Cited by 129Glycosylation and Glycoproteins ResearchCarbohydrate Chemistry and SynthesisProteoglycans and glycosaminoglycans research

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

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Macauley, Matthew S., Arlian, Britni M., Rillahan, Cory D., Pang, Poh-Choo, Bortell, Nikki, Marcondes, Maria Cecilia G., Haslam, Stuart M., Dell, Anne +1 more·2014·Journal of Biological Chemistry

Abstract

Sialic acid terminates glycans of glycoproteins and glycolipids that play numerous biological roles in health and disease. Although genetic tools are available for interrogating the effects of decreased or abolished sialoside expression in mice, pharmacological inhibition of the sialyltransferase family has, to date, not been possible. We have recently shown that a sialic acid analog, 2,4,7,8,9-pentaacetyl-3Fax-Neu5Ac-CO2Me (3F-NeuAc), added to the media of cultured cells shuts down sialylation by a mechanism involving its intracellular conversion to CMP-3F-NeuAc, a competitive inhibitor of all sialyltransferases. Here we show that administering 3F-NeuAc to mice dramatically decreases sialylated glycans in cells of all tissues tested, including blood, spleen, liver, brain, lung, heart, kidney, and testes. A single dose results in greatly decreased sialoside expression for over 7 weeks in some tissues. Although blockade of sialylation with 3F-NeuAc does not affect viability of cultured cells, its use in vivo has a deleterious "on target" effect on liver and kidney function. After administration of 3F-NeuAc, liver enzymes in the blood are dramatically altered, and mice develop proteinuria concomitant with dramatic loss of sialic acid in the glomeruli within 4 days, leading to irreversible kidney dysfunction and failure to thrive. These results confirm a critical role for sialosides in liver and kidney function and document the feasibility of pharmacological inhibition of sialyltransferases for in vivo modulation of sialoside expression.

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Crossref · 10.1074/jbc.m114.606517

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Authors
Macauley, M. S., Arlian, B. M., Rillahan, C. D., Pang, P.-C., Bortell, N., Marcondes, M. C. G., Haslam, S. M., Dell, A., & Paulson, J. C.
Affiliations
  • Scripps Research Institute (US)
  • Imperial College London (GB)
Corresponding author
Paulson, James C.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2014-12
Volume
289
Issue
51
Pages
35149-35158
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2126381976
Cited by
129
References
47
Citations by year
2026: 11 · 2025: 15 · 2024: 16 · 2023: 10 · 2022: 12 · 2021: 14 · 2020: 10 · 2019: 8 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 9 · 2013: 1
FWCI
3.42
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (HL107151)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
sialylation, sialic acid, sialyltransferase, sialic acid analogues, competitive inhibition, sialosides, liver function, renal dysfunction, proteinuria, pharmacological inhibition
MeSH terms
Animals, Brain, Dose-Response Relationship, Drug, Enzyme Inhibitors, Flow Cytometry, Glycolipids, Glycoproteins, Kidney, Leukocytes, Liver, Lung, Male, Mice, Inbred C57BL, Myocardium, Polysaccharides, Sialic Acids, Sialyltransferases, Mass Spectrometry, Spleen, Time Factors, Blotting, Western, N-Acetylneuraminic Acid

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