二磷酸（羟甲基）吡咯烷二醇对聚（ADP-核糖）糖苷水解酶的特异性抑制作用
Specific inhibition of poly(ADP-ribose) glycohydrolase by adenosine diphosphate (hydroxymethyl)pyrrolidinediol.
作者信息
Slama J T, Aboul-Ela N, Goli D M, Cheesman B V, Simmons A M, Jacobson M K
机构信息
Department of Medicinal and Biological Chemistry, University of Toledo, Ohio 43606.
出版信息
J Med Chem. 1995 Jan 20;38(2):389-93. doi: 10.1021/jm00002a021.
Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD), an NH analog of ADP-ribose, was chemically synthesized and shown to be a potent and specific inhibitor of poly-(ADP-ribose) glycohydrolase. The synthetic starting material was the protected pyrrolidine, (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal. This starting pyrrolidine was phosphorylated, coupled to adenosine 5'-monophosphate, and deprotected, yielding the title inhibitor ADP-HPD. ADP-HDP was shown to inhibit the activity of poly(ADP-ribose) glycohydrolase by 50% (IC50) at 0.12 microM, a value 1000-times lower than the IC50 of the product, ADP-ribose. The NAD glycohydrolase from Bungarus fasciatus venom was less sensitive to inhibition by ADP-HPD, exhibiting an IC50 of 260 microM. ADP-HPD did not inhibit either poly(ADP-ribose) polymerase or NAD:arginine mono(ADP-ribosyl)-transferase A at inhibitor concentrations up to 1 mM. At low ADP-HPD concentration, inhibition was therefore shown to be highly specific for poly(ADP-ribose) glycohydrolase, the hydrolytic enzyme in the metabolism of ADP-ribose polymers.
二磷酸腺苷（羟甲基）吡咯烷二醇（ADP-HPD）是一种ADP-核糖的NH类似物，已通过化学合成，并被证明是聚（ADP-核糖）糖苷水解酶的一种强效且特异性抑制剂。合成起始原料是受保护的吡咯烷，即（2R，3R，4S）-1-（苄氧羰基）-2-（羟甲基）吡咯烷-3,4-二醇3,4-O-异亚丙基缩醛。该起始吡咯烷被磷酸化，与5'-单磷酸腺苷偶联，然后脱保护，得到标题抑制剂ADP-HPD。结果表明，ADP-HDP在0.12微摩尔时可将聚（ADP-核糖）糖苷水解酶的活性抑制50%（IC50），该值比产物ADP-核糖的IC50低1000倍。银环蛇毒液中的NAD糖苷水解酶对ADP-HPD的抑制作用不太敏感，IC50为260微摩尔。在抑制剂浓度高达1毫摩尔时，ADP-HPD对聚（ADP-核糖）聚合酶或NAD：精氨酸单（ADP-核糖基）转移酶A均无抑制作用。因此，在低ADP-HPD浓度下，抑制作用显示出对聚（ADP-核糖）糖苷水解酶具有高度特异性，该酶是ADP-核糖聚合物代谢中的水解酶。
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