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...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Nature Publishing Group
2019-10-01
|
Series: | Scientific Reports |
Online Access: | https://doi.org/10.1038/s41598-019-50673-4 |
id |
doaj-98cbd0cfb2e64e8c8b4f5fe2009a0e66 |
---|---|
record_format |
Article |
spelling |
doaj-98cbd0cfb2e64e8c8b4f5fe2009a0e662020-12-08T06:47:33ZengNature Publishing GroupScientific Reports2045-23222019-10-019111010.1038/s41598-019-50673-4The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrityElisa Mascolo0Anna Barile1Lorenzo Stufera Mecarelli2Noemi Amoroso3Chiara Merigliano4Arianna Massimi5Isabella Saggio6Torben Hansen7Angela Tramonti8Martino Luigi Di Salvo9Fabrizio Barbetti10Roberto Contestabile11Fiammetta Vernì12Dipartimento di Biologia e Biotecnologie “C. Darwin” Sapienza Università di RomaDipartimento di Scienze Biochimiche “A. Rossi Fanelli”, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci BolognettiDipartimento di Biologia e Biotecnologie “C. Darwin” Sapienza Università di RomaDipartimento di Biologia e Biotecnologie “C. Darwin” Sapienza Università di RomaUniversity of Southern California, Molecular and Computational Biology DepartmentDipartimento di Medicina Sperimentale, Università di Roma Tor VergataDipartimento di Biologia e Biotecnologie “C. Darwin” Sapienza Università di RomaNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenDipartimento di Scienze Biochimiche “A. Rossi Fanelli”, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci BolognettiDipartimento di Scienze Biochimiche “A. Rossi Fanelli”, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci BolognettiDipartimento di Medicina Sperimentale, Università di Roma Tor VergataDipartimento di Scienze Biochimiche “A. Rossi Fanelli”, Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci BolognettiDipartimento di Biologia e Biotecnologie “C. Darwin” Sapienza Università di RomaAbstract 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.https://doi.org/10.1038/s41598-019-50673-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2019-10-01 |
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. |
url |
https://doi.org/10.1038/s41598-019-50673-4 |
work_keys_str_mv |
AT elisamascolo theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT annabarile theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT lorenzostuferamecarelli theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT noemiamoroso theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT chiaramerigliano theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT ariannamassimi theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT isabellasaggio theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT torbenhansen theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT angelatramonti theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT martinoluigidisalvo theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT fabriziobarbetti theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT robertocontestabile theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT fiammettaverni theexpressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT elisamascolo expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT annabarile expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT lorenzostuferamecarelli expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT noemiamoroso expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT chiaramerigliano expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT ariannamassimi expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT isabellasaggio expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT torbenhansen expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT angelatramonti expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT martinoluigidisalvo expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT fabriziobarbetti expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT robertocontestabile expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity AT fiammettaverni expressionoffourpyridoxalkinasepdxkhumanvariantsindrosophilaimpactsongenomeintegrity |
_version_ |
1724391311064170496 |