Laboratório de Genética e Cardiologia Molecular, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 05403-000, São Paulo-SP, Brazil.
Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):226-31. doi: 10.1073/pnas.1011223108. Epub 2010 Dec 17.
Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and process the vitamin A-derived retinaldehyde into retinoic acid (RA), a small diffusible molecule and a pivotal chordate morphogen. In this study, we combine phylogenetic, structural, genomic, and developmental gene expression analyses to examine the evolutionary origins of ALDH substrate preference. Structural modeling reveals that processing of small aldehydes, such as acetaldehyde, by ALDH2, versus large aldehydes, including retinaldehyde, by ALDH1A is associated with small versus large substrate entry channels (SECs), respectively. Moreover, we show that metazoan ALDH1s and ALDH2s are members of a single ALDH1/2 clade and that during evolution, eukaryote ALDH1/2s often switched between large and small SECs after gene duplication, transforming constricted channels into wide opened ones and vice versa. Ancestral sequence reconstructions suggest that during the evolutionary emergence of RA signaling, the ancestral, narrow-channeled metazoan ALDH1/2 gave rise to large ALDH1 channels capable of accommodating bulky aldehydes, such as retinaldehyde, supporting the view that retinoid-dependent signaling arose from ancestral cellular detoxification mechanisms. Our analyses also indicate that, on a more restricted evolutionary scale, ALDH1 duplicates from invertebrate chordates (amphioxus and ascidian tunicates) underwent switches to smaller and narrower SECs. When combined with alterations in gene expression, these switches led to neofunctionalization from ALDH1-like roles in embryonic patterning to systemic, ALDH2-like roles, suggesting functional shifts from signaling to detoxification.
醛脱氢酶（ALDHs）能代谢有毒醛类物质，并将维生素 A 衍生的视黄醛转化为视黄酸（RA），这是一种小的扩散分子，也是脊索动物的关键形态发生素。在这项研究中，我们结合系统发生、结构、基因组和发育基因表达分析，研究 ALDH 底物偏好的进化起源。结构建模表明，ALDH2 处理小醛类物质（如乙醛），而 ALDH1A 处理大醛类物质（包括视黄醛），分别与小和大的底物进入通道（SEC）相关。此外，我们表明后生动物的 ALDH1 和 ALDH2 是单一 ALDH1/2 分支的成员，并且在进化过程中，真核生物的 ALDH1/2 通常在基因复制后在大 SEC 和小 SEC 之间切换，将狭窄的通道转变为宽开口的通道，反之亦然。祖先序列重建表明，在 RA 信号的进化出现过程中，原始、狭窄的后生动物 ALDH1/2 产生了能够容纳大醛类物质（如视黄醛）的大 ALDH1 通道，支持了视黄醇依赖的信号来自于祖先细胞解毒机制的观点。我们的分析还表明，在更受限制的进化尺度上，来自无脊椎脊索动物（文昌鱼和海鞘）的 ALDH1 重复经历了 SEC 向更小、更窄的转变。当与基因表达的改变相结合时，这些转变导致从胚胎模式形成的 ALDH1 样功能到全身的 ALDH2 样功能的新功能化，表明从信号转导到解毒的功能转变。
