Evolutionary and molecular foundations of multiple contemporary functions of the nitroreductase superfamily.
Evolutionary and molecular foundations of multiple contemporary functions of the nitroreductase superfamily.
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DOI：
10.1073/pnas.1706849114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Babbitt PC
中科院分区：
文献类型：
--
作者：
Akiva E;Copp JN;Tokuriki N;Babbitt PC
功能多样的酶超家族是一组同源物，它们保留结构折叠和机制细节，但执行各种不同的化学反应。祖先蛋白质分化产生现存酶的进化途径是什么？我们提出了一种将实验数据与计算工具相结合的方法，以追踪模型系统中的序列-结构-功能转变，即功能多样的黄素单核苷酸依赖性硝基还原酶（NTR）。我们的结果提出了一种进化模型，其中当代 NTR 类别通过关键位置的插入和功能残基的固定，从最小的黄素结合支架以放射状方式分化，产生当代酶的反应多功能性。这些原则将促进 NTR 的合理设计，并推进描述酶超家族功能多样性出现的一般方法。关于不同酶功能和反应如何从祖先支架进化而来的见解对于理解化学和进化生物学以及酶在生物技术中的开发至关重要。我们使用独特且全面的工具组合进行了广泛的计算分析，其中包括大规模系统发育重建，以确定功能多样的黄素单核苷酸依赖性硝基还原酶 (NTR) 超家族（来自生命所有领域的超过 24,000 个序列、54 个结构和超过 10 个酶功能）的序列、结构和功能关系。我们的结果提出了一种进化模型，其中超家族的当代亚群从最小的黄素结合支架以放射状方式分化。我们确定了这种分歧的结构设计原则：在最小支架的关键位置插入，与关键残基的固定相结合，导致了功能专门化。这些结果将有助于未来描绘酶超家族中功能多样性的出现，为未知功能超家族成员的功能推断提供线索，并促进NTR支架的合理重新设计。
Functionally diverse enzyme superfamilies are sets of homologs that conserve a structural fold and mechanistic details but perform various distinct chemical reactions. What are the evolutionary routes by which ancestral proteins diverge to produce extant enzymes? We present an approach that combines experimental data with computational tools to trace these sequence–structure–function transitions in a model system, the functionally diverse flavin mononucleotide-dependent nitroreductases (NTRs). Our results suggest an evolutionary model in which contemporary NTR classes have diverged in a radial manner from a minimal flavin-binding scaffold via insertions at key positions and fixation of functional residues, yielding the reaction versatility of contemporary enzymes. These principles will facilitate rational design of NTRs and advance general approaches for delineating the emergence of functional diversity in enzyme superfamilies. Insight regarding how diverse enzymatic functions and reactions have evolved from ancestral scaffolds is fundamental to understanding chemical and evolutionary biology, and for the exploitation of enzymes for biotechnology. We undertook an extensive computational analysis using a unique and comprehensive combination of tools that include large-scale phylogenetic reconstruction to determine the sequence, structural, and functional relationships of the functionally diverse flavin mononucleotide-dependent nitroreductase (NTR) superfamily (>24,000 sequences from all domains of life, 54 structures, and >10 enzymatic functions). Our results suggest an evolutionary model in which contemporary subgroups of the superfamily have diverged in a radial manner from a minimal flavin-binding scaffold. We identified the structural design principle for this divergence: Insertions at key positions in the minimal scaffold that, combined with the fixation of key residues, have led to functional specialization. These results will aid future efforts to delineate the emergence of functional diversity in enzyme superfamilies, provide clues for functional inference for superfamily members of unknown function, and facilitate rational redesign of the NTR scaffold.
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影响因子：
5.6
作者：
Ahmed, F. Hafna;Carr, Paul D.;Jackson, Colin J.
通讯作者：
Jackson, Colin J.
影响因子：
14.9
作者：
Finn RD;Mistry J;Tate J;Coggill P;Heger A;Pollington JE;Gavin OL;Gunasekaran P;Ceric G;Forslund K;Holm L;Sonnhammer EL;Eddy SR;Bateman A
通讯作者：
Bateman A
影响因子：
2.9
作者：
Chung, Hae-Won;Tu, Shiao-Chun
通讯作者：
Tu, Shiao-Chun
影响因子：
2.5
作者：
Curado, Silvia;Anderson, Ryan M.;Stainier, Didier Y. R.
通讯作者：
Stainier, Didier Y. R.
DOI：
10.1093/bioinformatics/bts532
发表时间：
2012-11-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Barber AE 2nd;Babbitt PC
通讯作者：
Babbitt PC