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Rules for priming and inhibition of glycosaminoglycan biosynthesis; probing the beta 4GalT7 active site

Siegbahn, Anna LU ; Manner, Sophie LU ; Persson, Andrea LU ; Tykesson, Emil LU ; Thorsheim, Karin LU ; Ochocinska, Agata LU ; Ronnols, Jerk; Sundin, Anders LU ; Mani, Katrin LU and Westergren-Thorsson, Gunilla LU , et al. (2014) In Chemical Science 5(9). p.3501-3508
Abstract
beta-1,4-Gatactosyltransferase 7 (beta 4GalT7) is an essential enzyme in the biosynthesis of glycosaminoglycan (GAG) chains of proteoglycans (PGs). Mammalian cells produce PGs, which are involved in biological processes such as cell growth and differentiation. The PGs consist of a core protein, with one or several GAG chains attached. Both the structure of the PGs and the GAG chains, and the expression of the enzymes involved in their biosynthesis and degradation, vary between normal cells and tumor cells. The biosynthesis of GAG chains is initiated by xylosylation of a serine residue of the core protein, followed by galactosylation by beta 4GalT7. The biosynthesis can also be initiated by exogenously added beta-D-xylopyranosides with... (More)
beta-1,4-Gatactosyltransferase 7 (beta 4GalT7) is an essential enzyme in the biosynthesis of glycosaminoglycan (GAG) chains of proteoglycans (PGs). Mammalian cells produce PGs, which are involved in biological processes such as cell growth and differentiation. The PGs consist of a core protein, with one or several GAG chains attached. Both the structure of the PGs and the GAG chains, and the expression of the enzymes involved in their biosynthesis and degradation, vary between normal cells and tumor cells. The biosynthesis of GAG chains is initiated by xylosylation of a serine residue of the core protein, followed by galactosylation by beta 4GalT7. The biosynthesis can also be initiated by exogenously added beta-D-xylopyranosides with hydrophobic aglycons, which thus can act as acceptor substrates for beta 4GalT7. To determine the structural requirements for beta 4GalT7 activity, we have cloned and expressed the enzyme and designed a focused library of 2-naphthyl beta-D-xylopyranosides with modifications of the xylose moiety. Based on enzymatic studies, that is galactosylation and its inhibition, conformational analysis and molecular modeling using the crystal structure, we propose that the binding pocket of beta 4GalT7 is very narrow, with a precise set of important hydrogen bonds. Xylose appears to be the optimal acceptor substrate for galactosylation by beta 4GalT7. However, we show that modifications of the xylose moiety of the beta-D-xylopyranosides can render inhibitors of galactosylation. Such compounds will be valuable tools for the exploration of GAG and PG biosynthesis and a starting point for development of anti-tumor agents. (Less)
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publication status
published
subject
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Chemical Science
volume
5
issue
9
pages
3501 - 3508
publisher
Royal Society of Chemistry
external identifiers
  • wos:000340695800020
  • scopus:84905195074
ISSN
2041-6539
DOI
10.1039/c4sc01244e
language
English
LU publication?
yes
id
e988c58e-a42f-40ca-b3b1-a1f3f7430eab (old id 4648888)
date added to LUP
2014-10-01 07:27:20
date last changed
2017-09-24 03:25:02
@article{e988c58e-a42f-40ca-b3b1-a1f3f7430eab,
  abstract     = {beta-1,4-Gatactosyltransferase 7 (beta 4GalT7) is an essential enzyme in the biosynthesis of glycosaminoglycan (GAG) chains of proteoglycans (PGs). Mammalian cells produce PGs, which are involved in biological processes such as cell growth and differentiation. The PGs consist of a core protein, with one or several GAG chains attached. Both the structure of the PGs and the GAG chains, and the expression of the enzymes involved in their biosynthesis and degradation, vary between normal cells and tumor cells. The biosynthesis of GAG chains is initiated by xylosylation of a serine residue of the core protein, followed by galactosylation by beta 4GalT7. The biosynthesis can also be initiated by exogenously added beta-D-xylopyranosides with hydrophobic aglycons, which thus can act as acceptor substrates for beta 4GalT7. To determine the structural requirements for beta 4GalT7 activity, we have cloned and expressed the enzyme and designed a focused library of 2-naphthyl beta-D-xylopyranosides with modifications of the xylose moiety. Based on enzymatic studies, that is galactosylation and its inhibition, conformational analysis and molecular modeling using the crystal structure, we propose that the binding pocket of beta 4GalT7 is very narrow, with a precise set of important hydrogen bonds. Xylose appears to be the optimal acceptor substrate for galactosylation by beta 4GalT7. However, we show that modifications of the xylose moiety of the beta-D-xylopyranosides can render inhibitors of galactosylation. Such compounds will be valuable tools for the exploration of GAG and PG biosynthesis and a starting point for development of anti-tumor agents.},
  author       = {Siegbahn, Anna and Manner, Sophie and Persson, Andrea and Tykesson, Emil and Thorsheim, Karin and Ochocinska, Agata and Ronnols, Jerk and Sundin, Anders and Mani, Katrin and Westergren-Thorsson, Gunilla and Widmalm, Goran and Ellervik, Ulf},
  issn         = {2041-6539},
  language     = {eng},
  number       = {9},
  pages        = {3501--3508},
  publisher    = {Royal Society of Chemistry},
  series       = {Chemical Science},
  title        = {Rules for priming and inhibition of glycosaminoglycan biosynthesis; probing the beta 4GalT7 active site},
  url          = {http://dx.doi.org/10.1039/c4sc01244e},
  volume       = {5},
  year         = {2014},
}