Fluorinated Galactoses Inhibit Galactose-1-Phosphate Uridyltransferase and Metabolically Induce Galactosemia-like Phenotypes in HEK-293 Cells.

Cells
Verena JanesFranz-Georg Hanisch

Abstract

Genetic defects of human galactose-1-phosphate uridyltransferase (hGALT) and the partial loss of enzyme function result in an altered galactose metabolism with serious long-term developmental impairment of organs in classic galactosemia patients. In search for cellular pathomechanisms induced by the stressor galactose, we looked for ways to induce metabolically a galactosemia-like phenotype by hGALT inhibition in HEK293 cells. In kinetic studies, we provide evidence for 2-fluorinated galactose-1-phosphate (F-Gal-1-P) to competitively inhibit recombinant hGALT with a KI of 0.9 mM. Contrasting with hepatic cells, no alterations of N-glycoprofiles in MIG (metabolic induction of galactosemia)-HEK293 cells were revealed for an inducible secretory netrin-1 probe by MALDI-MS. Differential fluorescence-activated cell sorting demonstrated reduced surface expression of N-glycosylated CD109, EGFR, DPP4, and rhMUC1. Membrane raft proteomes exhibited dramatic alterations pointing to an affection of the unfolded protein response, and of targeted protein traffick. Most prominent, a negative regulation of oxidative stress was revealed presumably as a response to a NADPH pool depletion during reduction of Gal/F-Gal. Cellular perturbations induc...Continue Reading

References

Aug 1, 1992·The Biochemical Journal·V GrossD Keppler
Dec 9, 1991·FEBS Letters·N LochW Reutter
Jun 6, 1998·Glycobiology·J CharlwoodB Winchester
May 16, 2000·The Journal of Biological Chemistry·C CrewsJ L Fridovich-Keil
Apr 23, 2002·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Gerry ShawFrank L Graham
May 11, 2005·Proceedings of the National Academy of Sciences of the United States of America·Michael W XieJing Huang
Dec 13, 2005·American Journal of Physiology. Cell Physiology·Beth A PotterOra A Weisz
Jul 14, 2006·Journal of Inherited Metabolic Disease·Annet M Bosch
Jul 24, 2007·Molecular Genetics and Metabolism·Tatiana I SlepakKent Lai
Jun 26, 2008·Chemistry : a European Journal·Cosme G FranciscoErnesto Suárez
Jun 4, 2010·Disease Models & Mechanisms·Rebekah F KushnerJudith L Fridovich-Keil
Dec 17, 2011·Genetics·Robbie Loewith, Michael N Hall
Oct 1, 2013·Disease Models & Mechanisms·Evandro A De-SouzaClaudio A Masuda
Feb 18, 2014·Cell·Constantinos DemetriadesAurelio A Teleman
Apr 1, 2016·Journal of the Royal Society, Interface·Boštjan ViharWerner Baumgartner
Mar 11, 2017·Journal of Inherited Metabolic Disease·Ana I CoelhoIsabel Rivera
Mar 30, 2017·Journal of Biotechnology·Claudia WahlLothar Elling
Aug 11, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Thomas FischöderLothar Elling
Oct 28, 2019·Journal of Proteome Research·Atef Mannaa, Franz-Georg Hanisch

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Citations

Jun 11, 2020·Chemical Society Reviews·Bruno LinclauJesús Jiménez-Barbero
Oct 28, 2019·Journal of Proteome Research·Atef Mannaa, Franz-Georg Hanisch

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Datasets Mentioned

BETA
GM01704

Methods Mentioned

BETA
glycosylation
Assay
FCS
light-scattering
enzymatic assay
enzyme
electrophoresis
FACS
GTPases
protein folding

Software Mentioned

FlowJo
GOTE
BD FACSDiva

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