Dalal Sagar, Pathak Rachana, Moh Edward X S, Packer Nicolle H
School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, 2109, Australia.
ARC Industrial Transformation Training Centre for Facilitated Advancement of Australia's Bioactives (FAAB), Sydney, NSW, 2109, Australia.
Glycoconj J. 2025 Feb;42(1):53-59. doi: 10.1007/s10719-024-10175-6. Epub 2025 Jan 16.
Chondroitin sulphate (CS) is a sulphated glycosaminoglycan (GAG) polysaccharide found on proteoglycans (CSPGs) in extracellular and pericellular matrices. Chondroitinase ABC (CSase ABC) derived from Proteus vulgaris is an enzyme that has gained attention for the capacity to cleave chondroitin sulphate (CS) glycosaminoglycans (GAG) from various proteoglycans such as Aggrecan, Neurocan, Decorin etc. The substrate specificity of CSase ABC is well-known for targeting various structural motifs of CS chains and has gained popularity in the field of neuro-regeneration by selective degradation of CS GAG chains. Within this context, our investigation into the biochemistry of CSase ABC led us to a previously unreported inhibition of CSase ABC activity by Dextran Sulphate (DexS). To understand the inhibitory effects of DexS, we compared its inhibition of CSase ABC to that of other polysaccharides such as Heparan Sulphate, Heparin, Colominic Acid, Fucoidan, and Dextran. This analysis identified key structural factors such as monosaccharide composition and linkage, sulphation degree and overall charge as influencing CSase ABC inhibition. Remarkably, DexS emerged as a unique inhibitor of CSase ABC, with distinctive inhibitory effects that correlate with its chain length. DexS has been used to reliably induce ulcerative colitis in mice, effectively mimicking inflammatory bowel diseases in humans, and has been previously shown to inhibit both RNA polymerase and reverse transcriptase. Our investigation emphasizes the interplay between the properties of DexS and CSase ABC, providing significant insights into the utilization of polysaccharide-based inhibitors for modulating enzyme activity.
硫酸软骨素（CS）是一种硫酸化糖胺聚糖（GAG）多糖，存在于细胞外和细胞周围基质中的蛋白聚糖（CSPG）上。源自普通变形杆菌的软骨素酶ABC（CSase ABC）是一种酶，因其能够从诸如聚集蛋白聚糖、神经蛋白聚糖、饰胶蛋白聚糖等各种蛋白聚糖中切割硫酸软骨素（CS）糖胺聚糖（GAG）而受到关注。CSase ABC的底物特异性以靶向CS链的各种结构基序而闻名，并通过选择性降解CS GAG链在神经再生领域受到欢迎。在此背景下，我们对CSase ABC生物化学的研究使我们发现了硫酸葡聚糖（DexS）对CSase ABC活性的一种此前未报道的抑制作用。为了了解DexS的抑制作用，我们将其对CSase ABC的抑制作用与其他多糖如硫酸乙酰肝素、肝素、结肠菌素酸、岩藻依聚糖和葡聚糖的抑制作用进行了比较。该分析确定了诸如单糖组成和连接、硫酸化程度和总电荷等关键结构因素对CSase ABC抑制作用的影响。值得注意的是，DexS成为CSase ABC的一种独特抑制剂，其独特的抑制作用与其链长相关。DexS已被用于可靠地诱导小鼠溃疡性结肠炎，有效模拟人类炎症性肠病，并且此前已被证明可抑制RNA聚合酶和逆转录酶。我们的研究强调了DexS和CSase ABC性质之间的相互作用，为利用基于多糖的抑制剂调节酶活性提供了重要见解。
