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J Biol Chem. 2014 Dec 19;289(51):35149-58. doi: 10.1074/jbc.M114.606517. Epub 2014 Nov 3.

Systemic blockade of sialylation in mice with a global inhibitor of sialyltransferases.

Author information

1
From the Departments of Cell and Molecular Biology, Chemical Physiology, and Immunology and Microbial Science and.
2
From the Departments of Cell and Molecular Biology, Chemical Physiology, and Immunology and Microbial Science and the Division of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, and.
3
the Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
4
the Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La, Jolla, California 92037.
5
From the Departments of Cell and Molecular Biology, Chemical Physiology, and Immunology and Microbial Science and jpaulson@scripps.edu.

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.

KEYWORDS:

Glycosylation Inhibitor; Glycosyltransferase; Kidney; Podocyte; Sialic Acid; Sialyltransferase

PMID:
25368325
PMCID:
PMC4271204
DOI:
10.1074/jbc.M114.606517
[Indexed for MEDLINE]
Free PMC Article

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