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J. Biol. Chem., Vol. 277, Issue 51, 49341-49351, December 20, 2002

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The Hexapeptide Inhibitor of Gal1,3GalNAc-specific 2,3-Sialyltransferase as a Generic Inhibitor of Sialyltransferases^*

Ki-Young Lee, Hyung Gu Kim^§, Mi Ran Hwang, Jung Il Chae, Jai Myung Yang^§, Young Choon Lee^¶, Young Kug Choo, Young Ik Lee^**, Sang-Soo Lee, and Su-Il Do^§§

From the  Animal Cell and Medical Glycobiology Laboratory and ^** Liver Cell Signal Transduction Laboratory, Korea Research Institute of Bioscience and Biotechnology, P.O. Box 115, Yusung, Taejon 305-333, South Korea, the ^§ Department of Life Science, Sogang University, Seoul 100-601, South Korea, the ^¶ Division of Natural Resources and Life Science, Dong-A University, Busan 604-022, South Korea, the  Division of Biological Science, WonKwang University, Iksan 570-749, South Korea, and the  Department of Biochemistry, Pai Chai University, Taejon 302-735, South Korea

The mammalian Gal1,3GalNAc-specific 2,3-sialyltransferase (ST3Gal I) was expressed as a secreted glycoprotein in High Five^TM (Trichoplusia ni) cells. Using this recombinant ST3Gal I, we screened the synthetic hexapeptide combinatorial library to explore a sialyltransferase inhibitor. We found that the hexapeptide, NH₂-GNWWWW, exhibited the most strong inhibition of ST3Gal I among five different hexapeptides that were finally selected. The kinetic analysis of ST3Gal I inhibition demonstrated that this hexapeptide could act as a competitive inhibitor (K_i = 1.1 µM) on CMP-NeuAc binding to the enzyme. Moreover, the hexapeptide was shown to strongly inhibit both N-glycan-specific 2,3- and 2,6-sialyltranferase in vitro, suggesting that this peptide may inhibit the broad range of sialyltransferases regardless of their linkage specificity. The inhibitory activity in vivo was investigated by RCA-I lectin blot analyses and by metabolic D-[6-³H]GlcNH₂ radiolabeling analyses of N- and O-linked oligosaccharides in Chines hamster ovary cells. Our results demonstrate that the hexapeptide can act as a generic inhibitor of the N- and O-glycan-specific sialyltransferases in mammalian cells, which results in the significantly reduced NeuAc expression on cellular glycoproteins in vivo.

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