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Naphthyl Thio- and Carba-xylopyranosides for Exploration of the Active Site of β-1,4-Galactosyltransferase 7 (β4GalT7)

Thorsheim, Karin LU ; Willén, Daniel LU ; Tykesson, Emil LU ; Ståhle, Jonas; Praly, Jean Pierre; Vidal, Sébastien; Johnson, Magnus T. LU ; Widmalm, Göran; Manner, Sophie LU and Ellervik, Ulf LU (2017) In Chemistry - A European Journal 23(71). p.18057-18065
Abstract

Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for β-1,4-galactosyltransferase 7 (β4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for β4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba-β-xylopyranoside in the d-configuration proved to be a good substrate for β4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues.... (More)

Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for β-1,4-galactosyltransferase 7 (β4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for β4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba-β-xylopyranoside in the d-configuration proved to be a good substrate for β4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues. Favorable π–π interactions between the 2-naphthyl moiety and a tyrosine side chain of the enzyme were observed for the thio analogues, which open up for the design of efficient GAG primers and inhibitors.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
carbohydrates, enzymes, structure–activity relationships, xylosides
in
Chemistry - A European Journal
volume
23
issue
71
pages
9 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85035223936
  • wos:000418356700030
ISSN
0947-6539
DOI
10.1002/chem.201704267
language
English
LU publication?
yes
id
50e95737-9077-4511-aedc-78824232ae51
date added to LUP
2018-01-05 08:13:12
date last changed
2018-10-03 10:58:29
@article{50e95737-9077-4511-aedc-78824232ae51,
  abstract     = {<p>Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for β-1,4-galactosyltransferase 7 (β4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for β4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba-β-xylopyranoside in the d-configuration proved to be a good substrate for β4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues. Favorable π–π interactions between the 2-naphthyl moiety and a tyrosine side chain of the enzyme were observed for the thio analogues, which open up for the design of efficient GAG primers and inhibitors.</p>},
  author       = {Thorsheim, Karin and Willén, Daniel and Tykesson, Emil and Ståhle, Jonas and Praly, Jean Pierre and Vidal, Sébastien and Johnson, Magnus T. and Widmalm, Göran and Manner, Sophie and Ellervik, Ulf},
  issn         = {0947-6539},
  keyword      = {carbohydrates,enzymes,structure–activity relationships,xylosides},
  language     = {eng},
  month        = {12},
  number       = {71},
  pages        = {18057--18065},
  publisher    = {John Wiley & Sons},
  series       = {Chemistry - A European Journal},
  title        = {Naphthyl Thio- and Carba-xylopyranosides for Exploration of the Active Site of β-1,4-Galactosyltransferase 7 (β4GalT7)},
  url          = {http://dx.doi.org/10.1002/chem.201704267},
  volume       = {23},
  year         = {2017},
}