碳酸酐酶IX的结构适用于低pH催化。
The Structure of Carbonic Anhydrase IX Is Adapted for Low-pH Catalysis.
作者信息
Mahon Brian P, Bhatt Avni, Socorro Lilien, Driscoll Jenna M, Okoh Cynthia, Lomelino Carrie L, Mboge Mam Y, Kurian Justin J, Tu Chingkuang, Agbandje-McKenna Mavis, Frost Susan C, McKenna Robert
机构信息
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine , Gainesville, Florida 32610, United States.
出版信息
Biochemistry. 2016 Aug 23;55(33):4642-53. doi: 10.1021/acs.biochem.6b00243. Epub 2016 Aug 5.
Abstract
Human carbonic anhydrase IX (hCA IX) expression in many cancers is associated with hypoxic tumors and poor patient outcome. Inhibitors of hCA IX have been used as anticancer agents with some entering Phase I clinical trials. hCA IX is transmembrane protein whose catalytic domain faces the extracellular tumor milieu, which is typically associated with an acidic microenvironment. Here, we show that the catalytic domain of hCA IX (hCA IX-c) exhibits the necessary biochemical and biophysical properties that allow for low pH stability and activity. Furthermore, the unfolding process of hCA IX-c appears to be reversible, and its catalytic efficiency is thought to be correlated directly with its stability between pH 3.0 and 8.0 but not above pH 8.0. To rationalize this, we determined the X-ray crystal structure of hCA IX-c to 1.6 Å resolution. Insights from this study suggest an understanding of hCA IX-c stability and activity in low-pH tumor microenvironments and may be applicable to determining pH-related effects on enzymes.
摘要
人类碳酸酐酶IX（hCA IX）在许多癌症中的表达与低氧肿瘤及患者的不良预后相关。hCA IX抑制剂已被用作抗癌药物，其中一些已进入I期临床试验。hCA IX是一种跨膜蛋白，其催化结构域面向细胞外肿瘤环境，该环境通常与酸性微环境相关。在此，我们表明hCA IX的催化结构域（hCA IX-c）具有实现低pH稳定性和活性所需的生化和生物物理特性。此外，hCA IX-c的去折叠过程似乎是可逆的，并且其催化效率被认为与pH 3.0至8.0之间的稳定性直接相关，但在pH 8.0以上则不然。为了阐明这一点，我们确定了hCA IX-c的X射线晶体结构，分辨率达到1.6 Å。这项研究的见解有助于理解hCA IX-c在低pH肿瘤微环境中的稳定性和活性，并且可能适用于确定pH对酶的相关影响。
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