Department of Pathology & Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Department of Pathology & Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; READS Unit, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Redox Biol. 2023 Oct;66:102851. doi: 10.1016/j.redox.2023.102851. Epub 2023 Aug 12.
NADPH oxidases are superoxide-producing enzymes that play a role in host defense, biosynthetic pathways, as well as cellular signaling. Humans have 7 NOX isoforms (NOX1-5, DUOX1,2), while mice and rats lack NOX5 and therefore have only 6 NOX isoforms. Whether all human NOX isoforms or their subunits (CYBA, NCF1, 2, 4, NOXO1, NOXA1, DUOXA1, 2) are present and conserved in other mammalian species is unknown. In this study, we have analyzed the conservation of the NOX family during mammalian evolution using an in-silico approach. Complete genomic sequences of 164 mammalian species were available. The possible absence of genes coding for NOX isoforms was investigated using the NCBI orthologs database followed by manual curation. Conservation of a given NOX isoform during mammalian evolution was evaluated by multiple alignment and identification of highly conserved sequences. There was no convincing evidence for the absence of NOX2, 3, 4, and DUOX1, 2 in all the available mammalian genome. However, NOX5 was absent in 27 of 31 rodent, in 2 of 3 lagomorph and in 2 out of 18 bat species. NOX1 was absent in all sequenced Afrotheria and Monotremata species, as well as in 3 of 18 bat species. NOXA1 was absent in all Afrotheria and in 3 out of 4 Eulipotyphla species. We also investigated amino acid sequence conservation among given NOX isoforms. Highly conserved sequences were observed for most isoforms except for NOX5. Interestingly, the highly conserved region of NOX2 sequence was relatively small (11 amino acids), as compared to NOX1, 3, 4. The highly conserved domains are different from one NOX isoform to the other, raising the possibility of distinct evolutionary conserved functional domains. Our results shed a new light on the essentiality of different NOX isoforms. We also identified isoform-defining sequences, i.e., hitherto undescribed conserved domains within specific NOX isoforms.
NADPH 氧化酶是产生超氧化物的酶，在宿主防御、生物合成途径以及细胞信号转导中发挥作用。人类有 7 种 NOX 同工型（NOX1-5、DUOX1、2），而小鼠和大鼠缺乏 NOX5，因此只有 6 种 NOX 同工型。其他哺乳动物是否存在所有人类 NOX 同工型或其亚基（CYBA、NCF1、2、4、NOXO1、NOXA1、DUOXA1、2）尚不清楚。在这项研究中，我们使用计算机分析方法分析了哺乳动物进化过程中 NOX 家族的保守性。有 164 种哺乳动物的完整基因组序列可用。使用 NCBI 同源物数据库调查 NOX 同工型编码基因的可能缺失情况，然后进行手动整理。通过多重比对和鉴定高度保守序列来评估给定 NOX 同工型在哺乳动物进化过程中的保守性。在所有可用的哺乳动物基因组中，没有令人信服的证据表明 NOX2、3、4 和 DUOX1、2 缺失。然而，NOX5 在 31 种啮齿动物中的 27 种、3 种兔形目动物和 18 种蝙蝠中的 2 种中缺失。NOX1 在所有已测序的非洲兽总目和单孔目动物以及 18 种蝙蝠中的 3 种中缺失。NOXA1 在所有非洲兽总目动物和 4 种欧亚大陆食虫目动物中的 3 种中缺失。我们还研究了给定 NOX 同工型之间的氨基酸序列保守性。除了 NOX5 之外，大多数同工型都观察到高度保守的序列。有趣的是，NOX2 序列的高度保守区域相对较小（11 个氨基酸），与 NOX1、3、4 相比。高度保守的结构域因一种 NOX 同工型而异，这增加了不同进化保守功能结构域的可能性。我们的结果为不同的 NOX 同工型的重要性提供了新的认识。我们还确定了同工型定义序列，即在特定的 NOX 同工型中，迄今为止未描述的保守结构域。
