacio Rubio, Vicente Sci Rep Article Human carbamoyl phosphate synthetase (CPS1), a 1500-residue multidomain enzyme, catalyzes the first step of ammonia detoxification to urea requiring N-acetyl-L-glutamate (NAG) as essential activator to prevent ammonia/amino acids depletion. Here we present the crystal structures of CPS1 in the absence and in the presence of NAG, clarifying the on/off-switching of the urea cycle by NAG. By binding at the C-terminal domain of CPS1, NAG triggers long-range conformational changes affecting the two distant phosphorylation domains. These changes, concerted with the binding of nucleotides, result in a dramatic remodeling that stabilizes the catalytically competent conformation and the building of the ~35 Å-long tunnel that allows migration of the carbamate intermediate from its site of formation to the second phosphorylation site, where carbamoyl phosphate is produced. These structures allow rationalizing the effects of mutations found in patients with CPS1 deficiency (presenting hyperammonemia, mental retardation and even death), as exemplified here for some mutations. Nature Publishing Group 2015-11-23 /pmc/articles/PMC4655335/ /pubmed/26592762 http://dx.doi.org/10.1038/srep16950 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article de Cima, Sergio Polo, Luis M. Díez-Fernández, Carmen Martínez, Ana I. Cervera, Javier Fita, Ignacio Rubio, Vicente Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis |
title | Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis |
title_full | Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis |
title_fullStr | Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis |
title_full_unstemmed | Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis |
title_short | Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis |
title_sort | structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655335/ https://www.ncbi.nlm.nih.gov/pubmed/26592762 http://dx.doi.org/10.1038/srep16950 |
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