Inhibition of diamino pelargonic acid aminotransferase, an enzyme of the biotin biosynthetic pathway, by amiclenomycin: A mechanistic study
Inhibition of diamino pelargonic acid aminotransferase, an enzyme of the biotin biosynthetic pathway, by amiclenomycin: A mechanistic study
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DOI：
10.1002/hlca.200390322
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发表时间：
2003-01-01
影响因子：
1.8
通讯作者：
Marquet, A
中科院分区：
文献类型：
--
作者：
Mann, S;Florentin, D;Marquet, A
阿霉素 (1a)（一种天然存在的二氨基壬酸转氨酶抑制剂）的作用机制已确定。该酶催化抑制剂和 5'-磷酸吡哆醛之间形成芳香族加合物。通过质谱测定，加合物的结构与报道的 X 射线晶体结构一致。观察到了 k(cat) 抑制剂特征的动力学参数，K-1 值为 2 mum，k(inact) 值为 0.4 min(-1)。尽管抑制剂和蛋白质之间不存在共价键，但观察到的失活的不可逆性揭示了加合物对活性位点的高亲和力。另外两种顺式-1-氨基-4-取代-环己-2,5-二烯，3a 和 4a，也被发现能有效抑制该酶。反式异构体的效力要么低得多（1b），要么无活性（3b 和 4b）。显然，负责抑制作用的氨基环己二烯部分可以构成用于设计新除草剂的原始药效基团。
The mechanism of action of amiclenomycin (1a), a naturally occuring inhibitor of diaminopelargonic acid aminotransferase, has been established. The enzyme catalyzes the formation of an aromatic adduct between the inhibitor and pyridoxal-5'-phosphate. The structure of the adduct, determined by mass spectrometry, is in agreement with the reported X-ray crystal structure. Kinetic parameters, characteristic of k(cat) inhibitors, have been observed, with a K-1 value of 2 mum and a k(inact) value of 0.4 min(-1). The irreversibility of the inactivation observed, in spite of the absence of covalent bond between the inhibitor and the protein, reveals the high affinity of the adduct for the active site. Two other cis-1-amino-4-substituted-cyclohexa-2,5-dienes, 3a and 4a, were also found to efficiently inhibit the enzyme. The trans-isomers were either much less potent (1b) or inactive (3b and 4b). The aminocyclohexadiene moiety, which is, apparently, responsible for the inhibition, could constitute an original pharmacophore for the design of new herbicides.