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The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome
Nucleotide sugar-dependent glycosyltransferases (UGTs) are critical to the homeostasis of endogenous metabolites and the detoxification of xenobiotics. Their impact on the cell metabolome remains unknown. Cellular metabolic changes resulting from human UGT expression were profiled by untargeted meta...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9609030/ https://www.ncbi.nlm.nih.gov/pubmed/36295907 http://dx.doi.org/10.3390/metabo12101006 |
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author | Audet-Delage, Yannick Rouleau, Michèle Villeneuve, Lyne Guillemette, Chantal |
author_facet | Audet-Delage, Yannick Rouleau, Michèle Villeneuve, Lyne Guillemette, Chantal |
author_sort | Audet-Delage, Yannick |
collection | PubMed |
description | Nucleotide sugar-dependent glycosyltransferases (UGTs) are critical to the homeostasis of endogenous metabolites and the detoxification of xenobiotics. Their impact on the cell metabolome remains unknown. Cellular metabolic changes resulting from human UGT expression were profiled by untargeted metabolomics. The abundant UGT1A1 and UGT2B7 were studied as UGT prototypes along with their alternative (alt.) splicing-derived isoforms displaying structural differences. Nineteen biochemical routes were modified, beyond known UGT substrates. Significant variations in glycolysis and pyrimidine pathways, and precursors of the co-substrate UDP-glucuronic acid were observed. Bioactive lipids such as arachidonic acid and endocannabinoids were highly enriched by up to 13.3-fold (p < 0.01) in cells expressing the canonical enzymes. Alt. UGT2B7 induced drastic and unique metabolic perturbations, including higher glucose (18-fold) levels and tricarboxylic acid cycle (TCA) cycle metabolites and abrogated the effects of the UGT2B7 canonical enzyme when co-expressed. UGT1A1 proteins promoted the accumulation of branched-chain amino acids (BCAA) and TCA metabolites upstream of the mitochondrial oxoglutarate dehydrogenase complex (OGDC). Alt. UGT1A1 exacerbated these changes, likely through its interaction with the OGDC component oxoglutarate dehydrogenase-like (OGDHL). This study expands the breadth of biochemical pathways associated with UGT expression and establishes extensive connectivity between UGT enzymes, alt. proteins and other metabolic processes. |
format | Online Article Text |
id | pubmed-9609030 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96090302022-10-28 The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome Audet-Delage, Yannick Rouleau, Michèle Villeneuve, Lyne Guillemette, Chantal Metabolites Article Nucleotide sugar-dependent glycosyltransferases (UGTs) are critical to the homeostasis of endogenous metabolites and the detoxification of xenobiotics. Their impact on the cell metabolome remains unknown. Cellular metabolic changes resulting from human UGT expression were profiled by untargeted metabolomics. The abundant UGT1A1 and UGT2B7 were studied as UGT prototypes along with their alternative (alt.) splicing-derived isoforms displaying structural differences. Nineteen biochemical routes were modified, beyond known UGT substrates. Significant variations in glycolysis and pyrimidine pathways, and precursors of the co-substrate UDP-glucuronic acid were observed. Bioactive lipids such as arachidonic acid and endocannabinoids were highly enriched by up to 13.3-fold (p < 0.01) in cells expressing the canonical enzymes. Alt. UGT2B7 induced drastic and unique metabolic perturbations, including higher glucose (18-fold) levels and tricarboxylic acid cycle (TCA) cycle metabolites and abrogated the effects of the UGT2B7 canonical enzyme when co-expressed. UGT1A1 proteins promoted the accumulation of branched-chain amino acids (BCAA) and TCA metabolites upstream of the mitochondrial oxoglutarate dehydrogenase complex (OGDC). Alt. UGT1A1 exacerbated these changes, likely through its interaction with the OGDC component oxoglutarate dehydrogenase-like (OGDHL). This study expands the breadth of biochemical pathways associated with UGT expression and establishes extensive connectivity between UGT enzymes, alt. proteins and other metabolic processes. MDPI 2022-10-21 /pmc/articles/PMC9609030/ /pubmed/36295907 http://dx.doi.org/10.3390/metabo12101006 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Audet-Delage, Yannick Rouleau, Michèle Villeneuve, Lyne Guillemette, Chantal The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome |
title | The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome |
title_full | The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome |
title_fullStr | The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome |
title_full_unstemmed | The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome |
title_short | The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome |
title_sort | glycosyltransferase pathway: an integrated analysis of the cell metabolome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9609030/ https://www.ncbi.nlm.nih.gov/pubmed/36295907 http://dx.doi.org/10.3390/metabo12101006 |
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