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.

Characterization of novel pathogenic variants causing pyridox(Am)ine 5′-phosphate oxidase-dependent epilepsy / Barile, A.; Mills, P.; Di Salvo, M. L.; Graziani, C.; Bunik, V.; Clayton, P.; Contestabile, R.; Tramonti, A.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:21(2021). [10.3390/ijms222112013]

Characterization of novel pathogenic variants causing pyridox(Am)ine 5′-phosphate oxidase-dependent epilepsy

Barile A.;Di Salvo M. L.;Contestabile R.
;
Tramonti A.
2021

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.
Neonatal epileptic en-cephalopathy; PNPO deficiency; Pyridox(am)ine 5′-phosphate oxidase; Pyridoxal 5′-phosphate
01 Pubblicazione su rivista::01a Articolo in rivista
Characterization of novel pathogenic variants causing pyridox(Am)ine 5′-phosphate oxidase-dependent epilepsy / Barile, A.; Mills, P.; Di Salvo, M. L.; Graziani, C.; Bunik, V.; Clayton, P.; Contestabile, R.; Tramonti, A.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:21(2021). [10.3390/ijms222112013]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1599972
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