Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive InhibitorCitation formats

  • External authors:
  • Marissa Maciej
  • Chun Shao
  • Joseph Zaia
  • Catherine Merry

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Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor. / Maciej, Marissa; Dubaissi, Eamon; Shao, Chun; Zaia, Joseph; Amaya, Enrique; Flitsch, Sabine; Merry, Catherine.

In: International Journal of Molecular Sciences, Vol. 22, No. 13, 6988, 01.07.2021.

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Maciej, Marissa ; Dubaissi, Eamon ; Shao, Chun ; Zaia, Joseph ; Amaya, Enrique ; Flitsch, Sabine ; Merry, Catherine. / Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor. In: International Journal of Molecular Sciences. 2021 ; Vol. 22, No. 13.

Bibtex

@article{b32b6abb9c6e4df0a8ddb23fa151c8b4,
title = "Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor",
abstract = "The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds provide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac4GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac4GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole organisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems.",
keywords = "Azido sugar, Biorthogonal chemistry, Carbohydrate biosynthesis, Glycosaminoglycan, Heparan sulfate, Small molecule inhibitor",
author = "Marissa Maciej and Eamon Dubaissi and Chun Shao and Joseph Zaia and Enrique Amaya and Sabine Flitsch and Catherine Merry",
note = "Funding Information: Funding: This work was supported by a BBSRC DTC Studentship Grant No. 978724 and MRC grant (MR/L007525/1). Publisher Copyright: {\textcopyright} by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = jul,
day = "1",
doi = "10.3390/ijms22136988",
language = "English",
volume = "22",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "MDPI",
number = "13",

}

RIS

TY - JOUR

T1 - Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor

AU - Maciej, Marissa

AU - Dubaissi, Eamon

AU - Shao, Chun

AU - Zaia, Joseph

AU - Amaya, Enrique

AU - Flitsch, Sabine

AU - Merry, Catherine

N1 - Funding Information: Funding: This work was supported by a BBSRC DTC Studentship Grant No. 978724 and MRC grant (MR/L007525/1). Publisher Copyright: © by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/7/1

Y1 - 2021/7/1

N2 - The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds provide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac4GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac4GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole organisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems.

AB - The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds provide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac4GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac4GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole organisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems.

KW - Azido sugar

KW - Biorthogonal chemistry

KW - Carbohydrate biosynthesis

KW - Glycosaminoglycan

KW - Heparan sulfate

KW - Small molecule inhibitor

U2 - 10.3390/ijms22136988

DO - 10.3390/ijms22136988

M3 - Article

AN - SCOPUS:85108840919

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 13

M1 - 6988

ER -