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Inhibition of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase by beta-D-4-O-sulfo-N-acetylgalactosaminides Bearing Various Hydrophobic Aglycons

Inhibition of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase by beta-D-4-O-sulfo-N-acetylgalactosaminides Bearing Various Hydrophobic Aglycons

Hiroko Nozaki, Yuri Tomoyama, Hideyuki Takagi, Koutaro Yokoyama, Chika Yamada, Ken-ichi Kaio, Masaki Tsukimori, Kazuya Nagao, Yuya Itakura, Shiori Ohtake-Niimi, Hirofumi Nakano, Osami Habuchi

Glycoconj J. 2010 Feb;27(2):237-48.

PMID: 20016933

Abstract:

N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) transfers sulfate to position 6 of GalNAc(4SO4) residues of chondroitin sulfate to yield chondroitin sulfate E (CS-E). We have previously demonstrated that phenyl-beta-D-GalNAc(4SO4) could serve as an acceptor for GalNAc4S-6ST, thereby inhibiting GalNAc4S-6ST competitively. In this paper we compared the inhibitory effects of various glycosides in which various hydrophobic aglycons were attached to D-GalNAc(4SO4) via ss anomeric configuration. p-Nitrophenyl-beta-D-GalNAc(4SO4) and p-chlorophenyl-beta-D-GalNAc(4SO4) were stronger inhibitors than phenyl-beta-D-GalNAc(4SO4). Among inhibitors examined here, 3-estradiol-beta-D-GalNAc(4SO4) was the strongest inhibitor; the Ki of 3-estradiol-beta-D-GalNAc(4SO4) for the competitive inhibition was 0.008 mM, which was much lower than the Ki of phenyl-beta-D-GalNAc(4SO4), 0.98 mM. In contrast, 7-estradiol-beta-D-GalNAc(4SO4) showed only weak inhibition to GalNAc4S-6ST. 3-Estradiol-beta-D-GalNAc(4SO4) did not inhibit chondroitin 6-sulfotransferase and chondroitin 4-sulfotransferase under the concentration where GalNAc4S-6ST was inhibited by 90%. When 3-estradiol-beta-D-GalNAc(4SO4) was added to the culture medium of chondrosarcoma cells expressing human GalNAc4S-6ST, a significant, albeit small, reduction in the cellular synthesis of CS-E was observed. These results suggest that estradiol group of 3-estradiol-beta-D-GalNAc(4SO4) may enhance the inhibitory activity of the glycoside through increasing the affinity to the enzyme and may allow the glycosides to diffuse at a low efficiency into the cells to inhibit cellular synthesis of CS-E.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4249530	Beta D-4 human			Price

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