Application of QM/MM Methods in the Study of PNPOx

• DOI: 10.3390/mol2net-04-06005
• Publication Date: 2018-12-25T08:55:52Z
• Authors: Nuno Cerqueira; André Pina; Sérgio Sousa

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, is an essential cofactor required by more than 160 families enzymes. Its role as electron sink makes it imperative for catalysis a myriad chemical reactions. Contrarily to microorganisms and plants, humans other mammals are not able synthesize PLP de novo, resorting "salvage pathway" that helps maintain homeostasis [1]. The correct functioning this salvage pathway crucial cell, demonstrated correlation between low levels occurrence severe neurological disorders [2]. It was found major culprit pyridoxine/pyridoxamine oxidase (PNPOx), FMN-dependent homodimeric enzyme responsible recycling pyridoxine (PNP) pyridoxamine (PMP) into [3]. Therefore, in order better understand its these disorders, utmost importance unveil catalytic mechanism PNPOx. To do so we used computational means, namely QM/MM hybrid methodologies [4], evaluate different mechanistic proposals related PNPOx reactivity. Models were prepared evaluated enabling important aspects modelling be validated. results obtained present work provide details about PNPOx, helping us some key residues site can have implications PLP-deficiency disorders. More studies fully enzyme. Acknowledgments: We acknowledge FCT financial support PhD grant SFRH/BD/136594/2018, Starting grants IF/01310/2013 IF/00052/2014, Project PTDC/QUI-QFI/31689/2017. References [1] Di Salvo, M L, et al. Vitamin B6 Salvage Enzymes: Mechanism, Structure Regulation. BBA-Proteins Proteomics 2011, 1814(11), 1597–1608 [2] Mills, P B, Neonatal Epileptic Encephalopathy Caused Mutations PNPO Gene Encoding Pyridox(Am)Ine 5′-Phosphate Oxidase. Hum Mol Genet 2005, 14(8), 1077–1086 [3] Mechanism Escherichia Coli Pyridoxine 2003, 1647(1–2), 76–82 [4] Chung, L. W, ONIOM Method Applications. Chem Rev 2015, 115(12), 5678–5796