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@article{Macauley:2014:10.1074/jbc.M114.606517,
author = {Macauley, MS and Arlian, BM and Rillahan, CD and Pang, P and Bortell, N and Marcondes, MCG and Haslam, SM and Dell, A and Paulson, JC},
doi = {10.1074/jbc.M114.606517},
journal = {Journal of Biological Chemistry},
pages = {35149--35158},
title = {Systemic blockade of sialylation in mice with a global inhibitor of sialyltransferases},
url = {http://dx.doi.org/10.1074/jbc.M114.606517},
volume = {289},
year = {2014}
}

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TY  - JOUR
AB  - Sialic acid terminates glycans of glycoproteins and glycolipids that play numerous biological roles in health and disease. While 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, 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. While 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.
AU  - Macauley,MS
AU  - Arlian,BM
AU  - Rillahan,CD
AU  - Pang,P
AU  - Bortell,N
AU  - Marcondes,MCG
AU  - Haslam,SM
AU  - Dell,A
AU  - Paulson,JC
DO  - 10.1074/jbc.M114.606517
EP  - 35158
PY  - 2014///
SN  - 0021-9258
SP  - 35149
TI  - Systemic blockade of sialylation in mice with a global inhibitor of sialyltransferases
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1074/jbc.M114.606517
UR  - http://www.jbc.org/content/early/2014/11/03/jbc.M114.606517.abstract
UR  - https://www.sciencedirect.com/science/article/pii/S0021925819560537?via%3Dihub
VL  - 289
ER  -

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Dr Poh-Choo Pang

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