Modeling the architecture of the regulatory system controlling methylenomycin production in Streptomyces coelicolor.
Modeling the architecture of the regulatory system controlling methylenomycin production in Streptomyces coelicolor.
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DOI：
10.1186/s13036-017-0071-6
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发表时间：
2017
影响因子：
5.6
通讯作者：
Bates DG
中科院分区：
文献类型：
--
作者：
Bowyer JE;Lc de Los Santos E;Styles KM;Fullwood A;Corre C;Bates DG
抗生素亚甲霉素 A 由链霉菌的模式生物天蓝色链霉菌 A3(2) 天然产生。这种化合物引起了合成生物学家的特别兴趣，因为所有相关的生物合成、调节和抗性基因都位于 SCP1 质粒上的单个簇上，使得整个模块可以在不同细菌菌株之间轻松转移。进一步了解亚甲霉素产生基因簇的调控和生物合成有助于识别可在合成调控系统中利用的基序，以合理设计新型天然产物和抗生素。我们使用数学建模方法确定并验证了控制天蓝链球菌亚甲霉素生产的监管系统的合理架构。通过近似贝叶斯计算 (ABC) 方法进行模型选择，从 48 个可能的候选模型中识别出最有可能产生可用实验数据的三个候选模型架构。随后对这些模型架构的参数进行全局优化，确定了一个能够最准确地再现系统动态响应的单一模型，如亚甲霉素生产的时间序列数据所捕获的那样。对该模型架构的变体的进一步分析捕捉了基因敲除的影响，也再现了在突变型天蓝色链球菌菌株中观察到的定性实验结果。本研究开发的机械数学模型概括了当前有关亚甲霉素产生基因簇的调控和生物合成的生物学知识，可在未来的研究中用于做出可检验的预测和制定实验，以进一步提高我们对这一复杂调控系统的理解。
The antibiotic methylenomycin A is produced naturally by Streptomyces coelicolor A3(2), a model organism for streptomycetes. This compound is of particular interest to synthetic biologists because all of the associated biosynthetic, regulatory and resistance genes are located on a single cluster on the SCP1 plasmid, making the entire module easily transferable between different bacterial strains. Understanding further the regulation and biosynthesis of the methylenomycin producing gene cluster could assist in the identification of motifs that can be exploited in synthetic regulatory systems for the rational engineering of novel natural products and antibiotics. We identify and validate a plausible architecture for the regulatory system controlling methylenomycin production in S. coelicolor using mathematical modeling approaches. Model selection via an approximate Bayesian computation (ABC) approach identifies three candidate model architectures that are most likely to produce the available experimental data, from a set of 48 possible candidates. Subsequent global optimization of the parameters of these model architectures identifies a single model that most accurately reproduces the dynamical response of the system, as captured by time series data on methylenomycin production. Further analyses of variants of this model architecture that capture the effects of gene knockouts also reproduce qualitative experimental results observed in mutant S. coelicolor strains. The mechanistic mathematical model developed in this study recapitulates current biological knowledge of the regulation and biosynthesis of the methylenomycin producing gene cluster, and can be used in future studies to make testable predictions and formulate experiments to further improve our understanding of this complex regulatory system.
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DOI：
10.1073/pnas.0805530105
发表时间：
2008-11-11
影响因子：
11.1
作者：
Corre, Christophe;Song, Lijiang;Challis, Gregory L.
通讯作者：
Challis, Gregory L.
影响因子：
3.2
作者：
Corre, C;Challis, GL
通讯作者：
Challis, GL
影响因子：
3.2
作者：
HOBBS, G;OBANYE, AIC;OLIVER, SG
通讯作者：
OLIVER, SG
影响因子：
4.3
作者：
Woods, Mae L.;Barnes, Chris P.
通讯作者：
Barnes, Chris P.
影响因子：
3.6
作者：
O'Rourke, Sean;Wietzorrek, Andreas;Chater, Keith F.
通讯作者：
Chater, Keith F.