Adaptive evolution of multiple-variable exons and structural diversity of drug-metabolizing enzymes.
Adaptive evolution of multiple-variable exons and structural diversity of drug-metabolizing enzymes.
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多变量外显子的适应性演变和药物代谢酶的结构多样性。
DOI：
10.1186/1471-2148-7-69
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发表时间：
2007-05-02
影响因子：
3.4
通讯作者：
Wu, Qiang
中科院分区：
文献类型：
--
作者：
Li, Can;Wu, Qiang
人类基因组包含大量具有多变量第一外显子的基因簇，包括药物代谢的UDP葡萄糖醛基转移酶（UGT1）和i -分支β-1,6- n -乙酰氨基葡萄糖转移酶（GCNT2，也称为IGNT）簇，它们以串联阵列组织，类似于原钙粘蛋白（PCDH）、免疫球蛋白（IG）和t细胞受体（TCR）簇。为了深入了解可能形成其多样性的进化过程，我们对脊椎动物多变量第一外显子簇进行了全面的比较分析。我们发现在脊椎动物Ugt1， Gcnt2和Ugt2a集群中存在物种特异性的可变外显子重复和突变，并且它们的可变和恒定基因组组织是保守的和脊椎动物特异性的。此外，对人类、小鼠和大鼠密切相关的Ugt2集群的完整谱进行分析，揭示了广泛的谱系特异性重复。与Pcdh基因簇相比，基因转换在脊椎动物Ugt1、Gcnt2和Ugt2基因簇的进化中并不起主导作用。因此，它们巨大的多样性是通过“生与死”的进化实现的。对比分析和同源建模表明，脊椎动物UGT蛋白具有相似的三维结构，分别具有n端和c端结合受体和供体底物的罗斯曼折叠结构域。分子对接实验确定了供体和受体识别的关键残基，揭示了UGT糖醛酸化的催化机制，表明人UGT1A1残基组氨酸39 （H39）是一般碱基，残基天冬氨酸151 （D151）是重要的电子转移辅助分子。此外，我们在n端Rossmann结构域中发现了四个形成受体结合口袋的高变区。最后，分析非同义和同义核苷酸替换的模式，确定了在分子水平上受达尔文选择影响的密码子位点。这些多样化的残留物可能在识别无数的外源性和内源性药物中发挥重要作用。我们的研究结果表明，脊椎动物多变量第一外显子的巨大多样性是通过出生和死亡进化实现的，特定密码子位点的适应性进化增强了脊椎动物UGT的多样性，以防御环境因子。我们的结果对于化学解毒和药物清除所需的惊人分子多样性也有有趣的含义。
The human genome contains a large number of gene clusters with multiple-variable-first exons, including the drug-metabolizing UDP glucuronosyltransferase (UGT1) and I-branching β-1,6-N-acetylglucosaminyltransferase (GCNT2, also known as IGNT) clusters, organized in a tandem array, similar to that of the protocadherin (PCDH), immunoglobulin (IG), and T-cell receptor (TCR) clusters. To gain insight into the evolutionary processes that may have shaped their diversity, we performed comprehensive comparative analyses for vertebrate multiple-variable-first-exon clusters. We found that there are species-specific variable-exon duplications and mutations in the vertebrate Ugt1, Gcnt2, and Ugt2a clusters and that their variable and constant genomic organizations are conserved and vertebrate-specific. In addition, analyzing the complete repertoires of closely-related Ugt2 clusters in humans, mice, and rats revealed extensive lineage-specific duplications. In contrast to the Pcdh gene clusters, gene conversion does not play a predominant role in the evolution of the vertebrate Ugt1, Gcnt2 and Ugt2 gene clusters. Thus, their tremendous diversity is achieved through "birth-and-death" evolution. Comparative analyses and homologous modeling demonstrated that vertebrate UGT proteins have similar three-dimensional structures each with N-terminal and C-terminal Rossmann-fold domains binding acceptor and donor substrates, respectively. Molecular docking experiments identified key residues in donor and acceptor recognition and provided insight into the catalytic mechanism of UGT glucuronidation, suggesting the human UGT1A1 residue histidine 39 (H39) as a general base and the residue aspartic acid 151 (D151) as an important electron-transfer helper. In addition, we identified four hypervariable regions in the N-terminal Rossmann domain that form an acceptor-binding pocket. Finally, analyzing patterns of nonsynonymous and synonymous nucleotide substitutions identified codon sites that are subject to positive Darwinian selection at the molecular level. These diversified residues likely play an important role in recognition of myriad xenobiotics and endobiotics. Our results suggest that enormous diversity of vertebrate multiple variable first exons is achieved through birth-and-death evolution and that adaptive evolution of specific codon sites enhances vertebrate UGT diversity for defense against environmental agents. Our results also have interesting implications regarding the staggering molecular diversity required for chemical detoxification and drug clearance.
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DOI：
10.1016/s0925-4439(98)00030-1
发表时间：
1998-07-01
影响因子：
6.2
作者：
Ciotti, M;Chen, F;Owens, IS
通讯作者：
Owens, IS
DOI：
10.1097/00005176-199902000-00024
发表时间：
1999-02-01
影响因子：
2.9
作者：
Ciotti, M;Werlin, SL;Owens, IS
通讯作者：
Owens, IS
DOI：
10.3324/haematol.10585
发表时间：
2007-01-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
D'Apolito, Maria;Marrone, Agnese;Iolascon, Achille
通讯作者：
Iolascon, Achille
影响因子：
4.1
作者：
Ghosh, SS;Lu, Y;Roy-Chowdhury, N
通讯作者：
Roy-Chowdhury, N
影响因子：
9.8
作者：
Chen, FC;Li, WH
通讯作者：
Li, WH