Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes.
Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes.
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DOI：
10.1186/1471-2148-7-178
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发表时间：
2007-09-27
影响因子：
3.4
通讯作者：
Lambeth, J. David
中科院分区：
文献类型：
--
作者：
Kawahara, Tsukasa;Lambeth, J. David
产生活性氧的NADPH氧化酶(NOX)具有多种生物学功能，大致可分为受亚单位相互作用调控的NOX和受钙调控的NOX。典型的亚基调控的NOX，NOX2，是吞噬细胞NADPH-氧化酶的膜相关催化亚基。NOX2与完整的膜蛋白p22Phox形成异二聚体，该异二聚体与调节亚基p47Phox、p67Phox、p40Phox和小GTPase Rac结合，触发超氧化物的产生。NOX组织者蛋白1(NOXO1)和NOX活化子1(NOXA1)分别是p47Phox和p67Phox的同源物，与p22Phox和Rac一起激活NOX2的非吞噬同源物Nox1。NOXO1和p22Phox也调节Nox3，而NOX4只需要p22Phox。在这项研究中，我们组装和分析了脊椎动物、脊索动物、棘皮动物、软体动物、蛇类、脊椎动物、真菌和黏菌变形虫的NOx调节亚基同源基因的氨基酸序列，以探讨这些亚基的进化历史。除蜕皮动物外，在后生动物中广泛发现了祖先的p47Phox、p67Phox和p22Phox基因。短节鞭毛虫Monosiga brevicollis是单细胞生物体，是多细胞动物的近亲，编码p22Phox、p47Phox的早期原型，也是Nox1-3亚家族中已知的最早的类似NOX2的祖先。在海胆、紫球海胆和帽贝巨藻中都发现了类似p67Phox和p47Phox的基因，它们也拥有与脊椎动物Nox1-3类似的NOX2同源基因。原始的p47Phox和p67Phox基因在脊椎动物中存在复制，复制的分支进化为NOXO1和NOXA1。对调控亚基的特征结构域的分析为NOx的进化提供了一种新的观点：在鱼类中，p40Phox参与了对Nox1和NOX2的调控，但在哺乳动物出现后，Nox1(而不是NOX2)独立于p40Phox。在宽阔的鱼类中，NOXO1同源基因保留了哺乳动物p47Phox特有的自我抑制区域，后来在后来的脊椎动物中，这一区域从NOXO1中消失了。详细的氨基酸序列比较发现，推测的关键残基保守在特征结构域和以前未知的保守区。此外，还确定了真菌和阿米巴中的候选组织者/激活蛋白，并提出了假想的激活模型。这是第一个提供关于NOx酶调节亚基分子进化的全面观察的报告。这一方法为理解调控亚单位依赖的NOx酶的生化和生理功能的进化提供了线索。
The reactive oxygen-generating NADPH oxidases (Noxes) function in a variety of biological roles, and can be broadly classified into those that are regulated by subunit interactions and those that are regulated by calcium. The prototypical subunit-regulated Nox, Nox2, is the membrane-associated catalytic subunit of the phagocyte NADPH-oxidase. Nox2 forms a heterodimer with the integral membrane protein, p22phox, and this heterodimer binds to the regulatory subunits p47phox, p67phox, p40phox and the small GTPase Rac, triggering superoxide generation. Nox-organizer protein 1 (NOXO1) and Nox-activator 1 (NOXA1), respective homologs of p47phox and p67phox, together with p22phox and Rac, activate Nox1, a non-phagocytic homolog of Nox2. NOXO1 and p22phox also regulate Nox3, whereas Nox4 requires only p22phox. In this study, we have assembled and analyzed amino acid sequences of Nox regulatory subunit orthologs from vertebrates, a urochordate, an echinoderm, a mollusc, a cnidarian, a choanoflagellate, fungi and a slime mold amoeba to investigate the evolutionary history of these subunits. Ancestral p47phox, p67phox, and p22phox genes are broadly seen in the metazoa, except for the ecdysozoans. The choanoflagellate Monosiga brevicollis, the unicellular organism that is the closest relatives of multicellular animals, encodes early prototypes of p22phox, p47phox as well as the earliest known Nox2-like ancestor of the Nox1-3 subfamily. p67phox- and p47phox-like genes are seen in the sea urchin Strongylocentrotus purpuratus and the limpet Lottia gigantea that also possess Nox2-like co-orthologs of vertebrate Nox1-3. Duplication of primordial p47phox and p67phox genes occurred in vertebrates, with the duplicated branches evolving into NOXO1 and NOXA1. Analysis of characteristic domains of regulatory subunits suggests a novel view of the evolution of Nox: in fish, p40phox participated in regulating both Nox1 and Nox2, but after the appearance of mammals, Nox1 (but not Nox2) became independent of p40phox. In the fish Oryzias latipes, a NOXO1 ortholog retains an autoinhibitory region that is characteristic of mammalian p47phox, and this was subsequently lost from NOXO1 in later vertebrates. Detailed amino acid sequence comparisons identified both putative key residues conserved in characteristic domains and previously unidentified conserved regions. Also, candidate organizer/activator proteins in fungi and amoeba are identified and hypothetical activation models are suggested. This is the first report to provide the comprehensive view of the molecular evolution of regulatory subunits for Nox enzymes. This approach provides clues for understanding the evolution of biochemical and physiological functions for regulatory-subunit-dependent Nox enzymes.
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影响因子：
5.3
作者：
Bionda, C;Li, XJ;Stasia, MJ
通讯作者：
Stasia, MJ
影响因子：
4.8
作者：
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Lambeth, J. David
影响因子：
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作者：
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Clamp, M
DOI：
10.1006/bbrc.2001.5629
发表时间：
2001-09-28
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
4.8
作者：
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