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

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 Verni

doi:10.1038/s41598-019-50673-4

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

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 Verni

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Abstract

In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B₆salvage 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 dPdxk¹ 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 dPdxk¹ 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.

Original language	English
Journal	Scientific Reports
Volume	9
Number of pages	10
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-019-50673-4
Publication status	Published - 1 Dec 2019

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The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrityFinal published version, 2.18 MB

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

abstract = "In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B6salvage 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 dPdxk1 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 dPdxk1 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.",

author = "Elisa Mascolo and Anna Barile and Mecarelli, {Lorenzo Stufera} and Noemi Amoroso and Chiara Merigliano and Arianna Massimi and Isabella Saggio and Torben Hansen and Angela Tramonti and {Di Salvo}, {Martino Luigi} and Fabrizio Barbetti and Roberto Contestabile and Fiammetta Verni",

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doi = "10.1038/s41598-019-50673-4",

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T1 - The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity

AU - Mascolo, Elisa

AU - Barile, Anna

AU - Mecarelli, Lorenzo Stufera

AU - Amoroso, Noemi

AU - Merigliano, Chiara

AU - Massimi, Arianna

AU - Saggio, Isabella

AU - Hansen, Torben

AU - Tramonti, Angela

AU - Di Salvo, Martino Luigi

AU - Barbetti, Fabrizio

AU - Contestabile, Roberto

AU - Verni, Fiammetta

PY - 2019/12/1

Y1 - 2019/12/1

N2 - In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B6salvage 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 dPdxk1 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 dPdxk1 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.

AB - In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B6salvage 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 dPdxk1 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 dPdxk1 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.

U2 - 10.1038/s41598-019-50673-4

DO - 10.1038/s41598-019-50673-4

M3 - Journal article

C2 - 31578392

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

ER -

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

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