Danzin C, Marchal P, Casara P
Merrell Dow Research Institute, Strasbourg Research Centre, France.
Biochem Pharmacol. 1990 Oct 1;40(7):1499-503. doi: 10.1016/0006-2952(90)90446-r.
5'-([(Z)-4-Amino-2-butenyl]methylamino)-5'-deoxyadenosine [Z)-AbeAdo) was tested in vitro and in vivo as a potential inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC), a pyruvoyl-containing enzyme, purified from rat liver. In vitro (Z)-AbeAdo produces a time- and dose-dependent irreversible inhibition of the enzyme. Saturation kinetics are observed when the enzyme is preincubated with (Z)-AbeAdo in the presence of 50 microM putrescine, a known activator of AdoMetDC. Under these conditions kinetic constants were measured (Ki = 0.56 +/- 0.04 microM; tau 1/2 = 0.51 +/- 0.03 min). The inhibition is not relieved by prolonged dialysis of the inactivated enzyme. The turnover number for (Z)-AbeAdo, i.e. the number of inactivator molecules required to inactivate one enzyme molecule, is approximately 1.5. The selectivity of (Z)-AbeAdo was explored: the compound is not a substrate of adenosine deaminase, mitochondrial monoamine oxidase and diamine oxidase, but is slowly oxidized by benzylamine oxidase from rat aorta. The (E)-isomer of AbeAdo, is at least 100-fold less active than (Z)-AbeAdo as a time-dependent inhibitor of rat liver AdoMetDC. In rats, intraperitoneal administration of (Z)-AbeAdo produces a rapid, long-lasting and dose-dependent decrease of AdoMetDC activity in ventral prostate, testis and brain.
5'-([(Z)-4-氨基-2-丁烯基]甲基氨基)-5'-脱氧腺苷[Z)-AbeAdo]作为一种潜在的S-腺苷-L-甲硫氨酸脱羧酶（AdoMetDC）抑制剂，在体外和体内进行了测试。AdoMetDC是一种含丙酮酰的酶，从大鼠肝脏中纯化得到。在体外，(Z)-AbeAdo对该酶产生时间和剂量依赖性的不可逆抑制作用。当在50微摩尔腐胺（一种已知的AdoMetDC激活剂）存在的情况下，将酶与(Z)-AbeAdo预孵育时，观察到饱和动力学。在这些条件下测量了动力学常数（Ki = 0.56 ± 0.04微摩尔；半衰期 = 0.51 ± 0.03分钟）。通过对失活酶进行长时间透析并不能解除抑制作用。(Z)-AbeAdo的转换数，即使一个酶分子失活所需的失活剂分子数，约为1.5。研究了(Z)-AbeAdo的选择性：该化合物不是腺苷脱氨酶、线粒体单胺氧化酶和二胺氧化酶的底物，但会被大鼠主动脉中的苄胺氧化酶缓慢氧化。AbeAdo的(E)-异构体作为大鼠肝脏AdoMetDC的时间依赖性抑制剂，其活性比(Z)-AbeAdo至少低100倍。在大鼠中，腹腔注射(Z)-AbeAdo会使腹侧前列腺、睾丸和大脑中的AdoMetDC活性迅速、持久且剂量依赖性地降低。
