Systemic Blockade of Sialylation in Mice with a Global Inhibitor of Sialyltransferases

Macauley, Matthew S.; Arlian, Britni M.; Rillahan, Cory D.; Pang, Poh-Choo; Bortell, Nikki; Marcondes, Maria Cecília Garibaldi; Haslam, Stuart M.; Dell, Anne; Paulson, James C.

doi:10.1074/jbc.m114.606517

Cited by 100 publications

(93 citation statements)

References 46 publications

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“…For example, the heavily sialylated protein podocalyxin on glomerular podocyte foot processes (474)(475)(476)(477)(478) and heparan sulfate glycosaminoglycans within the glomerular basement membrane (479)(480)(481)(482)(483)(484) seem to play important roles in maintaining the integrity of blood plasma filtration by the kidney. Pathological or experimental damage to such glycans causes large molecules like albumin to escape into the urine, and is associated with glomerular diseases (478,(485)(486)(487)(488)(489)(490)(491).…”

Section: Diffusion Barriersmentioning

confidence: 99%

Biological roles of glycans

2016

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Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.

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Section: Diffusion Barriersmentioning

confidence: 99%

Biological roles of glycans

2016

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“…Paulson and co-workers reported peracetylated analogs of sialic acid bearing a fluorine atom proximal to the endocyclic oxygen (P-3F ax -Neu5Ac, 1, Fig. 3) as a cell-permeable specific inhibitor of the sialyltransferases [21,22]. This is an elegant approach by taking advantage of the relaxed substrate specificity of enzymes in the sialic acid salvage pathways and its ability to accommodate unnatural analogs of sialic acid.…”

Section: Sialic Acid Analogsmentioning

confidence: 99%

Sialyltransferase inhibition and recent advances

Wang

Liu

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Sialic acids, existing as terminal sugars of glycoconjugates, play important roles in various physiological and pathological processes, such as cell-cell adhesion, immune defense, tumor cell metastasis, and inflammation. Sialyltransferases (STs) catalyze the transfer of sialic acid residues to non-reducing oligosaccharide chains of proteins and lipids, using cytidine monophosphate N-acetylneuraminic acid (CMP-Neu5Ac) as the donor. Elevated sialyltransferase activity leads to overexpression of cell surface sialic acids and contributes to many disease developments, such as cancer and inflammation. Therefore, sialyltransferases are considered as potential drug targets for disease treatment. Inhibitors of sialyltransferases thus are of medicinal interest, especially for the cancer therapy. In addition, sialyltransferase inhibitors are useful tool to study sialyltransferase function and related mechanisms. This review highlights recent development of inhibitors of sialyltransferases reported since 2004. The inhibitors are summarized as eight groups: 1) sialic acid analogs, 2) CMP-sialic acid analogs, 3) cytidine analogs, 4) oligosaccharide derivatives, 5) aromatic compounds, 6) flavonoids, 7) lithocholic acid analogs, and 8) others. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions.

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“…Recently a study has reported the pharmacologic potential of cell permeable inhibitors of both FucTs and sialyltransferases. These are fluorinated analogs of fucose and sialic acids and have been shown to inhibit fucosylation and sialylation in vitro [168, 169] .…”

Section: Glycans As Therapeutic Targetsmentioning

confidence: 99%

Pathobiological implications of mucin glycans in cancer: Sweet poison and novel targets

Chugh

Gnanapragassam

Jain

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Mucins are large glycoproteins expressed on the epithelia that provide a protective barrier against harsh insults from toxins and pathogenic microbes. These glycoproteins are classified primarily as being secreted and membrane-bound; both forms are involved in pathophysiological functions including inflammation and cancer. The high molecular weight of mucins is attributed to their large polypeptide backbone that is extensively covered by glycan moieties that modulate the function of mucins and, hence, play an important role in physiological functions. Deregulation of glycosylation machinery during malignant transformation results in altered mucin glycosylation. This review describes the functional implications and pathobiological significance of altered mucin glycosylation in cancer. Further, this review delineates various factors such as glycosyltransferases and tumor microenvironment that contribute to dysregulation of mucin glycosylation during cancer. Finally, this review discusses the scope of mucin glycan epitopes as potential diagnostic and therapeutic targets.

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Systemic Blockade of Sialylation in Mice with a Global Inhibitor of Sialyltransferases

Cited by 100 publications

References 46 publications

Biological roles of glycans

Biological roles of glycans

Sialyltransferase inhibition and recent advances

Pathobiological implications of mucin glycans in cancer: Sweet poison and novel targets

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