PDF(Pubmed)
Abstract：
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.
摘要：
戊二酸1型（GA1）是一种严重的先天性代谢错误，没有药物治疗。治疗这种疾病的新策略是将有毒的生化中间体转移到毒性较小或无毒的代谢物。这里,我们报告了一个假定的新目标，琥珀酰辅酶A：戊二酸辅酶A转移酶（SUGCT），我们假设通过减少戊二酰辅酶A和衍生的3-羟基戊二酸来抑制GA1代谢表型。SUGCT是使用琥珀酰-CoA和戊二酸作为底物的III型CoA转移酶。我们报告了糖的结构，开发基于酶和细胞的检测方法，并在FDA批准的化合物的高通量筛选中鉴定缬沙坦和氯沙坦羧酸作为酶的抑制剂。SUGCT与氯沙坦羧酸的共晶结构揭示了活性位点的新口袋，并进一步验证了高通量筛选方法。这些结果可能为未来开发新的药物干预治疗GA1奠定基础。
