Goldstone Jared V, Goldstone Heather M H, Morrison Ann M, Tarrant Ann, Kern Suzanne E, Woodin Bruce R, Stegeman John J
Department of Biology, Woods Hole Oceanographic Institution, Woods Hole.
Mol Biol Evol. 2007 Dec;24(12):2619-31. doi: 10.1093/molbev/msm200. Epub 2007 Oct 4.
Cytochrome P450 family 1 (CYP1) proteins are important in a large number of toxicological processes. CYP1A and CYP1B genes are well known in mammals, but the evolutionary history of the CYP1 family as a whole is obscure; that history may provide insight into endogenous functions of CYP1 enzymes. Here, we identify CYP1-like genes in early deuterostomes (tunicates and echinoderms), and several new CYP1 genes in vertebrates (chicken, Gallus gallus and frog, Xenopus tropicalis). Profile hidden Markov models (HMMs) generated from vertebrate CYP1A and CYP1B protein sequences were used to identify 5 potential CYP1 homologs in the tunicate Ciona intestinalis genome. The C. intestinalis genes were cloned and sequenced, confirming the predicted sequences. Orthologs of 4 of these genes were found in the Ciona savignyi genome. Bayesian phylogenetic analyses group the tunicate genes in the CYP1 family, provisionally in 2 new subfamilies, CYP1E and CYP1F, which fall in the CYP1A and CYP1B/1C clades. Bayesian and maximum likelihood analyses predict functional divergence between the tunicate and vertebrate CYP1s, and regions within CYP substrate recognition sites were found to differ significantly in position-specific substitution rates between tunicates and vertebrates. Subsequently, 10 CYP1-like genes were found in the echinoderm Strongylocentrotus purpuratus (sea urchin) genome. Several of the tunicate and echinoderm CYP1-like genes are expressed during development. Canonical xenobiotic response elements are present in the upstream genomic sequences of most tunicate and sea urchin CYP1s, and both groups are predicted to possess an aryl hydrocarbon receptor (AHR), suggesting possible regulatory linkage of AHR and these CYPs. The CYP1 family has undergone multiple rounds of gene duplication followed by functional divergence, with at least one gene lost in mammals. This study provides new insight into the origin and evolution of CYP1 genes.
细胞色素P450家族1（CYP1）蛋白在大量毒理学过程中起着重要作用。CYP1A和CYP1B基因在哺乳动物中广为人知，但整个CYP1家族的进化历史却模糊不清；这段历史可能有助于深入了解CYP1酶的内源性功能。在此，我们在早期后口动物（被囊动物和棘皮动物）中鉴定出CYP1样基因，并在脊椎动物（鸡，原鸡和青蛙，热带爪蟾）中发现了几个新的CYP1基因。利用从脊椎动物CYP1A和CYP1B蛋白序列生成的轮廓隐马尔可夫模型（HMM），在被囊动物肠鳃纲动物基因组中鉴定出5个潜在的CYP1同源物。对肠鳃纲动物基因进行克隆和测序，证实了预测的序列。在萨氏海鞘基因组中发现了其中4个基因的直系同源物。贝叶斯系统发育分析将被囊动物基因归入CYP1家族，暂时分为2个新亚家族，即CYP1E和CYP1F，它们属于CYP1A和CYP1B/1C进化枝。贝叶斯分析和最大似然分析预测了被囊动物和脊椎动物CYP1之间的功能差异，并且发现CYP底物识别位点内的区域在被囊动物和脊椎动物之间的位置特异性替代率上存在显著差异。随后，在棘皮动物紫球海胆基因组中发现了10个CYP1样基因。一些被囊动物和棘皮动物的CYP1样基因在发育过程中表达。大多数被囊动物和海胆CYP1的上游基因组序列中存在典型的外源性物质反应元件，并且预计这两组都拥有芳烃受体（AHR），这表明AHR与这些CYP之间可能存在调控联系。CYP1家族经历了多轮基因复制，随后发生功能分化，在哺乳动物中至少有一个基因丢失。这项研究为CYP1基因的起源和进化提供了新的见解。
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