Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Hum Mol Genet. 2020 May 8;29(7):1168-1179. doi: 10.1093/hmg/ddaa037.
Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA. Here, we show that loss of DHTKD1 in glutaryl-CoA dehydrogenase-deficient HEK-293 cells leads to a 2-fold decrease in the established GA1 clinical biomarker glutarylcarnitine and demonstrate that oxoglutarate dehydrogenase (OGDH) is responsible for this remaining glutarylcarnitine production. We furthermore show that DHTKD1 interacts with OGDH, dihydrolipoyl succinyltransferase and dihydrolipoamide dehydrogenase to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex. In summary, 2-oxoadipic acid is a substrate for DHTKD1, but also for OGDH in a cell model system. The classical 2-oxoglutaric dehydrogenase complex can exist as a previously undiscovered hybrid containing DHTKD1 displaying improved kinetics towards 2-oxoadipic acid.
1 型戊二酸尿症（GA1）是一种赖氨酸降解的先天性错误，其特征是特定的脑病，由赖氨酸降解中间产物的毒性积累引起。通过抑制 DHTKD1（缺陷的谷氨酰辅酶 A 脱氢酶上游的酶）来减少底物，已被研究作为一种潜在的治疗方法，但揭示了谷氨酰辅酶 A 的替代酶源的存在。在这里，我们表明，在谷氨酰辅酶 A 脱氢酶缺陷的 HEK-293 细胞中缺失 DHTKD1 会导致已建立的 GA1 临床生物标志物戊二酰肉碱减少 2 倍，并且证明草酰戊二酸脱氢酶（OGDH）负责这种剩余的戊二酰肉碱的产生。我们进一步表明，DHTKD1 与 OGDH、二氢硫辛酰基琥珀酰基转移酶和二氢硫辛酰胺脱氢酶相互作用，形成混合的 2-酮戊二酸和 2-酮己二酸脱氢酶复合物。总之，2-酮己二酸是 DHTKD1 的底物，但在细胞模型系统中也是 OGDH 的底物。经典的 2-酮戊二酸脱氢酶复合物可以作为一种以前未被发现的包含 DHTKD1 的混合体存在，显示出对 2-酮己二酸的改进动力学。
