Barile, A;
Mills, P;
di Salvo, ML;
Graziani, C;
Bunik, V;
Clayton, P;
Contestabile, R;
(2021)
Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5 '-Phosphate Oxidase-Dependent Epilepsy.
International Journal of Molecular Sciences
, 22
(21)
, Article 12013. 10.3390/ijms222112013.
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Abstract
Several variants of the enzyme pyridox(am)ine 5′-phosphate oxidase (PNPO), responsible for a rare form of vitamin B6-dependent neonatal epileptic encephalopathy known as PNPO deficiency (PNPOD), have been reported. However, only a few of them have been characterised with respect to their structural and functional properties, despite the fact that the knowledge of how variants affect the enzyme may clarify the disease mechanism and improve treatment. Here, we report the characterisation of the catalytic, allosteric and structural properties of recombinantly expressed D33V, R161C, P213S, and E50K variants, among which D33V (present in approximately 10% of affected patients) is one of the more common variants responsible for PNPOD. The D33V and E50K variants have only mildly altered catalytic properties. In particular, the E50K variant, given that it has been found on the same chromosome with other known pathogenic variants, may be considered non-pathogenic. The P213S variant has lower thermal stability and reduced capability to bind the FMN cofactor. The variant involving Arg161 (R161C) largely decreases the affinity for the pyridoxine 5′-phosphate substrate and completely abolishes the allosteric feedback inhibition exerted by the pyridoxal 5′-phosphate product.
| Type: | Article |
|---|---|
| Title: | Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5 '-Phosphate Oxidase-Dependent Epilepsy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/ijms222112013 |
| Publisher version: | https://doi.org/10.3390/ijms222112013 |
| Language: | English |
| Additional information: | 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 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/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemistry & Molecular Biology, Chemistry, Multidisciplinary, Chemistry, pyridox(am)ine 5 '-phosphate oxidase, pyridoxal 5 '-phosphate, neonatal epileptic encephalopathy, PNPO deficiency, PNPO DEFICIENCY, PYRIDOXAL-PHOSPHATE, MUTATIONS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10138902 |
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