Slama J T, Aboul-Ela N, Jacobson M K
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Ohio 43606, USA.
J Med Chem. 1995 Oct 13;38(21):4332-6. doi: 10.1021/jm00021a023.
Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD), a nitrogen-in-the-ring analog of ADP-ribose, was recently shown to be a potent and specific inhibitor of poly(ADP-ribose) glycohydrolase. Analysis of the inhibition kinetics of the hydrolase by ADP-HPD using the method of Lineweaver and Burk yields a noncompetitive double-reciprocal plot. Both the intercept (1/V) versus [inhibitor] replot and the slope (Km/V) versus [inhibitor] replot are hyperbolic, indicating partial noncompetitive inhibition. Inhibitor dissociation constants Kii = 52 nM and Kis = 80 nM were determined for ADP-HPD by analysis of the intercept versus [inhibitor] and slope versus [inhibitor] replots. These results show that although ADP-HPD is extremely potent in inhibiting poly(ADP-ribose) glycohydrolase, its effectiveness is limited by its partial inhibition. ADP-HPD was significantly less potent as an inhibitor of the NAD glycohydrolase from Bungarus fasciatus venom. Analysis of the inhibition kinetics using the Lineweaver and Burk method indicated that ADP-HPD was a linear-competitive inhibitor of the NAD glycohydrolase with a Ki of 94 microM. The results indicate that at low concentration ADP-HPD will be a selective inhibitor of poly(ADP-ribose) glycohydrolase; however, complete inactivation of the activity will be difficult to obtain.
二磷酸腺苷（羟甲基）吡咯烷二醇（ADP - HPD）是一种环状含氮的ADP - 核糖类似物，最近被证明是聚（ADP - 核糖）糖苷水解酶的一种强效且特异性的抑制剂。使用Lineweaver和Burk方法分析ADP - HPD对该水解酶的抑制动力学，得到非竞争性双倒数图。截距（1/V）对[抑制剂]的重绘图和斜率（Km/V）对[抑制剂]的重绘图均为双曲线，表明是部分非竞争性抑制。通过分析截距对[抑制剂]和斜率对[抑制剂]的重绘图，确定ADP - HPD的抑制剂解离常数Kii = 52 nM和Kis = 80 nM。这些结果表明，尽管ADP - HPD在抑制聚（ADP - 核糖）糖苷水解酶方面极具效力，但其有效性受到部分抑制的限制。作为眼镜蛇毒NAD糖苷水解酶的抑制剂，ADP - HPD的效力明显较低。使用Lineweaver和Burk方法分析抑制动力学表明，ADP - HPD是NAD糖苷水解酶的线性竞争性抑制剂，Ki为94 microM。结果表明，在低浓度下，ADP - HPD将是聚（ADP - 核糖）糖苷水解酶的选择性抑制剂；然而，很难实现该酶活性的完全失活。
