Downstream Products are Potent Inhibitors of the Heparan Sulfate 2-O-Sulfotransferase.
Downstream Products are Potent Inhibitors of the Heparan Sulfate 2-O-Sulfotransferase.
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DOI：
10.1038/s41598-018-29602-4
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发表时间：
2018-08-07
影响因子：
4.6
通讯作者：
Woods RJ
中科院分区：
文献类型：
--
作者：
Thieker DF;Xu Y;Chapla D;Nora C;Qiu H;Felix T;Wang L;Moremen KW;Liu J;Esko JD;Woods RJ
硫酸乙酰肝素（HS）是一种与从癌症到病毒侵入等病理过程相关的细胞信号分子，但其生物合成的基本方面仍未完全了解。本文研究了脲基2- o -硫基转移酶（HS2ST）与变硫化六糖的结合偏好。令人惊讶的是，由后期作用的硫转移酶形成的重硫酸化低聚糖与HS2ST的结合比其天然底物或产物更紧密。抑制试验也表明IC50值与低聚糖硫酸化程度简单相关。结构分析预测了一种抑制模式，其中位于高硫酸低聚糖中氨基葡萄糖残基上的6- o -硫酸盐基团占据了核苷酸辅因子的典型结合位点。与HS生物合成后期相关的低聚糖抑制HS2ST的意外发现表明，在体内生物合成过程中，酶必须在时间和/或空间上与下游产物分离，并突出了体外酶合成长HS链的挑战。
Heparan Sulfate (HS) is a cell signaling molecule linked to pathological processes ranging from cancer to viral entry, yet fundamental aspects of its biosynthesis remain incompletely understood. Here, the binding preferences of the uronyl 2-O-sulfotransferase (HS2ST) are examined with variably-sulfated hexasaccharides. Surprisingly, heavily sulfated oligosaccharides formed by later-acting sulfotransferases bind more tightly to HS2ST than those corresponding to its natural substrate or product. Inhibition assays also indicate that the IC50 values correlate simply with degree of oligosaccharide sulfation. Structural analysis predicts a mode of inhibition in which 6-O-sulfate groups located on glucosamine residues present in highly-sulfated oligosaccharides occupy the canonical binding site of the nucleotide cofactor. The unexpected finding that oligosaccharides associated with later stages in HS biosynthesis inhibit HS2ST indicates that the enzyme must be separated temporally and/or spatially from downstream products during biosynthesis in vivo, and highlights a challenge for the enzymatic synthesis of lengthy HS chains in vitro.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
4.6
作者：
Hsieh PH;Thieker DF;Guerrini M;Woods RJ;Liu J
通讯作者：
Liu J
影响因子：
4.8
作者：
Barth, H;Schäfer, C;Baumert, TF
通讯作者：
Baumert, TF
影响因子：
4.8
作者：
de Graffenried, CL;Bertozzi, CR
通讯作者：
Bertozzi, CR
DOI：
10.1006/bbrc.2000.3453
发表时间：
2000-09-16
影响因子：
3.1
作者：
Hernaiz, M;Liu, J;Linhardt, RJ
通讯作者：
Linhardt, RJ