Wu Y, Woster P M
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan 48202.
J Med Chem. 1992 Aug 21;35(17):3196-201. doi: 10.1021/jm00095a015.
The compound S-(5'-deoxy-5'-adenosyl)-1-ammonio-4-(methylsulfonio)-2- cyclopentene (AdoMac) was prepared and evaluated as an irreversible inhibitor of S-adenosylmethionine decarboxylase (AdoMet-DC). AdoMac was shown to inhibit AdoMet-DC in a time-dependent manner with a KI of 18.3 microM and a kinact of 0.133 min-1. In addition, AdoMet-DC activity could not be restored following extensive dialysis of the enzyme-inhibitor complex, and the enzyme was protected from irreversible inactivation by the known competitive inhibitor methylglyoxal bis(guanylhydrazone). HPLC analysis of the enzymatic reaction products revealed a time-dependent decrease in the peak coeluting with AdoMac, and a corresponding increase in the peak coeluting with (methylthio)adenosine (MTA), a byproduct of the irreversible binding of AdoMac to the enzyme. Thus, AdoMac appears to function as an enzyme-activated, irreversible inhibitor of AdoMet-DC.
制备了化合物S-(5'-脱氧-5'-腺苷基)-1-铵基-4-(甲基硫代)-2-环戊烯（AdoMac），并将其作为S-腺苷甲硫氨酸脱羧酶（AdoMet-DC）的不可逆抑制剂进行评估。结果表明，AdoMac以时间依赖性方式抑制AdoMet-DC，其抑制常数（KI）为18.3微摩尔，失活速率常数（kinact）为0.133分钟-1。此外，对酶-抑制剂复合物进行广泛透析后，AdoMet-DC的活性无法恢复，并且已知的竞争性抑制剂甲基乙二醛双（胍腙）可保护该酶不被不可逆失活。对酶促反应产物的HPLC分析显示，与AdoMac共洗脱的峰随时间减少，而与（甲硫基）腺苷（MTA）共洗脱的峰相应增加，MTA是AdoMac与该酶不可逆结合的副产物。因此，AdoMac似乎作为一种酶激活的AdoMet-DC不可逆抑制剂发挥作用。
