Identification and characterization of flavonoids as sialyltransferase inhibitors.
Sialyltransferases biosynthesize sialyl-glycoconjugates involved in many biological and pathological processes. We investigated and characterized synthetic flavonoid derivatives as sialyltransferase inhibitors. We first examined 54 compounds by solid-phase enzyme assay using beta-galactoside alpha2,6-sialyltransferase 1 (ST6Gal I) and beta-galactoside alpha2,3-sialyltransferase. Several compounds inhibited sialyltransferase enzyme activity regardless of sialyl-linkage reactions. Among them, two compounds showed inhibitory activity against ST6Gal I with IC(50) values less than 10 microM. Three characteristic features of flavonoids were determined by structure-inhibitory activity relationships. First, a double bond between C2-C3 linkages is required for the activity. Second, increasing hydrophilic properties on the B-ring markedly augmented the inhibitory effect. Third, a hydrophobic functional group introduced on the hydroxyl groups of the A-ring enhanced the inhibitory activity. Kinetic analysis using human ST6Gal I indicated a mixed inhibition mechanism of the compounds. In conclusion, the flavonoids identified could be applied for control of cellular expression of sialic acid.
Hidari
Kazuya I P J
KI
Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, Japan and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. hidari@u-shizuoka-ken.ac.jp
Oyama
Kin-ichi
K
Ito
Go
G
Nakayama
Miho
M
Inai
Makoto
M
Goto
Shiho
S
Kanai
Yugo
Y
Watanabe
Kei-ichi
K
Yoshida
Kumi
K
Furuta
Takumi
T
Kan
Toshiyuki
T
Suzuki
Takashi
T
D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012799:Sialyltransferases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D011994:Recombinant Proteins; D012799:Sialyltransferases