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Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5$\prime$-Phosphate Oxidase-Dependent Epilepsyстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 24 ноября 2021 г.
- Авторы: Barile Anna, Mills Philippa, di Salvo Martino L., Graziani Claudio, Bunik Victoria, Clayton Peter, Contestabile Roberto, Tramonti Angela
- Журнал: International Journal of Molecular Sciences
- Том: 22
- Номер: 21
- Год издания: 2021
- Издательство: MDPI
- Местоположение издательства: Basel, Switzerland
- Первая страница: 1
- Последняя страница: 11
- Номер статьи: 12013
- DOI: 10.3390/ijms222112013
- Аннотация: 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.
- Добавил в систему: Буник-Фаренвальд Виктория-Лариса Ивановна