Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme
Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme
复制标题
DOI：
10.1021/bi000593q
复制
发表时间：
2000-08-01
期刊：
影响因子：
2.9
通讯作者：
Dive, V
中科院分区：
文献类型：
--
作者：
Coates, D;Isaac, RE;Dive, V
人体细胞血管紧张素I转换酶（sACE）具有两个活性位点，存在于两个同源的蛋白质结构域中，这是由串联的基因重复引起的。已经提出N-和C-末端活性位点可以具有特定的体内作用。在果蝇中，Ance和Acer编码两个ACE样单结构域蛋白，也被预测具有不同的生理作用。我们已经调查了Ance和宏基的N-和C-结构域的人sACE基因组序列分析，并通过使用结构域选择性抑制剂，包括RXP 407，选择性抑制剂的人N-结构域的关系。这些次膦酸肽是槭属植物的有效抑制剂。但不是Ance的，我们得出结论，N-结构域和Acer的活性位点共享允许不寻常的RXP 307抑制剂的结合和更宽范围的肽结构的水解的结构特征。相比之下，Ance，像人类ACE的C-结构域，显示更大的抑制剂选择性。从已发表的果蝇2号染色体的Adh区域的序列分析，其中携带Ance，宏基，和四个额外的ACE样基因，我们还建议，这种功能的保护反映在一个祖先的基因结构中，可识别的原口和后口谱系，在脊椎动物基因组中看到的重复早于这些谱系的分歧。ACE酶在脊椎动物和无脊椎动物进化过程中具有不同的活性位点，进一步证明了这两种活性位点具有不同的生理功能。
Human somatic angiotensin I-converting enzyme (sACE) has two active sites present in two homologous protein domains, resulting from a tandem gene duplication. It has been proposed that the N-and C-terminal active sites can have specific in vivo roles. In Drosophila melanogaster, Ance and Acer code for two ACE-like single-domain proteins, also predicted to have distinct physiological roles. We have investigated the relationship of Ance and Acer to the N- and C-domains of human sACE by genomic sequence analysis and by using domain-selective inhibitors, including RXP 407, a selective inhibitor of the human N-domain. These phosphinic peptides were potent inhibitors of Acer. but not of Ance, We conclude that the active sites of the N-domain and of Acer share structural features that permit the binding of the unusual RXP307 inhibitor and the hydrolysis of a broader range of peptide structures. In comparison, Ance, like the human C-domain of ACE, displays greater inhibitor selectivity. From the analysis of the published sequence of the Adh region of Drosophila chromosome 2, which carries Ance, Acer, and four additional ACE-like genes, we also suggest that this functional conservation is reflected in an ancestral gene structure identifiable in both protostome and deuterostome lineages and that the duplication seen in vertebrate genomes predates the divergence of these lineages. The conservation of ACE enzymes with distinct active sites in the evolution of both vertebrate and invertebrate species provides further evidence that these two kinds of active sites have different physiological functions.