<br>Siastatin B 抑制乙酰肝素酶和 β-葡萄糖醛酸酶的分子基础,Journal of the American Chemical Society

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Siastatin B 抑制乙酰肝素酶和 β-葡萄糖醛酸酶的分子基础
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-12-20 , DOI: 10.1021/jacs.3c04162
Yurong Chen ₁ , Adrianus M C H van den Nieuwendijk ₁ , Liang Wu ₂ , Elisha Moran ₂ , Foteini Skoulikopoulou ₁ , Vera van Riet ₁ , Hermen S Overkleeft ₁ , Gideon J Davies ₂ , Zachary Armstrong _{1,

2}

Affiliation

Siastatin B 是三种不同糖苷酶类别的强效且有效的亚氨基糖抑制剂，即唾液酸酶、β- d-葡萄糖醛酸酶和N-乙酰氨基葡萄糖苷酶。与唾液酸酶相比，葡萄糖醛酸酶的抑制模式长期以来一直是个谜，因为西阿他汀 B 看起来太大并且被错误地取代而无法容纳在 β- d-葡萄糖醛酸酶活性位点袋中。在此，我们通过蛋白质-抑制剂复合物的晶体分析表明，西阿他丁 B 产生半胺醛和 3-孪二醇亚氨基糖 (3-GDI)，它们而不是母体化合物直接负责酶抑制。半胺产品是首次观察到属于新霉素类抑制剂的天然产品。此外，3-GDI 代表了一类新型、有效的亚氨基糖苷酶抑制剂。为了证实我们的发现，我们合成了葡萄糖和半乳糖配置的 3-GDI，并在结构和动力学上表征了它们与外切-β- d-葡萄糖醛酸酶和抗癌靶标人乙酰肝素酶的结合。这揭示了外切-β- d-葡萄糖醛酸酶的亚微摩尔抑制作用以及此类新型抑制剂前所未有的结合模式。我们的研究结果揭示了 siastatin B 作为广谱糖苷酶抑制剂的作用机制，鉴定了一类新型糖苷酶抑制剂，并提出了可纳入未来几代糖苷酶抑制剂的新功能。

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Molecular Basis for Inhibition of Heparanases and β-Glucuronidases by Siastatin B

Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, β-d-glucuronidases, and N-acetyl-glucosaminidases. The mode of inhibition of glucuronidases, in contrast to sialidases, has long been enigmatic as siastatin B appears too bulky and incorrectly substituted to be accommodated within a β-d-glucuronidase active site pocket. Herein, we show through crystallographic analysis of protein-inhibitor complexes that siastatin B generates both a hemiaminal and a 3-geminal diol iminosugar (3-GDI) that are, rather than the parent compound, directly responsible for enzyme inhibition. The hemiaminal product is the first observation of a natural product that belongs to the noeuromycin class of inhibitors. Additionally, the 3-GDI represents a new and potent class of the iminosugar glycosidase inhibitor. To substantiate our findings, we synthesized both the gluco- and galacto-configured 3-GDIs and characterized their binding both structurally and kinetically to exo-β-d-glucuronidases and the anticancer target human heparanase. This revealed submicromolar inhibition of exo-β-d-glucuronidases and an unprecedented binding mode by this new class of inhibitor. Our results reveal the mechanism by which siastatin B acts as a broad-spectrum glycosidase inhibitor, identify a new class of glycosidase inhibitor, and suggest new functionalities that can be incorporated into future generations of glycosidase inhibitors.

更新日期：2023-12-20

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