INHIBITORS OF POLYAMINE BIOSYNTHESIS .8. IRREVERSIBLE INHIBITION OF MAMMALIAN S-ADENOSYL-L-METHIONINE DECARBOXYLASE BY SUBSTRATE-ANALOGS
INHIBITORS OF POLYAMINE BIOSYNTHESIS .8. IRREVERSIBLE INHIBITION OF MAMMALIAN S-ADENOSYL-L-METHIONINE DECARBOXYLASE BY SUBSTRATE-ANALOGS
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DOI：
10.1021/jm00176a004
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发表时间：
1980-01-01
影响因子：
7.3
通讯作者：
ABDELMONEM, MM
中科院分区：
文献类型：
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作者：
PANKASKIE, M;ABDELMONEM, MM
合成了S-腺苷-L-蛋氨酸类似物，并评价了其对大鼠肝脏S-腺苷-L-蛋氨酸脱羧酶的抑制作用。合成的化合物为S-(5‘’-deoxy-5‘’-adenosyl)-(.+-.)-2-methylhomocysteine(10)，S-(5‘’-deoxy-5‘’-adenosyl)-(.+-.)-2-methylmethionine硫酸二氢(11)，S-(5‘’-deoxy-5‘’-adenosyl)-(.+-.)-2-methylhomocysteine亚砜(12)，S-(5‘’-deoxy-5‘’-adenosyl)-(.+-.)-1-methyl-3-thiopropylamine硫酸氢盐(16)、S-(5‘’-deoxy-5‘’-adenosyl)-(.+-.)-1-methyl-3-(methylthio)propylamine硫酸二氢盐(17)、S-(5‘’-deoxy-5‘’-adenosyl)-(.+-.)-1-methyl-3-thiopropylamine亚砜硫酸氢盐(18)、N-(cyanoethyl)-N-methyl-5‘’-amino-5‘’-deoxyadenosine(20)和N-(aminopropyl)-N-methyl-5‘’-amino-5‘’-deoxyadenosine二盐酸盐(21)。在最后的纯化步骤中，S-腺苷-L-蛋氨酸脱羧酶被部分从大鼠肝匀浆中分离纯化。在使用的最高浓度下(2.5倍。10~(-4)M)，化合物10、12、16、18和20不抑制[14C]羧基标记的S-腺苷-L-蛋氨酸的酶促脱羧反应。化合物11、17和21是S-腺苷-L-蛋氨酸脱羧酶的竞争性抑制剂，其表观KI值为1.8倍。10-4，1.2倍。10-4和1.1倍。10-4M。化合物11和17与酶活性中心的一个必需的羰基形成甲亚胺键，该基团可被氰基硼氢化钠还原。这两种抑制剂引起的酶失活是时间依赖性的，这依赖于孵育液中抑制剂的浓度。化合物21不与该酶形成甲亚胺键，也不会导致该酶失活。显然，硫类似物11和17与酶活性部位的结合方式与氮类似物21不同。
Analogs of S-adenosyl-L-methionine were synthesized and evaluated as inhibitors of the enzyme S-adenosyl-L-methionine decarboxylase from rat liver. The compounds synthesized were S-(5''-deoxy-5''-adenosyl)-(.+-.)-2-methylhomocysteine (10), S-(5''-deoxy-5''-adenosyl)-(.+-.)-2-methylmethionine dihydrogen sulfate (11), S-(5''-deoxy-5''-adenosyl)-(.+-.)-2-methylhomocysteine sulfoxide (12), S-(5''-deoxy-5''-adenosyl)-(.+-.)-1-methyl-3-thiopropylamine hydrogen sulfate (16), S-(5''-deoxy-5''-adenosyl)-(.+-.)-1-methyl-3-(methylthio)propylamine dihydrogen sulfate (17), S-(5''-deoxy-5''-adenosyl)-(.+-.)-1-methyl-3-thiopropylamine sulfoxide hydrogen sulfate (18), N-(cyanoethyl)-N-methyl-5''-amino-5''-deoxyadenosine (20) and N-(aminopropyl)-N-methyl-5''-amino-5''-deoxyadenosine dihydrochloride (21). S-Adenosyl-L-methionine decarboxylase was partially purified from rat liver homogenate using a methylglyoxal bis(guanylhydrazone) linked Sepharose column in the final purification step. At the highest concentration used (2.5 .times. 10-4 M), compounds 10, 12, 16, 18 and 20 did not produce inhibition of the enzymatic decarboxylation of [14C]carboxyl-labeled S-adenosyl-L-methionine. Compounds 11, 17 and 21 were competitive inhibitors of S-adenosyl-L-methionine decarboxylase, and the apparent Ki values for the compounds were calculated to be 1.8 .times. 10-4, 1.2 .times. 10-4 and 1.1 .times. 10-4 M, respectively. Compounds 11 and 17 formed azomethine bonds with an essential carbonyl group in the enzyme active site which was reducible with sodium cyanoborohydride. The 2 inhibitors caused a time-dependent inactivation of the enzyme, which was dependent on the concentration of the inhibitor in the incubation media. Compound 21 did not form an azomethine bond with the enzyme and did not cause inactivation of the enzyme. Apparently the sulfonium analogs 11 and 17 have a binding mode to the enzyme active site which is different than that for the nitrogen analog 21.