Hidari Kazuya I P J, Oyama Kin-ichi, Ito Go, Nakayama Miho, Inai Makoto, Goto Shiho, Kanai Yugo, Watanabe Kei-ichi, Yoshida Kumi, Furuta Takumi, Kan Toshiyuki, Suzuki Takashi
Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, Japan and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Biochem Biophys Res Commun. 2009 May 8;382(3):609-13. doi: 10.1016/j.bbrc.2009.03.082. Epub 2009 Mar 19.
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.
唾液酸转移酶参与生物合成多种生物和病理过程中涉及的唾液酸化糖缀合物。我们对合成类黄酮衍生物作为唾液酸转移酶抑制剂进行了研究和表征。我们首先使用β-半乳糖苷α2,6-唾液酸转移酶1（ST6Gal I）和β-半乳糖苷α2,3-唾液酸转移酶通过固相酶法检测了54种化合物。无论唾液酸连接反应如何，几种化合物均能抑制唾液酸转移酶的酶活性。其中，两种化合物对ST6Gal I表现出抑制活性，其IC50值小于10微摩尔。通过结构-抑制活性关系确定了类黄酮的三个特征。首先，C2-C3键之间的双键是活性所必需的。其次，B环上亲水性的增加显著增强了抑制作用。第三，在A环羟基上引入疏水官能团增强了抑制活性。使用人ST6Gal I进行的动力学分析表明这些化合物具有混合抑制机制。总之，所鉴定的类黄酮可用于控制唾液酸的细胞表达。
