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A common sugar‐nucleotide‐mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F‐GalNAc (Ac 3 )
Author(s) -
Wijk Xander M.,
Lawrence Roger,
Thijssen Victor L.,
Broek Sebastiaan A.,
Troost Ran,
Scherpenzeel Monique,
Naidu Natasha,
Oosterhof Arie,
Griffioen Arjan W.,
Lefeber Dirk J.,
Delft Floris L.,
Kuppevelt Toin H.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-264226
Subject(s) - nucleotide sugar , biochemistry , glycan , biosynthesis , chemistry , dermatan sulfate , chondroitin , glucosamine , uridine diphosphate , nucleotide , glycosaminoglycan , glycosyltransferase , chondroitin sulfate , glycosidic bond , heparan sulfate , gene , enzyme , glycoprotein
Glycosaminoglycan (GAG) polysaccharides have been implicated in a variety of cellular processes, and alterations in their amount and structure have been associated with diseases such as cancer. In this study, we probed 11 sugar analogs for their capacity to interfere with GAG biosynthesis. One analog, with a modification not directly involved in the glycosidic bond formation, 6F‐ N ‐acetyl‐D‐galactosamine (Ga***lNAc) (Ac 3 ), was selected for further study on its metabolic and biologic effect. Treatment of human ovarian carcinoma cells with 50 μM 6F‐GalNAc (Ac 3 ) inhibited biosynthesis of GAGs (chondroitin/dermatan sulfate by ~50‐60%, heparan sulfate by ~35%), N ‐acetyl‐D‐glucosamine (GlcNAc)/GalNAc containing glycans recognized by the lectins Datura stramonium and peanut agglutinin (by ~74 and ~43%, respectively), and O ‐GlcNAc protein modification. With respect to function, 6F‐GalNAc (Ac 3 ) treatment inhibited growth factor signaling and reduced in vivo angiogenesis by ~33%. Although the analog was readily transformed in cells into the uridine 5'‐diphosphate (UDP)‐activated form, it was not incorporated into GAGs. Rather, it strongly reduced cellular UDP‐GalNAc and UDP‐GlcNAc pools. Together with data from the literature, these findings indicate that nucleotide sugar depletion without incorporation is a common mechanism of sugar analogs for inhibiting GAG/glycan biosynthesis.—Van Wijk, X. M., Lawrence, R., Thijssen, V. L., van den Broek, S. A., Troost, R., van Scherpenzeel, M., Naidu, N., Oosterhof, A., Griffioen, A. W., Lefeber, D. J., van Delft, F. L., van Kuppevelt, T. H. A common sugar‐nucleotide‐mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F‐GalNAc (Ac 3 ). FASEB J . 29, 2993‐3002 (2015). www.fasebj.org