Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA.
Bioorg Med Chem Lett. 2024 May 15;104:129740. doi: 10.1016/j.bmcl.2024.129740. Epub 2024 Apr 9.
Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid. Here we provide a detailed biochemical characterization of the adduct formed between LAR phosphatase and illudalic acid. A mass spectrometric analysis indicates that two cysteine residues are covalently labeled by illudalic acid and a related analog. Mutational analysis supports the hypothesis that inhibition of LAR phosphatase activity is due primarily to the adduct with the catalytic cysteine residue. A computational study suggests potential interactions between the illudalic acid moiety and the enzyme active site. Taken together, these data offer novel insights into the mechanism of inhibition of LAR phosphatase activity by illudalic acid.
白细胞抗原相关（LAR）磷酸酶是一种受体型蛋白酪氨酸磷酸酶，参与细胞信号转导，并与人类疾病相关，包括癌症和代谢紊乱。通过特征明确且经过充分验证的小分子选择性抑制 LAR 磷酸酶活性，将为了解 LAR 磷酸酶在健康和疾病中的作用提供关键见解，但识别 LAR 磷酸酶活性的选择性抑制剂一直具有挑战性。最近，我们描述了真菌天然产物伊鲁达酸对 LAR 磷酸酶活性的强效和选择性抑制。在这里，我们提供了 LAR 磷酸酶与伊鲁达酸形成的加合物的详细生化特征。质谱分析表明，两个半胱氨酸残基被伊鲁达酸及其相关类似物共价标记。突变分析支持这样的假设，即 LAR 磷酸酶活性的抑制主要归因于与催化半胱氨酸残基的加合物。计算研究表明伊鲁达酸部分与酶活性位点之间存在潜在相互作用。综上所述，这些数据为伊鲁达酸抑制 LAR 磷酸酶活性的机制提供了新的见解。
