Soil dwelling Streptomyces species are faced with large variations in carbon or nitrogen sources, phosphate, oxygen, iron, sulfur, and other nutrients. These drastic changes in key nutrients result in an unbalanced metabolism that have undesirable consequences for growth, cell differentiation, reproduction, and secondary metabolites biosynthesis. In the last decades evidence has accumulated indicating that mechanisms to correct metabolic unbalances in Streptomyces species take place at the transcriptional level, mediated by different transcriptional factors. For example, the master regulator PhoP and the large SARP-type regulator AfsR bind to overlapping sequences in the afsS promoter and, therefore, compete in the integration of signals of phosphate starvation and S-adenosylmethionine (SAM) concentrations. The cross-talk between phosphate control of metabolism, mediated by the PhoR-PhoP system, and the pleiotropic orphan nitrogen regulator GlnR, is very interesting; PhoP represses GlnR and other nitrogen metabolism genes. The mechanisms of control by GlnR of several promoters of ATP binding cassettes (ABC) sugar transporters and carbon metabolism are highly elaborated. Another important cross-talk that governs nitrogen metabolism involves the competition between GlnR and the transcriptional factor MtrA. GlnR and MtrA exert opposite effects on expression of nitrogen metabolism genes. MtrA, under nitrogen rich conditions, represses expression of nitrogen assimilation and regulatory genes, including GlnR, and competes with GlnR for the GlnR binding sites. Strikingly, these sites also bind to PhoP. Novel examples of interacting transcriptional factors, discovered recently, are discussed to provide a broad view of this interactions. Altogether, these findings indicate that cross-talks between the major transcriptional factors protect the cell metabolic balance. A detailed analysis of the transcriptional factors binding sequences suggests that the transcriptional factors interact with specific regions, either by overlapping the recognition sequence of other factors or by binding to adjacent sites in those regions. Additional interactions on the regulatory backbone are provided by sigma factors, highly phosphorylated nucleotides, cyclic dinucleotides, and small ligands that interact with cognate receptor proteins and with TetR-type transcriptional regulators. We propose to define the signal integration DNA regions (so called integrator sites) that assemble responses to different stress, nutritional or environmental signals. These integrator sites constitute nodes recognized by two, three, or more transcriptional factors to compensate the unbalances produced by metabolic stresses. This interplay mechanism acts as a safety net to prevent major damage to the metabolism under extreme nutritional and environmental conditions.

中文翻译：

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平衡代谢安全网：链霉菌及相关放线菌中转录因子相互作用引起的应激信号整合。

居住在土壤中的链霉菌种面临着碳或氮源，磷酸盐，氧气，铁，硫和其他养分的巨大差异。关键营养素的这些急剧变化会导致新陈代谢失衡，从而对生长，细胞分化，繁殖和次生代谢产物的生物合成产生不良影响。在过去的几十年中，已有证据表明，纠正链霉菌属物种代谢不平衡的机制是在转录水平上发生的，由不同的转录因子介导。例如，主调节剂PhoP和大SARP型调节剂AfsR与afsS启动子中的重叠序列结合，因此竞争磷酸饥饿和S-腺苷甲硫氨酸（SAM）浓度的信号整合。由PhoR-PhoP系统介导的磷酸盐代谢控制与多效孤儿氮调节剂GlnR之间的相互作用非常有趣。PhoP抑制GlnR和其他氮代谢基因。高度详细地阐述了由GlnR控制ATP结合盒（ABC）糖转运蛋白的几个启动子和碳代谢的机制。控制氮代谢的另一个重要串扰涉及GlnR和转录因子MtrA之间的竞争。GlnR和MtrA对氮代谢基因的表达具有相反的作用。在富氮条件下，MtrA抑制氮同化和调节基因（包括GlnR）的表达，并与GlnR竞争GlnR结合位点。令人惊讶的是，这些位点也与PhoP结合。相互作用的转录因子的新例子，对最近发现的内容进行了讨论，以提供对此交互作用的广泛了解。总而言之，这些发现表明主要转录因子之间的串扰保护了细胞代谢平衡。对转录因子结合序列的详细分析表明，转录因子通过重叠其他因子的识别序列或结合到那些区域中的相邻位点来与特定区域相互作用。调节主链上的其他相互作用由sigma因子，高度磷酸化的核苷酸，环状二核苷酸和与同源受体蛋白以及TetR型转录调节因子相互作用的小配体提供。我们建议定义信号整合DNA区域（所谓的整合位点），以整合对不同压力的响应，营养或环境信号。这些整合位点构成被两个，三个或更多个转录因子识别的节点，以补偿由代谢应激产生的不平衡。这种相互作用机制可作为安全网，以防止在极端营养和环境条件下对新陈代谢的重大破坏。