Inhibition of cell growth and glycosaminoglycan biosynthesis by xylose analog 2-Az-Xyl

Abstract

Sugar analogs are versatile chemical tools for probing or inhibiting glycan functions. However, chemical tools are insufficient for glycosaminoglycans (GAGs), which play crucial roles in various biological processes, such as extracellular matrix formation and growth factor signaling. To develop a new compound for detecting GAGs or manipulating GAG functions, we chemically synthesized 2-azide-xylose (2-Az-Xyl), an azide-type analog of Xyl that is a component of the common linkage tetrasaccharide in GAGs, and explored its application to biological experiments. Treatment of cultured cells with 2-Az-Xyl inhibited cell proliferation and reduced the levels of GAGs, particularly heparan sulfate (HS). Although this sugar analog did not perturb the biosynthesis of nucleotide sugars and expression of the key enzymes for HS biosynthesis, 2-Az-Xyl directly inhibited the activity of XYLT2, an initial enzyme for GAG biosynthesis, indicating that 2-Az-Xyl directly inhibits GAG biosynthesis. These findings suggest that 2-Az-Xyl inhibits cell proliferation by blocking GAG biosynthesis through inhibiting XYLT2 activity.

Keywords: Glycosaminoglycan; Glycosylation; Heparan sulfate; Sugar analog; XYLT2; Xylose.