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.
Cytidine-5'-monophospho 5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonulopyranosonic acid
Cytidine-5'-monophospho 5-acetamido-3,5-dideoxy-3-fluoro-D-erythro-α-L-manno-2-nonulopyranosonic acid
Cytidine-5'-monophospho 5-acetamido-3,5-dideoxy-3-fluoro-D-erythro-α-L-gluco-2-nonulopyranosonic acid
Fluorescein-5-carbamidoethyl (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonic acid)-(2->3)-(β-D-galactopyranosyl)-(1->4)-2-acetamido-2-deoxy-β-D-glucopyranoside
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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).
Rolling Velocity Measurement of control (DMSO) treated HL-60 cells on E-Selectin at 3 dynes/cm2
Rolling Velocity Measurement of 2F-Fuc (2) treated HL-60 cells on ESelectin at 3 dynes/cm2
Rolling Velocity Measurement of 3Fax-Neu5Ac (8) treated HL-60 cells on E-Selectin at 3 dynes/cm2
Rolling Velocity Measurement of control (DMSO) treated HL-60 cells on P-Selectin at 3 dynes/cm2
Rolling Velocity Measurement of 2F-Fuc (2) treated HL-60 cells on PSelectin at 3 dynes/cm2
Rolling Velocity Measurement of 3Fax-Neu5Ac (8) treated HL-60 cells on P-Selectin at 3 dynes/cm2
Tethering Analysis of Control (DMSO) treated HL-60 cells on E-Selectin
Tethering Analysis of 2F-Fuc (2) treated HL-60 cells on E-Selectin
Tethering Analysis of 3Fax-Neu5Ac (8) treated HL-60 cells on E-Selectin
Tethering Analysis of Control (DMSO) treated HL-60 cells on PSelectin
Tethering Analysis of 2F-Fuc (2) treated HL-60 cells on P-Selectin
Tethering Analysis of 3Fax-Neu5Ac (8) treated HL-60 cells on PSelectin
About this article
Breast Cancer Research (2017)