The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity

Abstract In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B6 salvage pathway to produce pyridoxal 5′-phosphate (PLP), the active form of the vitamin, which is implicated in numerous crucial metabolic reactions. In Drosophila, mutations in the dPdxk gene cause chromosome aberrations (CABs) and...

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Autores principales:	Elisa Mascolo, Anna Barile, Lorenzo Stufera Mecarelli, Noemi Amoroso, Chiara Merigliano, Arianna Massimi, Isabella Saggio, Torben Hansen, Angela Tramonti, Martino Luigi Di Salvo, Fabrizio Barbetti, Roberto Contestabile, Fiammetta Vernì
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/98cbd0cfb2e64e8c8b4f5fe2009a0e66
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spelling	oai:doaj.org-article:98cbd0cfb2e64e8c8b4f5fe2009a0e662021-12-02T15:08:46ZThe expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity10.1038/s41598-019-50673-42045-2322https://doaj.org/article/98cbd0cfb2e64e8c8b4f5fe2009a0e662019-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-50673-4https://doaj.org/toc/2045-2322Abstract In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B6 salvage pathway to produce pyridoxal 5′-phosphate (PLP), the active form of the vitamin, which is implicated in numerous crucial metabolic reactions. In Drosophila, mutations in the dPdxk gene cause chromosome aberrations (CABs) and increase glucose content in larval hemolymph. Both phenotypes are rescued by the expression of the wild type human PDXK counterpart. Here we expressed, in dPdxk 1 mutant flies, four PDXK human variants: three (D87H, V128I and H246Q) listed in databases, and one (A243G) found in a genetic screening in patients with diabetes. Differently from human wild type PDXK, none of the variants was able to completely rescue CABs and glucose content elicited by dPdxk 1 mutation. Biochemical analysis of D87H, V128I, H246Q and A243G proteins revealed reduced catalytic activity and/or reduced affinity for PLP precursors which justify this behavior. Although these variants are rare in population and carried in heterozygous condition, our findings suggest that in certain metabolic contexts and diseases in which PLP levels are reduced, the presence of these PDXK variants could threaten genome integrity and increase cancer risk.Elisa MascoloAnna BarileLorenzo Stufera MecarelliNoemi AmorosoChiara MeriglianoArianna MassimiIsabella SaggioTorben HansenAngela TramontiMartino Luigi Di SalvoFabrizio BarbettiRoberto ContestabileFiammetta VernìNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-10 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elisa Mascolo Anna Barile Lorenzo Stufera Mecarelli Noemi Amoroso Chiara Merigliano Arianna Massimi Isabella Saggio Torben Hansen Angela Tramonti Martino Luigi Di Salvo Fabrizio Barbetti Roberto Contestabile Fiammetta Vernì The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity
description	Abstract In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B6 salvage pathway to produce pyridoxal 5′-phosphate (PLP), the active form of the vitamin, which is implicated in numerous crucial metabolic reactions. In Drosophila, mutations in the dPdxk gene cause chromosome aberrations (CABs) and increase glucose content in larval hemolymph. Both phenotypes are rescued by the expression of the wild type human PDXK counterpart. Here we expressed, in dPdxk 1 mutant flies, four PDXK human variants: three (D87H, V128I and H246Q) listed in databases, and one (A243G) found in a genetic screening in patients with diabetes. Differently from human wild type PDXK, none of the variants was able to completely rescue CABs and glucose content elicited by dPdxk 1 mutation. Biochemical analysis of D87H, V128I, H246Q and A243G proteins revealed reduced catalytic activity and/or reduced affinity for PLP precursors which justify this behavior. Although these variants are rare in population and carried in heterozygous condition, our findings suggest that in certain metabolic contexts and diseases in which PLP levels are reduced, the presence of these PDXK variants could threaten genome integrity and increase cancer risk.
format	article
author	Elisa Mascolo Anna Barile Lorenzo Stufera Mecarelli Noemi Amoroso Chiara Merigliano Arianna Massimi Isabella Saggio Torben Hansen Angela Tramonti Martino Luigi Di Salvo Fabrizio Barbetti Roberto Contestabile Fiammetta Vernì
author_facet	Elisa Mascolo Anna Barile Lorenzo Stufera Mecarelli Noemi Amoroso Chiara Merigliano Arianna Massimi Isabella Saggio Torben Hansen Angela Tramonti Martino Luigi Di Salvo Fabrizio Barbetti Roberto Contestabile Fiammetta Vernì
author_sort	Elisa Mascolo
title	The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity
title_short	The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity
title_full	The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity
title_fullStr	The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity
title_full_unstemmed	The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity
title_sort	expression of four pyridoxal kinase (pdxk) human variants in drosophila impacts on genome integrity
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/98cbd0cfb2e64e8c8b4f5fe2009a0e66
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The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity

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