The steady state kinetic mechanism of succinic semialdehyde reductase AKR7A5

Abstract:

The inhibitor of succinic semialdehyde reductase AKR7A5 would be the potential drug for succinic semialdehyde dehydrogenase deficiency. The steady state kinetic mechanism of AKR7A5 and the mechanism of inhibitor interacting with the target enzyme are critical in the development of drug candidates. In spite of two crystal structures of succinic semialdehyde reductases, the details of the kinetic mechanism of AKR7A5 are unclear. Here we report the study of steady state kinetic mechanism of AKR7A5 and found the enzyme reacts in the ordered ternary complex mechanism. Based on the mechanism, we concluded that the substrate inhibition of succinic semialdehyde is caused by the wrong binding to the binary complex AKR7A5 and NADP+. The substrate analogue succinate is uncompetitive inhibitor by binding to the binary complex of AKR7A5 and NADP+. This information is necessary to obtain the ternary complex structure of AKR7A5 and succinate or other uncompetitive inhibitors, as the structural basis for inhibitor optimization.