Human glucocerebrosidase mediates formation of xylosyl-cholesterol by β-xylosidase and transxylosidase reactions.

Glucosylceramidase
Gaucher disease XYLOSYLATION ceramides cerebrosides glycolipids inborn errors of metabolism metabolism

Journal

Journal of lipid research
ISSN: 1539-7262
Titre abrégé: J Lipid Res
Pays: United States
ID NLM: 0376606

Informations de publication

Date de publication:
2021
Historique:
received: 25 07 2020
revised: 14 12 2020
accepted: 23 12 2020
pubmed: 29 12 2020
medline: 11 3 2022
entrez: 28 12 2020
Statut: ppublish

Résumé

Deficiency of glucocerebrosidase (GBA), a lysosomal β-glucosidase, causes Gaucher disease. The enzyme hydrolyzes β-glucosidic substrates and transglucosylates cholesterol to cholesterol-β-glucoside. Here we show that recombinant human GBA also cleaves β-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as an acceptor for the subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced β-glucosidase activity were similarly impaired in β-xylosidase, transglucosidase, and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from patients with Gaucher disease. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous β-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing β-glucosidase GBA2. We later sought an endogenous β-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyze the formation of XylCer. Thus, food-derived β-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.

Identifiants

DOI: 10.1194/jlr.RA120001043 PMID: 33361282 PMC: PMC7903134
pubmed: 33361282
pii: S0022-2275(20)43741-1
doi: 10.1194/jlr.RA120001043
pmc: PMC7903134
pii:
doi:

Substances chimiques

GBA protein, human EC 3.2.1.45
Glucosylceramidase EC 3.2.1.45

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

100018

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

Auteurs

Daphne E Boer (DE)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Mina Mirzaian (M)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Maria J Ferraz (MJ)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Kimberley C Zwiers (KC)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Merel V Baks (MV)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Marc D Hazeu (MD)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Roelof Ottenhoff (R)

Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.

André R A Marques (ARA)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Rianne Meijer (R)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Jonathan C P Roos (JCP)

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Timothy M Cox (TM)

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Rolf G Boot (RG)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Navraj Pannu (N)

Department of Biophysical Structural Chemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Herman S Overkleeft (HS)

Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Marta Artola (M)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.

Johannes M Aerts (JM)

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands. Electronic address: j.m.f.g.aerts@lic.leidenuniv.nl.

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › Glucosidases › Glucosylceramidase › Human glucocerebrosidase mediates formation of...