L-serine deficiency: on the properties of the Asn133Ser variant of human phosphoserine phosphatase.

Details

Serval ID
serval:BIB_121DFA429DA3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
L-serine deficiency: on the properties of the Asn133Ser variant of human phosphoserine phosphatase.
Journal
Scientific reports
Author(s)
Pollegioni L., Campanini B., Good J.M., Motta Z., Murtas G., Buoli Comani V., Pavlidou D.C., Mercier N., Mittaz-Crettol L., Sacchi S., Marchesani F.
ISSN
2045-2322 (Electronic)
ISSN-L
2045-2322
Publication state
Published
Issued date
30/05/2024
Peer-reviewed
Oui
Volume
14
Number
1
Pages
12463
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
The non-essential amino acid L-serine is involved in a number of metabolic pathways and in the brain its level is largely due to the biosynthesis from the glycolytic intermediate D-3-phosphoglycerate by the phosphorylated pathway (PP). This cytosolic pathway is made by three enzymes proposed to generate a reversible metabolon named the "serinosome". Phosphoserine phosphatase (PSP) catalyses the last and irreversible step, representing the driving force pushing L-serine synthesis. Genetic defects of the PP enzymes result in strong neurological phenotypes. Recently, we identified the homozygous missense variant [NM_004577.4: c.398A > G p.(Asn133Ser)] in the PSPH, the PSP encoding gene, in two siblings with a neurodevelopmental syndrome and a myelopathy. The recombinant Asn133Ser enzyme does not show significant alterations in protein conformation and dimeric oligomerization state, as well as in enzymatic activity and functionality of the reconstructed PP. However, the Asn133Ser variant is less stable than wild-type PSP, a feature also apparent at cellular level. Studies on patients' fibroblasts also highlight a strong decrease in the level of the enzymes of the PP, a partial nuclear and perinuclear localization of variant PSP and a stronger perinuclear aggregates formation. We propose that these alterations contribute to the formation of a dysfunctional serinosome and thus to the observed reduction of L-serine, glycine and D-serine levels (the latter playing a crucial role in modulating NMDA receptors). The characterization of patients harbouring the Asn133Ser PSP substitution allows to go deep into the molecular mechanisms related to L-serine deficit and to suggest treatments to cope with the observed amino acids alterations.
Keywords
Humans, Serine/metabolism, Mutation, Missense, Phosphoric Monoester Hydrolases/metabolism, Phosphoric Monoester Hydrolases/genetics, Fibroblasts/metabolism, Male, Neurodevelopmental Disorders/genetics, Neurodevelopmental Disorders/metabolism, Female, Genetic disease, Phosphorylated pathway, Serine deficiency, Structure–function relationships
Pubmed
Web of science
Open Access
Yes
Create date
14/06/2024 13:38
Last modification date
15/06/2024 7:04
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