Opportunities for Therapeutic Modulation of O-GlcNAc DOI

Steven S. Cheng,

Alison Mody,

Christina M. Woo

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(22), P. 12918 - 13019

Published: Nov. 7, 2024

O-Linked β-N-acetylglucosamine (O-GlcNAc) is an essential, dynamic monosaccharide post-translational modification (PTM) found on serine and threonine residues of thousands nucleocytoplasmic proteins. The installation removal O-GlcNAc controlled by a single pair enzymes, transferase (OGT) O-GlcNAcase (OGA), respectively. Since its discovery four decades ago, has been diverse classes proteins, playing important functional roles in many cellular processes. Dysregulation homeostasis implicated the pathogenesis disease, including neurodegeneration, X-linked intellectual disability (XLID), cancer, diabetes, immunological disorders. These foundational studies disease biology have motivated efforts to target therapeutically, with multiple clinical candidates under evaluation. In this review, we describe characterization biochemistry OGT OGA, regulation, development OGA inhibitors, pathophysiology, progress modulators, emerging opportunities for targeting O-GlcNAc. This comprehensive resource should motivate further study into function inspire strategies therapeutic modulation

Language: Английский

Monitoring carbohydrate 3D structure quality with the Privateer database DOI Creative Commons
Jordan S. Dialpuri, Haroldas Bagdonas, Lucy C. Schofield

et al.

Beilstein Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 20, P. 931 - 939

Published: April 24, 2024

The remediation of the carbohydrate data Protein Data Bank (PDB) has brought numerous enhancements to findability and interpretability deposited glycan structures, yet crucial quality indicators are either missing or hard find on PDB pages. Without a way access wider glycochemical context, problematic structures may be taken as fact by keen but inexperienced scientists. Privateer software is validation analysis tool that provides number metrics links external experimental resources, allowing users evaluate using carbohydrate-specific methods. Here, we present database, free resource aims complement growing content PDB.

Language: Английский

Citations

3
Diaminocyclopentane – l-Lysine Adducts: Potent and selective inhibitors of human O-GlcNAcase DOI Creative Commons
Patrick Weber, Pavla Bojarová, Jitka Brouzdová

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 148, P. 107452 - 107452

Published: May 13, 2024

A new class of compounds, namely highly substituted diaminocyclopentane-l-lysine adducts, have been discovered as potent inhibitors O-GlcNAcase, an enzyme crucial for protein de-O-glycosylation. These exhibit exceptional selectivity and reversibility are the first example human O-GlcNAcase that structurally related to transition state rate-limiting step with "aglycon" still in bond-length proximity. The ease their preparation, remarkable biological activities, stability, non-toxicity make them promising candidates development anti-tau-phosphorylation agents holding significant potential treatment Alzheimer's disease.

Language: Английский

Citations

1
The non-catalytic domains of O-GlcNAc cycling enzymes present new opportunities for function-specific control DOI

Chia‐Wei Hu,

Ke Wang,

Jiaoyang Jiang

et al.

Current Opinion in Chemical Biology, Journal Year: 2024, Volume and Issue: 81, P. 102476 - 102476

Published: June 12, 2024

Language: Английский

Citations

1
Mechanism of PARP1 Elongation Reaction Revealed by Molecular Modeling DOI Creative Commons

Sergey V. Pushkarev,

Evgeny Kirilin, Vytas K. Švedas

et al.

Biochemistry (Moscow), Journal Year: 2024, Volume and Issue: 89(7), P. 1202 - 1210

Published: July 1, 2024

Abstract Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, is targeted by number of clinical inhibitors. Despite this, catalytic mechanism PARP1 remains largely underexplored because complex substrate/product structure. Using molecular modeling metadynamics simulations we have described detail elongation poly(ADP-ribose) chain active site. It was shown that reaction proceeds via S N 1-like involving formation intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2′ A -OH group acceptor substrate can be activated general base Glu988 not directly but through proton relay system including adjacent 3′ group.

Language: Английский

Citations

1
Opportunities for Therapeutic Modulation of O-GlcNAc DOI

Steven S. Cheng,

Alison Mody,

Christina M. Woo

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(22), P. 12918 - 13019

Published: Nov. 7, 2024

O-Linked β-N-acetylglucosamine (O-GlcNAc) is an essential, dynamic monosaccharide post-translational modification (PTM) found on serine and threonine residues of thousands nucleocytoplasmic proteins. The installation removal O-GlcNAc controlled by a single pair enzymes, transferase (OGT) O-GlcNAcase (OGA), respectively. Since its discovery four decades ago, has been diverse classes proteins, playing important functional roles in many cellular processes. Dysregulation homeostasis implicated the pathogenesis disease, including neurodegeneration, X-linked intellectual disability (XLID), cancer, diabetes, immunological disorders. These foundational studies disease biology have motivated efforts to target therapeutically, with multiple clinical candidates under evaluation. In this review, we describe characterization biochemistry OGT OGA, regulation, development OGA inhibitors, pathophysiology, progress modulators, emerging opportunities for targeting O-GlcNAc. This comprehensive resource should motivate further study into function inspire strategies therapeutic modulation

Language: Английский

Citations

1