The Diverse Contributions of Fucose Linkages in Cancer

Keeley, Tyler; Yang, Shung‐Haur; Lau, Eric

doi:10.3390/cancers11091241

Cited by 91 publications

(86 citation statements)

References 204 publications

(277 reference statements)

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“…Thus, different strategies for reducing core-fucosylation in therapeutic monoclonal antibodies have been developed to enhance ADCC 8 . Notably, FUT8 is upregulated in numerous types of cancer, suggesting that blocking its activity could be a promising strategy for improving antitumor immune responses 9 .…”

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confidence: 99%

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

et al. 2020

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Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the only enzyme responsible for this modification via the addition of an α-1,6-linked fucose to N-glycans. To date, the details of substrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystal structure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), which provides insight into both substrate recognition and catalysis. FUT8 follows an S N 2 mechanism and deploys a series of loops and an α-helix which all contribute in forming the binding site. An exosite, formed by one of these loops and an SH3 domain, is responsible for the recognition of branched sugars, making contacts specifically to the α1,3 arm GlcNAc, a feature required for catalysis. This information serves as a framework for inhibitor design, and helps to assess its potential as a therapeutic target.

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confidence: 99%

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

et al. 2020

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“…Fucosylation is a post-translational modification, involving the addition of fucose from GDP-fucose to glycoconjugates, in reactions catalyzed by Fut. To date, 13 Futs have been identified in the human genome [14,23,47,52]. Fut8 is the only Fut responsible for the important modification of N-glycans, involving α1, 6 fucosylation of the GlcNAc residue linked to the asparagine of glycoconjugates (core fucosylation) [32,53].…”

Section: How Conformational Changes Of Glycans Influence Sparccollagementioning

confidence: 99%

Dissecting the conformation of glycans and their interactions with proteins

Wang

Lee

et al. 2020

J Biomed Sci

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The use of in silico strategies to develop the structural basis for a rational optimization of glycan-protein interactions remains a great challenge. This problem derives, in part, from the lack of technologies to quantitatively and qualitatively assess the complex assembling between a glycan and the targeted protein molecule. Since there is an unmet need for developing new sugar-targeted therapeutics, many investigators are searching for technology platforms to elucidate various types of molecular interactions within glycan-protein complexes and aid in the development of glycan-targeted therapies. Here we discuss three important technology platforms commonly used in the assessment of the complex assembly of glycosylated biomolecules, such as glycoproteins or glycosphingolipids: Biacore analysis, molecular docking, and molecular dynamics simulations. We will also discuss the structural investigation of glycosylated biomolecules, including conformational changes of glycans and their impact on molecular interactions within the glycan-protein complex. For glycoproteins, secreted protein acidic and rich in cysteine (SPARC), which is associated with various lung disorders, such as chronic obstructive pulmonary disease (COPD) and lung cancer, will be taken as an example showing that the core fucosylation of N-glycan in SPARC regulates protein-binding affinity with extracellular matrix collagen. For glycosphingolipids (GSLs), Globo H ceramide, an important tumor-associated GSL which is being actively investigated as a target for new cancer immunotherapies, will be used to demonstrate how glycan structure plays a significant role in enhancing angiogenesis in tumor microenvironments.

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“…Specifically, fucosylation of cell membrane receptors and proteins such as EGFR, TGFb, E-cadherin, and integrins influences ligand binding, receptor dimerization, and signaling capacities (35)(36)(37)(38). Core fucosylation is frequently increased in tumor tissue and inhibiting the addition of a core fucose moiety to glycans reduces cancer progression (39). Despite these findings, we observed a decrease in both the core fucosylated (1485, 1647, and 1809 m/z) (Figure 2A-C This class is characterized by the addition of a b1,4-linked GlcNAc to the b-mannose residue of the glycan core, which inhibits further processing and elongation by glycosyltransferases (26,40,41).…”

Section: Core Fucosylated Bisecting and Sialylated N-glycans Are Prmentioning

confidence: 99%

Mass Spectrometry Imaging of N-Glycans Reveals Racial Discrepancies in Low Grade Prostate Tumors

Conroy

Young

Stanback

et al. 2020

Preprint

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Prostate cancer is the most common cancer in men worldwide. Despite its prevalence, there is a critical knowledge gap regarding the underlining molecular events that result in higher incidence and mortality rate in Black men. Identifying molecular features that separate racial disparities is a critical step in prostate cancer research that could lead to predictive biomarkers and personalized therapy. N-linked glycosylation is a co-translational event during protein folding that modulates a myriad of cellular processes. Recently, aberrant N-linked glycosylation has been reported in prostate cancers. However, the full clinical implications of dysregulated glycosylation in prostate cancer has yet to be explored. Herein, we performed high-throughput matrix-assisted laser desorption ionization mass spectrometry analysis to characterize the N-glycan profile from tissue microarrays of over 100 patient tumors with over 10 years of follow up data. We identified several species of N-glycans that were profoundly different between low grade prostate tumors resected from White and Black patients. Further, these glycans predict opposing overall survival between White and Black patients with prostate cancer. These data suggest differential N-linked glycosylation underline the racial disparity of prostate cancer prognosis. Our study highlights the potential applications of MALDI-MSI for digital pathology and biomarker to study racial disparity of prostate cancer patients.

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The Diverse Contributions of Fucose Linkages in Cancer

Cited by 91 publications

References 204 publications

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

Dissecting the conformation of glycans and their interactions with proteins

Mass Spectrometry Imaging of N-Glycans Reveals Racial Discrepancies in Low Grade Prostate Tumors

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