Abstract：
: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.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Rillahan CD,Antonopoulos A,Lefort CT,Sonon R,Azadi P,Ley K,Dell A,Haslam SM,Paulson JCdoi
10.1038/nchembio.999subject
Has Abstractpub_date
2012-07-01 00:00:00pages
661-8issue
7eissn
1552-4450issn
1552-4469pii
nchembio.999journal_volume
8pub_type
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