PXD029623

PXD029623 is an original dataset announced via ProteomeXchange.

Title	Identification of global inhibitors of cellular glycosylation
Description	Small molecule inhibitors of glycosylation enzymes can be valuable tools for dissecting glycan functions and present great potential as drug discovery candidates. Most screening campaigns for inhibitors of glycosyltransferases have been limited to in vitro enzyme assays using recombinant enzymes, which often have led to promising candidates that have been difficult to study further in cells and animals due to issues with permeability and toxicity. Here, we aimed to circumvent these issues by employing a cell-based screening assay using glycoengineered cells expressing tailored reporter glycoproteins, which allowed us to narrow in on specific steps in individual glycosylation pathways. We focused on GalNAc-type O-glycosylation, and initially selected the GalNAc-T11 isoenzyme that selectively initiates O-glycosylation of the endocytic low density lipoprotein receptor (LDLR)-related proteins as target. In our screen with a limited small molecule compound library, we did not identify selective inhibitors of GalNAc-T11 or the family of GalNAc-T isoenzymes, however we identified two potent compounds that broadly inhibited glycosylation processes in a reversible manner. We demonstrate that these compounds inhibit all Golgi-localized glycosylation and suggest that this is mediated by reversible fragmentation of the Golgi system, presumably via interactions with HSP90. Finally, we demonstrate how these compounds can be used in cell model studies to dissect roles of different types of glycosylation by showing the importance of Tn-expression for binding of cancer-specific antibodies and by validating further the importance of cellular heparan sulfate in the binding and infection of SARS-CoV-2
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:37:01.896.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sergey Vakhrushev
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-09 02:46:14	ID requested
1	2023-03-10 20:23:11	announced
⏵ 2	2023-11-14 08:37:02	announced	2023-11-14: Updated project metadata.

S, ø, rensen DM, B, ü, ll C, Madsen TD, Lira-Navarrete E, Clausen TM, Clark AE, Garretson AF, Karlsson R, Pijnenborg JFA, Yin X, Miller RL, Chanda SK, Boltje TJ, Schjoldager KT, Vakhrushev SY, Halim A, Esko JD, Carlin AF, Hurtado-Guerrero R, Weigert R, Clausen H, Narimatsu Y, Identification of global inhibitors of cellular glycosylation. Nat Commun, 14(1):948(2023) [pubmed]

submitter keyword: cell-based glycan array, O-glycosylation, SARS-CoV-2, compound library screen,Glycosylation inhibitor, 53 Golgi fragmentation, glycosyltransferases

Sergey Vakhrushev
contact affiliation	University of Copenhagen, Copenhagen Center for Glycomics, GlycoMS group
contact email	seva@sund.ku.dk
lab head
Sergey Vakhrushev
contact affiliation	Department of Cellular and Molecular Medicine
contact email	seva@sund.ku.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029623
     1. Label: PRIDE project
     2. Name: Identification of global inhibitors of cellular glycosylation