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首页> 外文期刊>Journal of Molecular Biology >Structural basis for featuring of steroid isomerase activity in alpha class glutathione transferases.
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Structural basis for featuring of steroid isomerase activity in alpha class glutathione transferases.

机译：α类谷胱甘肽转移酶中类固醇异构酶活性特征的结构基础。

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摘要

Glutathione transferases (GSTs) are abundant enzymes catalyzing the conjugation of hydrophobic toxic substrates with glutathione. In addition to detoxication, human GST A3-3 displays prominent steroid double-bond isomerase activity; e.g. transforming Delta(5)-androstene-3-17-dione into Delta(4)-androstene-3-17-dione (AD). This chemical transformation is a crucial step in the biosynthesis of steroids, such as testosterone and progesterone. In contrast to GST A3-3, the homologous GST A2-2 does not show significant steroid isomerase activity. We have solved the 3D structures of human GSTs A2-2 and A3-3 in complex with AD. In the GST A3-3 crystal structure, AD was bound in an orientation suitable for the glutathione (GSH)-mediated catalysis to occur. In GST A2-2, however, AD was bound in a completely different orientation with its reactive double bond distant from the GSH-binding site. The structures illustrate how a few amino acid substitutions in the active site spectacularly alter the binding mode of the steroid substrate in relation to the conserved catalytic groups and an essentially fixed polypeptide chain conformation. Furthermore, AD did not bind to the GST A2-2-GSH complex. Altogether, these results provide a first-time structural insight into the steroid isomerase activity of any GST and explain the 5000-fold difference in catalytic efficiency between GSTs A2-2 and A3-3. More generally, the structures illustrate how dramatic diversification of functional properties can arise via minimal structural alterations. We suggest a novel structure-based mechanism of the steroid isomerization reaction.
机译：谷胱甘肽转移酶（GSTs）是丰富的酶，可催化疏水性有毒底物与谷胱甘肽结合。除解毒外，人GST A3-3还显示出显着的类固醇双键异构酶活性。例如将Delta（5）-雄烯-3-17-二酮转化为Delta（4）-雄烯-3-17-二酮（AD）。这种化学转化是类固醇（例如睾丸激素和孕激素）生物合成的关键步骤。与GST A3-3相反，同源的GST A2-2没有显示出明显的类固醇异构酶活性。我们已经解决了与AD复合的人类GST A2-2和A3-3的3D结构。在GST A3-3晶体结构中，AD以适合于谷胱甘肽（GSH）介导的催化发生的方向结合。然而，在GST A2-2中，AD的反应性双键与GSH结合位点相距很远，其结合方向完全不同。该结构说明了活性位点的一些氨基酸取代如何相对于保守的催化基团和基本上固定的多肽链构象显着地改变甾族底物的结合模式。此外，AD不结合GST A2-2-GSH复合物。总之，这些结果首次揭示了任何GST的类固醇异构酶活性，并解释了GST A2-2和A3-3催化效率的5000倍差异。更一般而言，结构说明了如何通过最小的结构更改来实现功能特性的戏剧性多样化。我们建议类固醇异构化反应的一种新型的基于结构的机制。

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