Selective inhibition of beta-1,4- and alpha-1,3-galactosyltransferases: donor sugar-nucleotide based approach.
A combined rational and library approach was used to identify bisphosphonates (IC50 = 20 microM) and galactose type 1-N-iminosugar (IC50=45 microM) as novel motifs for selective inhibition of beta-1,4-galactosyltransferase (beta-1,4-GalT) and alpha-1,3-galactosyltransferase (alpha-1,3-GalT), respectively. Our results demonstrate that, though these two galactosyltransferases both utilize the same donor sugar-nucleotide (UDP-Gal), the difference in their mechanisms can be utilized to design donor sugar or nucleotide analogues with inhibitory activities selective for only one of the galactosyltransferases. Investigation of beta-1,4-GalT inhibition using UDP-2-deoxy-2-fluorogalactose (UDP-2-F-Gal), UDP, and bisphosphonates, also led to the observation of metal dependent inhibition of beta-1,4-GalT. These observations and the novel inhibitor motifs identified in this study pave the way for the design and identification of even more potent and selective galactosyltransferase inhibitors.
Takayama
S
S
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Chung
S J
SJ
Igarashi
Y
Y
Ichikawa
Y
Y
Sepp
A
A
Lechler
R I
RI
Wu
J
J
Hayashi
T
T
Siuzdak
G
G
Wong
C H
CH
D000818:Animals; D002417:Cattle; D004164:Diphosphonates / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D014531:Uridine Diphosphate Galactose / Q000378:metabolism
D004164:Diphosphonates; D014531:Uridine Diphosphate Galactose; D005700:Galactosyltransferases