Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/171164
Share/Export:
logo share SHARE logo core CORE BASE
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE
Title

The Study of Carbamoyl Phosphate Synthetase 1 Deficiency Sheds Light on the Mechanism for Switching On/Off the Urea Cycle

AuthorsDíez-Fernández, Carmen CSIC; Gallego, Jose; Haberle, Johannes; Cervera, Javier; Rubio, Vicente CSIC ORCID
KeywordsAllosteric regulation
Carbamoyl phosphate synthetase 1
Enzyme
Hyperammonemia
Inborn errors
Restrained molecular dynamics
Site-directed mutagenesis
Urea cycle diseases
Issue Date20-May-2015
PublisherElsevier
CitationJournal of Genetics and Genomics 42(5):249-60 (2015)
AbstractCarbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is an inborn error of the urea cycle having autosomal (2q34) recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 deficiency that map in the 20-kDa C-terminal domain of the enzyme. This domain turns on or off the enzyme depending on whether the essential allosteric activator of CPS1, N-acetyl-L-glutamate (NAG), is bound or is not bound to it. To carry out the present studies, we exploited a novel system that allows the expression in vitro and the purification of human CPS1, thus permitting site-directed mutagenesis. These studies have clarified disease causation by individual mutations, identifying functionally important residues, and revealing that a number of mutations decrease the affinity of the enzyme for NAG. Patients with NAG affinity-decreasing mutations might benefit from NAG site saturation therapy with N-carbamyl-L-glutamate (a registered drug, the analog of NAG). Our results, together with additional present and prior site-directed mutagenesis data for other residues mapping in this domain, suggest an NAG-triggered conformational change in the β4-α4 loop of the C-terminal domain of this enzyme. This change might be an early event in the NAG activation process. Molecular dynamics simulations that were restrained according to the observed effects of the mutations are consistent with this hypothesis, providing further backing for this structurally plausible signaling mechanism by which NAG could trigger urea cycle activation via CPS1.
Description12 páginas, 4 figuras, 2 tablas.
Publisher version (URL)http://dx.doi.org/10.1016/j.jgg.2015.03.009
URIhttp://hdl.handle.net/10261/171164
DOI10.1016/j.jgg.2015.03.009
ISSN1673-8527)
Appears in Collections:(IBV) Artículos




Files in This Item:
File Description SizeFormat
2015 J Genet Genomics 42-249 Author vers.pdf1,08 MBAdobe PDFThumbnail
View/Open
Show full item record
Review this work

SCOPUSTM   
Citations

19
checked on May 21, 2022

WEB OF SCIENCETM
Citations

18
checked on May 22, 2022

Page view(s)

250
checked on May 28, 2022

Download(s)

267
checked on May 28, 2022

Google ScholarTM

Check

Altmetric

Dimensions


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.