Yoon H Y, Hwang S H, Lee E Y, Kim T U, Cho E H, Cho S W
Department of Biochemistry, University of Ulsan College of Medicine, 388-1 Poongnap-dong, Songpa-ku, Seoul 138-736, South Korea.
Biochimie. 2001 Sep;83(9):907-13. doi: 10.1016/s0300-9084(01)01325-6.
Incubation of glutamate dehydrogenase isoproteins (GDH I and GDH II) from bovine brains with perphenazine resulted in a time-dependent loss of enzyme activity. 2-Oxoglutarate and NADH, separately or together, gave partial but not complete protection against the inhibition. Although there were no detectable differences between GDH I and GDH II in inhibition by perphenazine in the absence of ADP, the sensitivities to the inhibition by the drug were significantly distinct for the two isoproteins in the presence of ADP. Low concentrations of ADP (0.05-0.20 mM) did not interfere with the inhibition of GDH I and GDH II by perphenazine. However, in the presence of high concentrations of ADP (0.5-1.0 mM), inhibitory effects of perphenazine on GDH isoproteins were significantly diminished as determined by enzyme kinetics and quantitative affinity chromatography on perphenazine-Sepharose. GDH I was more sensitively reacted with ADP than GDH II on the inhibition by perphenazine. Since physiological ADP levels can vary from 0.05 to > 1.0 mM depending on the rate of oxidative phosphorylation, our results suggest a possibility that two types of GDHs are differently regulated by the antipsychotic actions of perphenazine depending on the physiological concentrations of ADP. GTP and L-leucine, other well-known allosteric regulators, did not affect the inhibitory actions of perphenazine on bovine brain GDH isoproteins.
将牛脑谷氨酸脱氢酶同工酶（GDH I和GDH II）与奋乃静一起孵育，会导致酶活性随时间而丧失。单独或一起使用2-氧代戊二酸和NADH可提供部分但非完全的保护以防止抑制作用。尽管在不存在ADP的情况下，GDH I和GDH II在奋乃静抑制方面没有可检测到的差异，但在存在ADP的情况下，这两种同工酶对该药物抑制作用的敏感性明显不同。低浓度的ADP（0.05 - 0.20 mM）不会干扰奋乃静对GDH I和GDH II的抑制作用。然而，在存在高浓度ADP（0.5 - 1.0 mM）的情况下，通过酶动力学和奋乃静-琼脂糖定量亲和色谱法测定，奋乃静对GDH同工酶的抑制作用显著减弱。在奋乃静抑制方面，GDH I比GDH II对ADP的反应更敏感。由于生理ADP水平可根据氧化磷酸化速率在0.05至>1.0 mM之间变化，我们的结果表明，根据ADP的生理浓度，两种类型的GDH可能受到奋乃静抗精神病作用的不同调节。GTP和L-亮氨酸，其他众所周知的变构调节剂，不影响奋乃静对牛脑GDH同工酶的抑制作用。
