琥珀酸半醛还原酶AKR7A5的稳态动力学机理分析

The steady state kinetic mechanism of succinic semialdehyde reductase AKR7A5

琥珀酸半醛还原酶的抑制剂可作为缓解琥珀酸半醛脱氢酶缺陷病症状的潜在药物.酶抑制剂的研发要以酶的动力学性质为基础,但琥珀酸半醛还原酶的稳态动力学性质还不清楚.本文通过对琥珀酸半醛还原酶AKR7A5稳态动力学性质的分析,判断AKR7A5是按照有序的三元复合物反应机理催化反应;在此基础上,推导出琥珀酸半醛发生底物抑制是由于错误地与AKR7A5:NADP+二元复合物结合;底物的结构类似物琥珀酸体现出反竞争抑制剂的特点,只能与AKR7A5:NADP+二元复合物相互作用,暗示只有通过抑制剂、酶、NADP+复合物的方向入手,才能获得反竞争抑制剂与AKR7A5的复合物晶体结构.

The inhibitor of succinic semialdehyde reductase AKR7A5 would be the potential drug for suc- cinic semialdehyde dehydrogenase deficiency. The steady state kinetic mechanism of AKRTA5 remains unclear but are critical in the development of drug candidates. Here the study of steady state kinetic mechanism of AKRTA5 was studied, which indicated the enzyme reacts in the ordered ternary complex mechanism. Based on the mechanism, it is concluded that the substrate inhibition of succinic semialde- hyde is caused by the wrong binding to the binary complex AKRTA5 and NADP＋. The substrate ana- logue succinate is uncompetitive inhibitor by binding to the binary complex of AKRTA5 and NADP＋. This information suggests that the ternary complex structure of AKR7A5 and succinate or other uncom- petitive inhibitors can only be obtained as the complex of AKRTAS, NADP＋ , and the uncompetitive in- hibitors.