TY - JOUR
T1 - Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome
AU - Rillahan, Cory D.
AU - Antonopoulos, Aristotelis
AU - Lefort, Craig T.
AU - Sonon, Roberto
AU - Azadi, Parastoo
AU - Ley, Klaus
AU - Dell, Anne
AU - Haslam, Stuart M.
AU - Paulson, James C.
N1 - Funding Information:
This work was supported by US National Institutes of Health grants to J.C.P. (R01AI050143 and P01HL107151), C.D.R. (T32AI007606), K.L. (R01HL111969), C.T.L. (T32AI060536) and the Complex Carbohydrate Research Center (1 P41 RR018502-01) as well as by funding from the Biotechnology and Biological Sciences Research Council to A.D. and S.M.H. (BBF0083091).
PY - 2012/7
Y1 - 2012/7
N2 - Despite the fundamental roles of sialyl- and fucosyltransferases in mammalian physiology, there are few pharmacological tools to manipulate their function in a cellular setting. Although fluorinated analogs of the donor substrates are well-established transition state inhibitors of these enzymes, they are not membrane permeable. By exploiting promiscuous monosaccharide salvage pathways, we show that fluorinated analogs of sialic acid and fucose can be taken up and metabolized to the desired donor substrate-based inhibitors inside the cell. Because of the existence of metabolic feedback loops, they also act to prevent the de novo synthesis of the natural substrates, resulting in a global, family-wide shutdown of sialyl- and/or fucosyltransferases and remodeling of cell-surface glycans. As an example of the functional consequences, the inhibitors substantially reduce expression of the sialylated and fucosylated ligand sialyl Lewis X on myeloid cells, resulting in loss of selectin binding and impaired leukocyte rolling.
AB - Despite the fundamental roles of sialyl- and fucosyltransferases in mammalian physiology, there are few pharmacological tools to manipulate their function in a cellular setting. Although fluorinated analogs of the donor substrates are well-established transition state inhibitors of these enzymes, they are not membrane permeable. By exploiting promiscuous monosaccharide salvage pathways, we show that fluorinated analogs of sialic acid and fucose can be taken up and metabolized to the desired donor substrate-based inhibitors inside the cell. Because of the existence of metabolic feedback loops, they also act to prevent the de novo synthesis of the natural substrates, resulting in a global, family-wide shutdown of sialyl- and/or fucosyltransferases and remodeling of cell-surface glycans. As an example of the functional consequences, the inhibitors substantially reduce expression of the sialylated and fucosylated ligand sialyl Lewis X on myeloid cells, resulting in loss of selectin binding and impaired leukocyte rolling.
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U2 - 10.1038/nchembio.999
DO - 10.1038/nchembio.999
M3 - Article
AN - SCOPUS:84862906051
SN - 1552-4450
VL - 8
SP - 661
EP - 668
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 7
ER -