Irreversible inhibition of S-adenosylmethionine decarboxylase of Trypanosoma brucei brucei by S-adenosylmethionine analogues.
Irreversible inhibition of S-adenosylmethionine decarboxylase of Trypanosoma brucei brucei by S-adenosylmethionine analogues.
复制标题
S-腺苷甲硫氨酸类似物对布氏锥虫的S-腺苷甲硫氨酸脱羧酶具有不可逆抑制作用。
DOI：
10.1016/0006-2952(92)90122-y
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发表时间：
1992
影响因子：
5.8
通讯作者：
Pegg,AE
中科院分区：
文献类型：
--
作者：
Tekwani,BL;Bacchi,CJ;Secrist3rd,JA;Pegg,AE
设计了s -腺苷蛋氨酸类似物作为活性位点定向抑制剂，体外测试了它们对布鲁氏锥虫s -腺苷蛋氨酸脱羧酶（AdoMetDC）的影响。这些类似物含有叔氮原子代替磺胺，并具有以反应基（肼基-，氨基-，肼基-或甲基亚硝基脲）结尾的可变长度侧链。肼基衍生物的ic50值在40 ~ 100 nM范围内是最有效的抑制剂。其中活性最高的化合物为5′-脱氧-5′-[（2-肼乙基）-甲氨基]腺苷（MHZEA）， ic50为0.04 μM。MHZEA的加入产生了时间依赖性的失活，表观ki值为0.4 μM， MHZEA饱和浓度下的酶半衰期为0.4 min。增加侧链的长度或将氮上的甲基改变为乙基会降低药效。用氨基基取代肼基部分导致抑制效力降低约30- 35倍。然而，这些氨基类似物的相对活性顺序与含有5'-脱氧-5'-[（2-arninooxyethyl）甲基胺]腺苷（MAOEA）的肼系相似，其活性最高，为1.3 μM。5′-脱氧-5′-[（3-肼基-3-氧丙基）-甲胺]腺苷对肼基类似物的抑制效果更差，最佳抑制剂的anic50值为8.7 μM。甲基亚硝基脲衍生物无活性。MHZEA或MAOEA对锥虫AdoMetDC的失活是不可逆的，并且受到腐胺（一种已知的酶激活剂）的极大刺激，表明这些化合物与活性位点结合并与酶形成共价键。这些抑制剂可能具有相当大的潜力，可作为治疗锥虫病和其他原生动物感染的化疗药物，也可用于研究AdoMetDC在这些生物体中调节多胺水平的作用。
S-Adenosylmethionine analogues designed as active-site directed inhibitors were testedin vitrofor their effects onS-adenosylmethionine decarboxylase (AdoMetDC) ofTrypanosoma brucei brucei. These analogues contained a tertiary nitrogen atom in place of the sulfonium and had a side chain of variable length ending in a reactive group (hydrazino-, aminooxy-, hydrazido- or a methylnitrosourea). The hydrazino- derivatives were the most potent inhibitors withic50values in the range of 40–100 nM. The most active compound (ic50of 0.04 μM) was 5'-deoxy-5'-[(2-hydrazinoethyl)-methylamino] adenosine (MHZEA). Addition of MHZEA produced a time-dependent inactivation with an apparentKi, of 0.4 μM, and the enzyme half-life at a saturating concentration of MHZEA was 0.4 min. Increasing the length of the side chain or changing the methyl group attached to the nitrogen to an ethyl group reduced the potency. Replacement of the hydrazino moiety with an aminooxy group resulted in about a 30- to 35-fold decrease in inhibition potency. However, the relative order of activities of these aminooxy analogues was similar to that found in the hydrazino series with 5'-deoxy-5'-[(2-arninooxyethyl) methylamino]adenosine (MAOEA), which had anic50of 1.3 μM, being the most active. The hydrazido analogs were even less effective with 5'-deoxy-5'-[(3-hydrazino-3-oxopropyl)-methylamino] adenosine, the best inhibitor, having anic50, value of 8.7 μM. The methylnitrosourea derivatives were inactive. The inactivation of trypanosomal AdoMetDC with MHZEA or MAOEA was irreversible and was greatly stimulated by putrescine, a known activator of the enzyme, indicating that the compounds bind to the active site and form a covalent bond with the enzyme. These inhibitors may have considerable potential as chemotherapeutic agents against trypanosomiasis and other protozoal infections and may also be useful in studying the role of AdoMetDC in the regulation of polyamine levels in these organisms.