Ruoxi Wu, Susmita Khamrui, Tetyana Dodatko, João Leandro, Amanda Sabovic, Sara Violante, Justin R. Cross, Eric Marsan, Kunal Kumar, Robert J. DeVita, Michael B. Lazarus* and Sander M. Houten*,
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引用次数: 0
摘要
戊二酸尿症 1 型(GA1)是一种严重的先天性代谢错误,目前尚无药物治疗方法。治疗这种疾病的新策略是将有毒的生化中间产物转化为毒性较低或无毒的代谢物。在这里,我们报告了一个假定的新靶点--琥珀酰-CoA:戊二酸-CoA 转移酶(SUGCT),我们假设它能通过减少戊二酸-CoA 和衍生的 3-羟基戊二酸来抑制 GA1 代谢表型。SUGCT 是一种 III 型 CoA 转移酶,以琥珀酰-CoA 和戊二酸为底物。我们报告了 SUGCT 的结构,开发了基于酶和细胞的检测方法,并在 FDA 批准化合物的高通量筛选中确定缬沙坦和洛沙坦羧酸为该酶的抑制剂。SUGCT 与洛沙坦羧酸的共晶体结构揭示了活性位点中的一个新口袋,进一步验证了高通量筛选方法。这些结果可能为今后开发治疗 GA1 的新药理干预措施奠定基础。
Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1
Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.