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国际分子科学杂志2022年12月; 23（23）：15085。
Two-Component Systems of Streptomyces coelicolor: An Intricate Network to Be Unraveled
天蓝色链霉菌的双组分系统：一个有待解开的复杂网络
Andreas Burkovski，学术编辑和Georg A. Sprenger，学术编辑
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Associated Data 关联数据
Abstract 摘要
Bacteria of the Streptomyces genus constitute an authentic biotech gold mine thanks to their ability to produce a myriad of compounds and enzymes of great interest at various clinical, agricultural, and industrial levels. Understanding the physiology of these organisms and revealing their regulatory mechanisms is essential for their manipulation and application. Two-component systems (TCSs) constitute the predominant signal transduction mechanism in prokaryotes, and can detect a multitude of external and internal stimuli and trigger the appropriate cellular responses for adapting to diverse environmental conditions. These global regulatory systems usually coordinate various biological processes for the maintenance of homeostasis and proper cell function. Here, we review the multiple TCSs described and characterized in Streptomyces coelicolor, one of the most studied and important model species within this bacterial group. TCSs are involved in all cellular processes; hence, unravelling the complex regulatory network they form is essential for their potential biotechnological application.
链霉菌属的细菌构成了一个真正的生物技术金矿，这要归功于它们能够产生无数的化合物和酶，这些化合物和酶在各种临床、农业和工业水平上都有很大的意义。了解这些生物体的生理和揭示其调控机制是必不可少的，他们的操纵和应用。双组分系统（Two-component systems，TCSs）是原核生物中最重要的信号转导机制，能够检测多种内外刺激，并触发相应的细胞反应以适应不同的环境条件。这些全局调节系统通常协调各种生物过程以维持稳态和适当的细胞功能。在这里，我们回顾了多个TCS的描述和特征在于天蓝色链霉菌，在这个细菌群中研究最多的和重要的模式物种之一。 TCS参与所有细胞过程;因此，解开它们形成的复杂调控网络对其潜在的生物技术应用至关重要。
关键词：链霉菌，双组分系统，信号转导和调控，分子微生物学
1. Streptomyces, the Biotech Gold Mine
1.链霉菌，生物技术金矿
Rapamycin, ivermectin, chloramphenicol, kanamycin, cycloheximide, and doxorubicin, among others, all key compounds for human medicine, are synthetized by bacteria of the genus Streptomyces. In addition to these compounds, a myriad of antibiotics, antifungals, antiparasitic agents, antivirals, immunosuppressors, antitumoral agents, and even multiple hydrolytic enzymes of great industrial value are produced by this group of microorganisms which act as an authentic biotech gold mine [1,2]. Moreover, owing to advances in sequencing genomes, it has been observed that these organisms contain a multitude of cryptic biosynthetic gene clusters (BCGs) that remain silent. As a consequence, their true potential as producers of compounds of biotechnological interest is much greater than initially estimated [3,4]. Based on these characteristics, much interest has been sparked in understanding the physiology of these bacteria, as well as unravelling the underlying regulatory mechanisms, that would allow for their manipulation and application.
雷帕霉素、伊维菌素、氯霉素、卡那霉素、放线菌酮和多柔比星等都是人类药物的关键化合物，都是由链霉菌属的细菌合成的。除了这些化合物，大量的抗生素，抗真菌剂，抗寄生虫剂，抗病毒药，免疫抑制剂，抗肿瘤剂，甚至多种具有巨大工业价值的水解酶都是由这组微生物产生的，它们作为真正的生物技术金矿[ 1，2]。此外，由于基因组测序的进展，已经观察到这些生物体含有大量保持沉默的隐蔽生物合成基因簇（BCGs）。因此，它们作为生物技术化合物生产者的真正潜力比最初估计的要大得多[ 3，4]。 基于这些特征，人们对了解这些细菌的生理学以及揭示潜在的调控机制产生了很大的兴趣，这将允许它们的操纵和应用。
At the taxonomic level, the genus Streptomyces forms part of the Bacteria superkingdom, the Actinomycetota phylum, the Actinomycetia class, the Streptomycetales order, and the Streptomycetaceae family [5,6]. These microorganisms are characterized as filamentous multicellular bacteria that are Gram-positive, facultatively aerobic, mesophilic, neutrophilic, and chemoorganotrophic, with an oxidative metabolism [7]. Concerning their life cycle, these bacteria develop a vegetative mycelium and an aerial mycelium that forms chains of immobile reproductive spores [7,8]. At the genomic level, these bacteria usually have a linear chromosome of 6–12 Mbp, with approximately 70% of GC content. The chromosomes are structured in a central region which is relatively conserved between different species and is where the essential genes are concentrated. The end of each chromosome is genetically unstable, with reorganizations, deletions, insertions, and duplications recurrently occurring [9,10].
在分类学水平上，链霉菌属形成细菌超王国、放线菌门、放线菌纲、链霉菌目和链霉菌科的一部分[ 5，6]。这些微生物被表征为丝状多细胞细菌，其为革兰氏阳性、兼性需氧、嗜中温、嗜酸性和化能有机营养型，具有氧化代谢[ 7]。考虑到它们的生活史，这些细菌发育出营养菌丝体和气生菌丝体，气生菌丝体形成固定的生殖孢子链[ 7，8]。在基因组水平上，这些细菌通常具有6-12 Mbp的线性染色体，具有约70%的GC含量。染色体结构在不同物种之间相对保守的中心区域，是必需基因集中的地方。每个染色体的末端在遗传上都是不稳定的，重组、缺失、插入和重复会反复发生[ 9，10]。
The main habitat of Streptomycetes is soil, which is an extremely complex and dynamic environment exposed to a diverse array of biotic and abiotic factors. It is also here that Streptomycetes play an essential role in nutrient recycling as saprophytic organisms [7,8], owing to the genomic plasticity, metabolic diversity, and complex regulatory networks they have developed. However, they have also been found in other ecological niches, such as marine environments [11,12,13], and even form part of the microbiota of other organisms [14,15].
链霉菌的主要栖息地是土壤，这是一个极其复杂和动态的环境，暴露于各种生物和非生物因素。也正是在这里，链霉菌作为腐殖生物在营养循环中发挥着至关重要的作用[ 7，8]，这是由于它们开发的基因组可塑性，代谢多样性和复杂的调控网络。然而，它们也被发现在其他生态环境中，如海洋环境[ 11，12，13]，甚至形成其他生物的微生物群的一部分[ 14，15]。
Additionally, both beneficial and harmful interactions with other organisms have been described. For example, certain insects use antibiotic-producing Streptomycetes to protect their resources [16,17], while some xylophagous beetles establish a commensalism relationship with some of these bacteria capable of degrading cellulosic substrates [18,19]. In the case of plants, some Streptomycetes which promote growth and act as biological control agents have been identified [20,21], whereas others are known to act as phytopathogens [22], all of which make these bacteria interesting from an agricultural perspective. Finally, although most of these bacteria are not harmful to humans, species such as Streptomyces somaliensis and Streptomyces sudanensis can cause mycetoma [23,24].
此外，已经描述了与其他生物体的有益和有害的相互作用。例如，某些昆虫使用产纤维素的链霉菌来保护它们的资源[ 16，17]，而一些食木甲虫与这些能够降解纤维素底物的细菌中的一些建立了共生关系[ 18，19]。在植物的情况下，已经鉴定了一些促进生长并充当生物控制剂的链霉菌[ 20，21]，而已知其他链霉菌充当植物病原体[ 22]，所有这些都使这些细菌从农业角度来看是有趣的。最后，虽然这些细菌中的大多数对人类无害，但诸如索马里链霉菌和苏丹链霉菌等物种可引起足菌肿[ 23，24]。
Within this group of microorganisms, S. coelicolor is one of the main model species, as it is one of the first to be morphologically and genetically characterized [25,26], and has been extensively studied at all levels during the past few decades. One of the main interests regarding this species is its applicability in understanding the regulatory mechanisms of antibiotic production. This species contains several synthesis clusters in its chromosome associated with actinorhodin (ACT), undecylprodigiosin (RED), and calcium-dependent antibiotic (CDA) production, of which the first two are colored, a characteristic that has been central to their experimental use.
在这组微生物中，S. coelicolor是主要的模式物种之一，因为它是第一个在形态学和遗传学上有特征的物种[ 25，26]，在过去几十年中，在各个层面上都得到了广泛的研究。关于该物种的主要兴趣之一是其在理解抗生素生产的调节机制方面的适用性。该物种在其染色体中含有几个与放线菌紫素（ACT），十一烷基灵菌红素（RED）和钙依赖性抗生素（CDA）生产相关的合成簇，其中前两个是有色的，这是其实验用途的核心特征。
2. Two-Component Systems: Essential Signal Transduction Systems for Bacteria
2.双组分系统：细菌的基本信号转导系统
All organisms are exposed to a multitude of environmental and internal signals that must be detected, integrated, and processed if an organism is to appropriately react and adapt to its surrounding conditions. In response to these signals, numerous signal transduction mechanisms carry out this function, which in the case of prokaryotic organisms are predominantly the so-called two-component systems (TCSs) [27,28].
所有生物体都暴露于大量的环境和内部信号，如果生物体要适当地反应和适应其周围条件，则必须检测，整合和处理这些信号。响应于这些信号，许多信号转导机制执行该功能，在原核生物的情况下，其主要是所谓的双组分系统（TCS）[ 27，28]。
TCSs act as global regulatory systems able to detect external and internal stimuli, triggering cellular responses. TCSs are also involved in all the biological functions of the organism, from growth to intercellular communication, through different metabolic processes and responses to different types of stress. They generally act as pleiotropic regulators that coordinate various biological processes to maintain homeostasis and proper cell function [29].
TCS作为全球监管系统，能够检测外部和内部刺激，触发细胞反应。TCS还参与生物体的所有生物功能，从生长到细胞间通讯，通过不同的代谢过程和对不同类型压力的反应。它们通常作为多效性调节剂，协调各种生物过程以维持稳态和适当的细胞功能[ 29]。
As the name suggests, TCSs are usually composed of two components: a sensor element called histidine kinase (HK), responsible for the perception of certain signals, and an effector element called a response regulator (RR), responsible for generating a cellular response to these signals. In general, the signaling cascade (Figure 1) begins with the perception of a specific stimulus by the HK, which results in its activation and autophosphorylation in a histidine residue. Subsequently, the phosphoryl group is transferred to an aspartate residue of the RR, which triggers its activation and allows it to carry out its function and generate a cellular response [30].
顾名思义，TCS通常由两种成分组成：一种称为组氨酸激酶（HK）的传感元件，负责感知某些信号，另一种称为反应调节因子（RR）的效应元件，负责对这些信号产生细胞反应。一般来说，信号级联（图1）始于HK对特定刺激的感知，这导致其激活和组氨酸残基中的自磷酸化。随后，磷酰基被转移到RR的天冬氨酸残基上，从而触发其激活并允许其执行其功能并产生细胞反应[ 30]。
Molecular mechanism of action of a two-component system: (1) if the activation signal is absent, the TCS remains inactive; (2) when the signal appears, the HK autophosphorylates a His residue (H) of the dimerization/phosphotransfer domain (DHp) through the catalytic ATP-binding domain (CA), which requires ATP; (3) the HK transfers the phosphoryl group via its His to an Asp residue (D) of the REC domain of the RR; (4) the RR generally dimerizes and triggers the cellular response, usually through the regulation of gene expression; (5) finally, the signaling cascade inactivates thanks to the dephosphorylation of the RR, usually through its own HK. The different domains of the canonical HK and RR are indicated on the left-side of the figure.
双组分系统的分子作用机制：（1）如果没有激活信号，TCS保持失活状态;（2）当信号出现时，HK通过催化ATP结合结构域（CA）自磷酸化二聚化/磷酸转移结构域（DHp）的His残基（H），这需要ATP;（3）HK通过其His将磷酰基转移到RR的REC结构域的Asp残基（D）;（4）RR通常二聚化并触发细胞应答，通常通过调节基因表达;（5）最后，由于RR的去磷酸化，信号级联失活，通常通过其自身的HK。在图的左侧指示了规范HK和RR的不同域。
HKs are usually embedded in the plasmatic membrane and form homodimers, although completely cytosolic HKs have also been described. The canonical architecture of an HK consists of a sensor domain, a transmembrane domain, a transmitter domain, a dimerization/phosphotransfer domain (DHp) containing the histidine residue that is phosphorylated, and an ATP-binding domain (CA) with kinase activity (Figure 1). The latter two domains constitute the catalytic core of an HK [27,28,31]. The variety of stimuli, both physical and chemical, that an HK can detect is immense, including temperature, light, oxygen concentration, different types of nutrients, and antibiotics, among other stimuli [32,33]. This is one of the reasons why the activation signals of most of the TCSs described are still unknown. Apart from this canonical architecture, there is another group of hybrid histidine kinases (hHKs) [30,32] that are characterized by the presence of additional phosphoacceptor receiver (REC), HPt, and/or DHp domains, which result in phosphotransfer events in the HK protein itself. The REC domain normally present in the RR has a phosphorylatable aspartate residue, while the HPt domain has a phosphorylatable histidine residue, although, unlike the DHp, they do not have a dimerization function. However, it is remarkable that the phosphotransfer process always takes place following the His→Asp→His→Asp scheme [30,32].
HK通常嵌入质膜并形成同源二聚体，尽管也描述了完全胞质的HK。HK的典型结构由传感器结构域、跨膜结构域、递质结构域、含有磷酸化组氨酸残基的二聚化/磷酸转移结构域（DHp）和具有激酶活性的ATP结合结构域（CA）组成（图1）。后两个结构域构成HK的催化核心[ 27，28，31]。HK可以检测到的各种物理和化学刺激是巨大的，包括温度，光线，氧气浓度，不同类型的营养素和抗生素，以及其他刺激[ 32，33]。这就是为什么所描述的大多数TCS的激活信号仍然未知的原因之一。 除了这种典型的结构，还有另一组杂合组氨酸激酶（hHK）[ 30，32]，其特征在于存在额外的磷酸受体受体（REC）、HPt和/或DHp结构域，这导致HK蛋白本身的磷酸转移事件。通常存在于RR中的REC结构域具有可磷酸化的天冬氨酸残基，而HPt结构域具有可磷酸化的组氨酸残基，尽管与DHp不同，它们不具有二聚化功能。然而，值得注意的是，磷酸转移过程总是按照His→Asp→His→Asp方案发生[ 30，32]。
RRs are cytosolic proteins that contain two domains: a receptor domain (REC) and an effector domain (Figure 1) [28,31]. The REC domain is present in all RRs and contains the aspartate residue that is phosphorylated by the HK through phosphotransfer, a process that results in the activation of this protein. This domain is also responsible for controlling RR oligomerization processes that take place after its activation [28,31]. The phosphorylation site is defined by a group of highly conserved key residues, except in the case of atypical RRs (aRRs) that present alternative mechanisms of activation [34]. The effector domain triggers the cellular responses, normally through the modulation of gene expression since it is usually a DNA-binding domain. However, RNA-binding domains, protein-binding domains, and domains with enzymatic activity have also been identified (sometimes is even absent) [35,36].
RR是含有两个结构域的胞质蛋白：受体结构域（REC）和效应子结构域（图1）[ 28，31]。REC结构域存在于所有RR中，并含有天冬氨酸残基，该残基通过磷酸转移被HK磷酸化，该过程导致该蛋白的活化。该结构域还负责控制其激活后发生的RR寡聚化过程[ 28，31]。磷酸化位点由一组高度保守的关键残基定义，但非典型RR（aRR）除外，其存在替代的激活机制[ 34]。效应结构域通常通过调节基因表达来触发细胞反应，因为它通常是DNA结合结构域。然而，RNA结合结构域、蛋白质结合结构域和具有酶活性的结构域也已被鉴定（有时甚至不存在）[35，36]。
Each HK is usually associated with a particular RR, forming a functional couple; normally, these HK-RR pairs are also together at the genomic level in the same operon [37]. The interaction between a HK and its associated RR is highly specific, which is key to proper cell function, since at certain times there may be a multitude of TCSs acting simultaneously. The specificity code depends on a set of amino acids mainly present in the DHp domain of the HK and in the REC domain of the RR, through which the interaction between the two proteins for the phosphotransfer process occurs [30,38]. This recognition at the molecular level establishes a kinetic preference between both proteins, which prevents non-specific interactions with other HKs and RRs [39,40]. Although crosstalk events between different TCSs have been described, these non-specific interactions do not appear to be relevant at the physiological level.
每个HK通常与特定的RR相关联，形成功能性配对;通常，这些HK-RR对也在基因组水平上在同一操纵子中一起[ 37]。HK与其相关RR之间的相互作用是高度特异性的，这是正常细胞功能的关键，因为在某些时候可能有大量TCS同时起作用。特异性密码取决于主要存在于HK的DHp结构域和RR的REC结构域中的一组氨基酸，通过这些氨基酸，两种蛋白质之间发生相互作用以进行磷酸转移过程[ 30，38]。分子水平上的这种识别在两种蛋白质之间建立了动力学偏好，这防止了与其他HK和RR的非特异性相互作用[ 39，40]。虽然已经描述了不同TCS之间的串扰事件，但这些非特异性相互作用似乎在生理水平上不相关。
However, it is not uncommon to observe the presence of orphan HKs (oHKs) and orphan RRs (oRRs) in the bacterial genomes, for which there are no associated pairs at the genomic level; however, this does not mean that there are no associated pairs at the functional level [34]. An oHK and an oRR can be functionally associated with each other [41,42] or participate in the signaling cascade of a TCS as another component of the transduction route [43]. The prediction of the functional pairs of these oHKs and oRRs is still a serious obstacle, despite the efforts made using algorithms to predict protein–protein interactions.
然而，在细菌基因组中观察到孤儿HK（oHK）和孤儿RR（oRR）的存在并不罕见，在基因组水平上没有相关配对;然而，这并不意味着在功能水平上没有相关配对[ 34]。oHK和oRR可以在功能上相互关联[ 41，42]或作为转导途径的另一组分参与TCS的信号级联[ 43]。这些oHK和oRR的功能对的预测仍然是一个严重的障碍，尽管使用算法来预测蛋白质-蛋白质相互作用的努力。
TCSs are involved in the regulation and coordination of a multitude of biological processes. Since these signaling cascades must respond dynamically, there are different modulation mechanisms such as the control of the expression levels of HKs and RRs, the modification of the phosphorylation state of RRs, the cross-regulation of the TCS, nonlinear signaling cascades, and the regulation of the TCS through feedback from their targets [37]. All of these mechanisms modulate the amount of phosphorylated RRs, which is what defines the level of activation of a given TCS.
TCS参与多种生物过程的调节和协调。由于这些信号级联必须动态响应，因此存在不同的调节机制，例如HK和RR表达水平的控制、RR磷酸化状态的修饰、TCS的交叉调节、非线性信号级联以及通过来自其靶标的反馈调节TCS [ 37]。所有这些机制都调节磷酸化RR的量，这是定义给定TCS激活水平的量。
3. Two-Component Systems of Streptomyces coelicolor
3.天蓝色链霉菌的双组分体系
The species S. coelicolor presents a large number of TCSs, specifically 110 HKs and 87 RRs, based on the P2CS (http://www.p2cs.org/; accessed on 27 May 2022) and P2RP (http://www.p2rp.org/; accessed on 3 June 2022) databases. The HKs have been classified based on their architecture, being either classic or hybrid (Figure 2), while RRs have been classified based on the type of effector domain they contain (Figure 2). These can include DNA-binding domains (NarL, OmpR, IclR, and LytTR), an RNA-binding domain (AmiR), enzymatic activity (RssB, TrxB, and ATPase), or the absence of an effector domain (REC only).
S. coelicolor基于P2CS（http：//www.p2cs.org/;于2022年5月27日访问）和P2 RP（http：//www.p2rp.org/;于2022年6月3日访问）数据库提供了大量TCS，具体为110个HK和87个RR。HK已根据其结构进行分类，为经典型或杂合型（图2），而RR已根据其所含效应结构域的类型进行分类（图2）。这些可以包括DNA结合结构域（NarL、OmpR、IclR和LytTR）、RNA结合结构域（AmiR）、酶活性（RssB、TrxB和ATP酶）或不存在效应子结构域（仅REC）。
Classification of HKs (top image) and RRs (bottom image) from S. coelicolor. In the case of the HKs, the predicted domain architectures of hybrid HKs are shown (based on InterPro). With respect to the RR, the subfamilies of each type of effector domain are indicated. Data were collected from the P2CS and P2RP databases.
来自S.天蓝色。在HK的情况下，示出了混合HK的预测结构域架构（基于InterPro）。关于RR，指示了每种类型的效应子结构域的亚家族。数据来自P2CS和P2RP数据库。
These proteins are organized into 66 HK-RR pairs and 2 triads (one of which two HKs and one RR and the other one with one HK and two RRs). The remaining proteins remain as orphan systems: 41 oHKs and 18 oRRs. The complete list is shown in Table 1.
这些蛋白质被组织成66个HK-RR对和2个三联体（其中一个具有两个HK和一个RR，另一个具有一个HK和两个RR）。剩余的蛋白质保持为孤儿系统：41个oHK和18个oRR。完整列表见表1。
Table 1 表1
TCSs of S. coelicolor. All HKs and RRs identified in this bacterium are indicated. They are listed in the SCO number and have been organized based on the pairs or triads they form at the genomic level since it usually indicates a functional association (orphans are indicated individually). The family to which they belong is included; in the case of the HKs, this is based on the architecture of the protein domains, while for the RRs, the type of effector domain is taken in account. The order in which the genes are found at the genomic level is also indicated.
S.天蓝色。指出了在该细菌中鉴定的所有HK和RR。它们被列在SCO编号中，并根据它们在基因组水平上形成的配对或三联体进行组织，因为它通常表示功能关联（单独表示孤儿）。包括它们所属的家族;对于HK，这是基于蛋白质结构域的架构，而对于RR，则考虑效应结构域的类型。还指出了基因在基因组水平上发现的顺序。
| Histidine Kinase (HK) 组氨酸激酶（HK） | Response Regulator (RR) 响应调节器（RR） | Organization 组织 (5′→3′) （5′→3′） | ||||
|---|---|---|---|---|---|---|
| Gene 基因 | Name 名称 | Family 家庭 | Gene 基因 | Name 名称 | Family 家庭 | |
| SCO0203 | OsdK/DevS | Classic 经典 | SCO0204 | OsdR/DevR | NarL 纳尔 | RR-HK |
| SCO0211 | - | Classic 经典 | oHK | |||
| SCO0422 | - | Classic 经典 | SCO0421 | - | NarL 纳尔 | HK-RR |
| SCO0551 | - | Classic 经典 | SCO0552 | - | OmpR | RR-HK |
| SCO0588 | CvnA11 | Classic 经典 | oHK | |||
| SCO0599 | - | Classic 经典 | oHK | |||
| SCO0676 | - | Classic 经典 | oHK | |||
| SCO0767 | - | Classic 经典 | oHK | |||
| SCO0871 | - | Classic 经典 | SCO0870 | - | CheY | RR-HK-RR |
| SCO0872 | - | RssB | ||||
| SCO0946 | - | Classic 经典 | oHK | |||
| SCO1071 | - | Classic 经典 | SCO1070 | - | NarL 纳尔 | HK-RR |
| SCO1137 | - | Classic 经典 | SCO1136 | - | IclR | HK-RR |
| SCO1160 | CvnA3 | Classic 经典 | oHK | |||
| SCO1217 | - | Classic 经典 | oHK | |||
| SCO1220 | - | LytTR | oRR | |||
| SCO1259 | - | Classic 经典 | SCO1260 | - | NarL 纳尔 | HK-RR |
| SCO1369 | - | Classic 经典 | SCO1370 | - | NarL 纳尔 | HK-RR |
| SCO1402 | CvnA4 | Classic 经典 | oHK | |||
| SCO1596 | OhkA | Classic 经典 | oHK | |||
| SCO1630 | CvnA9 cvna 9的 | Classic 经典 | oHK | |||
| SCO1654 | - | NarL 纳尔 | oRR | |||
| SCO1744 | AbrA1 ABRA 1 | Classic 经典 | SCO1745 | AbrA2 AbrA 2的 | NarL 纳尔 | HK-RR |
| SCO1802 | - | Classic 经典 | SCO1801 | - | NarL 纳尔 | HK-RR |
| SCO2013 | PdtaR | AmiR | oRR | |||
| SCO2121 | MacS | Classic 经典 | SCO2120 | MacR | NarL 纳尔 | HK-RR |
| SCO2142 | - | Classic 经典 | SCO2143 | - | OmpR | HK-RR |
| SCO2152 | - | CheY | oRR | |||
| SCO2166 | AbrB2 abrb 2 | Classic 经典 | SCO2165 | AbrB1 abrb 1 | NarL 纳尔 | HK-RR |
| SCO2215 | - | Classic 经典 | SCO2216 | - | NarL 纳尔 | HK-RR |
| SCO2281 | Aor1 aor 1 | NarL 纳尔 | oRR | |||
| SCO2307 | - | Classic 经典 | SCO2308 | - | NarL 纳尔 | HK-RR |
| SCO2359 | - | Classic 经典 | SCO2358 | - | NarL 纳尔 | HK-RR |
| SCO2452 | - | Classic 经典 | oHK | |||
| SCO2518 | EcrA1 ECRA 1 | Classic 经典 | SCO2517 | EcrA2 ECRA 2的 | NarL 纳尔 | HK-RR |
| SCO2800 | - | Classic 经典 | SCO2801 | - | OmpR | RR-HK |
| SCO2879 | CvnA12 CVNA 12 | Classic 经典 | oHK | |||
| SCO3008 | OrrA | NarL 纳尔 | oRR | |||
| SCO3012 | MtrB | Classic 经典 | SCO3013 | MtrA | OmpR | RR-HK |
| SCO3062 | DraK | Classic 经典 | SCO3063 | DraR | OmpR | RR-HK |
| SCO3119 | - | Classic 经典 | oHK | |||
| SCO3134 | - | NarL 纳尔 | oRR | |||
| SCO3144 | - | NarL | oRR | |||
| SCO3225 | AbsA1 | Classic | SCO3226 | AbsA2 | NarL | HK-RR |
| SCO3284 | - | Classic | oHK | |||
| SCO3359 | CseC | Classic | SCO3358 | CseB | OmpR | RR-HK |
| SCO3390 | SatK | Classic | SCO3389 | SatR | NarL | HK-RR |
| SCO3589 | VanS | Classic | SCO3590 | VanR | OmpR | RR-HK |
| SCO3639 | - | Classic | SCO3638 | - | NarL | HK-RR |
| SCO3641 | - | Classic | SCO3640 | - | NarL | HK-RR |
| SCO3654 | - | Classic | SCO3653 | - | NarL | HK-RR |
| SCO3740 | - | Classic | SCO3741 | - | OmpR | RR-HK |
| SCO3750 | - | Classic | oHK | |||
| SCO3757 | - | Classic | SCO3756 | - | NarL | HK-RR |
| SCO3796 | - | Classic | oHK | |||
| SCO3818 | - | NarL | oRR | |||
| SCO3948 | - | Classic | oHK | |||
| SCO4009 | - | Hybrid | oHK | |||
| SCO4021 | - | Classic | SCO4020 | - | OmpR | RR-HK |
| SCO4073 | RagK | Classic | SCO4072 | RagR | NarL | HK-RR |
| SCO4120 | - | Classic | oHK | |||
| SCO4124 | - | Classic | SCO4123 | - | NarL | HK-RR |
| SCO4155 | CssS | Classic | SCO4156 | CssR | OmpR | RR-HK |
| SCO4159 | GlnR | OmpR | oRR | |||
| SCO4201 | - | RssB | oRR | |||
| SCO4229 | PhoR | Classic | SCO4230 | PhoP | OmpR | HK-RR |
| SCO4275 | SenS | Classic | SCO4276 | SenR | NarL | HK-RR |
| SCO4362 | - | Classic | SCO4363 | - | NarL | HK-RR |
| SCO4597 | AbrC2 | Classic | SCO4596 | AbrC3 | NarL | HK-HK-RR |
| SCO4598 | AbrC1 | Classic | ||||
| SCO4667 | SitK | Classic | SCO4668 | SitR | NarL | HK-RR |
| SCO4768 | BldM | NarL | oRR | |||
| SCO4791 | - | Classic | SCO4792 | - | NarL | HK-RR |
| SCO4906 | AfsQ2 | Classic | SCO4907 | AfsQ1 | OmpR | RR-HK |
| SCO5006 | - | ATPase | oRR | |||
| SCO5040 | - | Classic | oHK | |||
| SCO5104 | - | Classic | oHK | |||
| SCO5131 | - | Classic | SCO5132 | - | NarL | HK-RR |
| SCO5239 | PdtaS | Classic | oHK | |||
| SCO5282 | - | Classic | SCO5283 | - | OmpR | RR-HK |
| SCO5289 | CvnA5 | Classic | oHK | |||
| SCO5304 | - | Classic | oHK | |||
| SCO5351 | - | CheY | oRR | |||
| SCO5378 | ChiS | Classic | SCO5377 | ChiR | NarL | HK-RR |
| SCO5404 | RapA2 | Classic | SCO5403 | RapA1 | OmpR | RR-HK |
| SCO5435 | - | Classic | SCO5434 | - | IclR | HK-RR |
| SCO5454 | - | Classic | SCO5455 | - | NarL | HK-RR |
| SCO5460 | - | Classic | oHK | |||
| SCO5540 | CvnA2 | Classic | oHK | |||
| SCO5544 | CvnA1 | Classic | oHK | |||
| SCO5683 | - | Classic | SCO5684 | - | NarL | HK-RR |
| SCO5748 | OsaA | Hybrid | SCO5749 | OsaB | OsaB | HK-RR |
| SCO5779 | GluK | Classic | SCO5778 | GluR | OmpR | RR-HK |
| SCO5784 | - | Classic | SCO5785 | - | NarL | HK-RR |
| SCO5824 | - | Classic | SCO5825 | - | NarL | HK-RR |
| SCO5829 | - | Classic | SCO5828 | - | NarL | HK-RR |
| SCO5863 | CutS | Classic | SCO5862 | CutR | OmpR | RR-HK |
| SCO5871 | KdepD | Classic | SCO5872 | KdpE | OmpR | HK-RR |
| SCO5881 | RedZ | NarL | oRR | |||
| SCO6029 | WhiI | NarL | oRR | |||
| SCO6069 | CvnA6 | Classic | oHK | |||
| SCO6139 | - | Classic | SCO6140 | - | NarL | HK-RR |
| SCO6163 | - | Classic | SCO6162 | - | NarL | HK-RR |
| SCO6253 | - | Classic | SCO6254 | - | NarL | HK-RR |
| SCO6268 | - | Classic | oHK | |||
| SCO6353 | - | Classic | SCO6354 | - | OmpR | RR-HK |
| SCO6362 | - | Classic | SCO6363 | - | NarL | HK-RR |
| SCO6364 | - | OmpR | oRR | |||
| SCO6369 | - | Classic | oHK | |||
| SCO6421 | EcrE1 | Classic | SCO6422 | EcrE2 | NarL | HK-RR |
| SCO6424 | - | Classic | oHK | |||
| SCO6484 | - | Classic | oHK | |||
| SCO6668 | - | Classic | SCO6667 | - | NarL | HK-RR |
| SCO6685 | RamR | NarL | oRR | |||
| SCO6794 | CvnA7 | Classic | oHK | |||
| SCO6943 | CvnA8 | Classic | oHK | |||
| SCO7009 | - | Classic | oHK | |||
| SCO7076 | - | Classic | SCO7075 | - | OmpR | RR-HK |
| SCO7089 | - | Classic | SCO7088 | - | NarL | HK-RR |
| SCO7220 | - | Classic | oHK | |||
| SCO7231 | - | Classic | SCO7230 | - | OmpR | RR-HK |
| SCO7297 | - | Classic | SCO7298 | - | TrxB | RR-HK |
| SCO7327 | - | Hybrid | oHK | |||
| SCO7354 | - | Classic | oHK | |||
| SCO7422 | CvnA10 | Classic | oHK | |||
| SCO7463 | CvnA13 | Classic | oHK | |||
| SCO7534 | - | Classic | SCO7533 | - | OmpR | RR-HK |
| SCO7649 | - | Classic | SCO7648 | - | NarL | HK-RR |
| SCO7711 | - | Classic | SCO7712 | - | NarL | HK-RR |
The different TCSs described in the literature are detailed below. They are listed in alphabetical order and there is a focus on their biological role and/or molecular mechanisms of action.
文献中描述的不同TCS详述如下。它们按字母顺序列出，重点是它们的生物作用和/或分子作用机制。
3.1. AbrA1/A2 (SCO1744/45)
3.1. AbrA1/A2（SCO1744/45）
This system has been described as a negative regulator of antibiotic production (ACT, RED, and CDA) and morphological differentiation [44]. The AbrA1/A2 TCS can self-regulate its expression since it acts as a positive regulator of its operon [45]. In addition, it has been observed that high levels of the AbrA2 RR in its phosphorylated state are toxic to the cell and that it is the AbrA1 HK that is responsible for maintaining an adequate balance of the level of phosphorylation of the RR through its phosphotransfer/phosphatase activities [45].
该系统已被描述为抗生素生产（ACT，RED和CDA）和形态分化的负调节因子[ 44]。AbrA 1/A2 TCS可以自我调节其表达，因为它充当其操纵子的正调节剂[ 45]。此外，已观察到高水平的磷酸化状态的AbrA 2 RR对细胞具有毒性，并且AbrA 1 HK负责通过其磷酸转移/磷酸酶活性维持RR磷酸化水平的充分平衡[ 45]。
At the genomic level, this TCS forms an operon with a potential ABC transport system encoded by the SCO1742/43 genes, which seems to be involved in its mechanism of action, although its role has not been determined.
在基因组水平上，该TCS与SCO 1742/43基因编码的潜在ABC转运系统形成操纵子，该操纵子似乎参与其作用机制，尽管其作用尚未确定。
At the biotechnological level, it is important to note that the strain lacking this TCS can act as a host strain with an improved capacity to produce heterologous compounds of interest, such as oviedomycin, which present antitumor and antibiotic activities [45].
在生物技术水平上，重要的是要注意，缺乏该TCS的菌株可以作为宿主菌株，其具有提高的生产异源目标化合物（例如具有抗肿瘤和抗生素活性的奥维霉素）的能力[ 45]。
It has been proposed that the activation signal of AbrA1 is iron since the self-induction capacity of this TCS depends on the level of this element [45].
有人提出AbrA 1的激活信号是铁，因为该TCS的自感应能力取决于该元素的水平[ 45]。
3.2. AbrB1/B2 (SCO2165/66)
3.2. AbrB1/B2（SCO2165/66）
This system has been described as a negative regulator of antibiotic production (ACT and RED) and a positive regulator of vancomycin resistance [46].
该系统已被描述为抗生素生产（ACT和RED）的负调节剂和万古霉素耐药性的正调节剂[ 46]。
This TCS is a homolog of VraR/S (Staphylococcus aureus) and LiaR/S (Enterococcus faecium), which act as sensors of cell wall damage and are involved in the cell envelope stress response, playing a key role in clinically relevant antibiotic-resistant bacteria [46].
该TCS是VraR/S（金黄色葡萄球菌）和LiaR/S（屎肠球菌）的同源物，其作为细胞壁损伤的传感器并参与细胞包膜应激反应，在临床相关的耐药细菌中发挥关键作用[ 46]。
3.3. AbrC1/C2/C3 (SCO4598/97/96)
3.3. AbrC1/C2/C3（SCO4598/97/96）
This atypical TCS consists of two HKs and one RR and has been described as a positive regulator of antibiotic production (ACT, RED, and CDA) and morphological differentiation [44,47]. It has been determined that the AbrC3 RR directly controls the specific regulator of the ACT synthesis pathway actII-ORF4, as well as other genes involved in different processes of primary metabolism, secondary metabolism, and morphological development; in addition, a potential binding sequence has been identified [47]. This system presents a cross-regulation with the AfsQ2/Q1 TCS [48].
这种非典型TCS由两个HK和一个RR组成，被描述为抗生素产生（ACT、RED和CDA）和形态分化的正调节因子[ 44，47]。已确定AbrC 3 RR直接控制ACT合成途径actII-ORF 4的特异性调节剂，以及参与初级代谢、次级代谢和形态发育的不同过程的其他基因;此外，还鉴定了潜在的结合序列[ 47]。该系统与AfsQ 2/Q1 TCS [ 48]存在交叉调节。
Both HKs (AbrC1 and AbrC2) show similar expression levels; however, the elimination of AbrC2 does not present clear phenotypic effects, unlike the elimination of AbrC1 which produces an increase in the production of antibiotics. These observations can be attributed to differences in the kinase/phosphatase functions of these HKs, although it has been seen that both can phosphorylate the AbrC3 RR [49]. In addition, it has been determined that high levels of AbrC3 in its phosphorylated state are toxic to the cells [49].
两种HK（AbrC 1和AbrC 2）显示出相似的表达水平;然而，AbrC 2的消除并不存在明确的表型效应，这与AbrC 1的消除不同，后者会增加抗生素的产量。这些观察结果可归因于这些HK的激酶/磷酸酶功能的差异，尽管已经发现两者都可以磷酸化AbrC 3 RR [ 49]。此外，已确定高水平的磷酸化状态的AbrC 3对细胞具有毒性[ 49]。
The fusion of the HKs AbrC1 and AbrC2, due to a deletion that covers part of the sequence of both genes (although maintaining the reading frame), gives rise to a chimeric HK called LinR. This mutation results in high resistance to lincomycin (an antibiotic that binds to ribosomes and inhibits protein synthesis), increases the production of the antibiotic ACT, and enhances morphological differentiation [50]. The heterologous expression of LinR in Escherichia coli confers resistance to lincomycin in this organism [50].
由于缺失了两个基因的部分序列（尽管保留了阅读框架），HK的AbrC1和AbrC2融合产生了称为LinR的嵌合HK。这种突变导致对林可霉素（一种结合核糖体并抑制蛋白质合成的抗生素）的高耐药性，增加抗生素ACT的产生，并增强形态分化[ 50]。LinR在大肠杆菌中的异源表达赋予该生物体对林可霉素的抗性[ 50]。
3.4. AbsA1/A2 (SCO3225/26)
3.4. AbsA1/A2（SCO3225/26）
This TCS was one of the first regulators of antibiotic production described in [51]. This system has been established as a negative regulator of the production of the antibiotics ACT, RED, and CDA [52,53,54,55,56], through the direct regulation of the specific regulators of the synthesis pathways actII-ORF4, redZ, and cdaR [55,57]. In the case of the regulation of CDA synthesis, it has been observed that AbsA2 is also able to directly regulate several genes of the cda cluster [55]. Furthermore, it has been found that this regulation depends on the phosphorylation state of the AbsA2 RR, which is controlled by the balance of kinase/phosphatase activities of the AbsA1 HK [58].
该TCS是[ 51]中描述的抗生素生产的第一个调节剂之一。通过直接调节合成途径actII-ORF 4、redZ和cdaR的特异性调节剂，该系统已被确立为抗生素ACT、RED和CDA生产的负调节剂[ 52、53、54、55、56][ 55、57]。在调节CDA合成的情况下，已经观察到AbsA 2也能够直接调节cda簇的几个基因[ 55]。此外，已经发现这种调节取决于AbsA 2 RR的磷酸化状态，其由AbsA 1 HK的激酶/磷酸酶活性的平衡控制[ 58]。
The AbsA1/A2 TCS can self-regulate its expression since it acts as a positive regulator of its operon [53,55]. However, it is important to note that different promoters have been identified in this operon, one of which involves the transcription of the complete operon. Additionally, there is another internal promoter that only regulates the expression of the AbsA2 RR, which explains the high levels of RR expression detected as compared to the HK [59].
AbsA 1/A2 TCS可以自我调节其表达，因为它充当其操纵子的正调节剂[ 53，55]。然而，重要的是要注意，在该操纵子中已经鉴定了不同的启动子，其中之一涉及完整操纵子的转录。此外，还有另一种内部启动子仅调节AbsA 2 RR的表达，这解释了与HK相比检测到的高水平RR表达[ 59]。
The transmembrane topology of AbsA1 HK has also been studied due to its atypical structure. It has been determined that this protein has five transmembrane domains, four of which are located at the N-terminus and the rest at the C-terminus. In fact, the extracellular portion of the protein (which probably includes the sensor domain) is located at the C-terminal end [60].
由于其非典型结构，AbsA 1 HK的跨膜拓扑结构也已被研究。已经确定该蛋白具有五个跨膜结构域，其中四个位于N-末端，其余位于C-末端。事实上，蛋白质的细胞外部分（可能包括传感器结构域）位于C末端[ 60]。
The biotechnological potential of this TCS has been demonstrated through the induction of antimicrobial activities in different Streptomycetes through the heterologous expression of the AbsA1 HK of S. coelicolor [61]. The design of this induction strategy is interesting in that the heterologous expression of AbsA1 can counteract the effect of its orthologous, leading to the dephosphorylation of the homologues of the AbsA2 RR, which should act normally as negative regulators of the production of antibiotics. This in turn can improve the expression of some genes of secondary metabolism [61].
该TCS的生物技术潜力已通过在不同链霉菌中通过异源表达S. coelicolor [ 61].这种诱导策略的设计是有趣的，因为AbsA1的异源表达可以抵消其正向异构体的作用，导致AbsA2 RR的同源物的去磷酸化，其通常应作为抗生素生产的负调节剂。这反过来又可以改善次级代谢的一些基因的表达[ 61]。
3.5. AfsQ2/Q1 (SCO4906/07)
3.5. AfsQ 2/Q1（SCO 4906/07）
This system is involved in the regulation of primary metabolism, secondary metabolism, and morphological development [48,62,63,64].
该系统参与初级代谢、次级代谢和形态发育的调节[ 48，62，63，64]。
The effect of this TCS depends largely on the medium and growing conditions. It was initially identified for its involvement in the regulation of the production of ACT and RED antibiotics in Streptomyces lividans [63]. Later studies have identified this system as a positive regulator of the synthesis of the antibiotics ACT, RED, and CDA (through the specific pathway regulators actII-ORF4, redD, redZ, and cdaR), and a negative regulator of morphological development, in the presence of glutamate as the only source of nitrogen [64]. AfsQ2/Q1 has also been shown to be a positive regulator of other compounds of secondary metabolism such as coelimycin P2, a positive regulator of genes involved in phosphate and carbon metabolism, and a negative regulator of genes involved in nitrogen metabolism (mainly those involved in nitrogen assimilation) [48,62].
这种TCS的效果在很大程度上取决于培养基和生长条件。它最初被鉴定为参与调节变铅青链霉菌中ACT和RED抗生素的产生[ 63]。后来的研究已经将该系统确定为抗生素ACT、RED和CDA合成的正调节剂（通过特定途径调节剂actII-ORF 4、redD、redZ和cdaR），以及在谷氨酸盐作为唯一氮源的情况下形态发育的负调节剂[ 64]。AfsQ 2/Q1也被证明是次级代谢的其他化合物的正调节剂，如coelimycin P2，参与磷酸盐和碳代谢的基因的正调节剂，以及参与氮代谢的基因的负调节剂（主要是参与氮同化的那些）[ 48，62]。
The regulation of nitrogen metabolism seems to be key in the AfsQ2/Q1 signaling pathway, as it is involved in maintaining homeostasis in nutrient utilization under conditions of high glutamate concentrations, establishing cross-regulation with oRR GlnR (a key regulator of nitrogen metabolism to be later discussed) [48].
氮代谢的调节似乎是AfsQ 2/Q1信号通路的关键，因为它参与在高谷氨酸浓度条件下维持营养利用的稳态，与oRR GlnR（稍后讨论的氮代谢的关键调节因子）建立交叉调节[ 48]。
The AfsQ2/Q1 signaling pathway also involves the sigma factor SigQ, encoded by the adjacent gene SCO4908, which is regulated by the AfsQ1 RR [64].
AfsQ 2/Q1信号通路还涉及由相邻基因SCO 4908编码的σ因子SigQ，其由AfsQ 1 RR调节[ 64]。
A final aspect to consider is that this TCS forms an operon with an additional gene, SCO4905, which encodes the potential lipoprotein AfsQ3 that could be involved in the signaling cascade through interaction with the HK in a similar way to other TCSs [32].
需要考虑的最后一个方面是，该TCS与额外的基因SCO4905形成操纵子，SCO4905编码潜在的脂蛋白AfsQ3，其可能以与其他TCS类似的方式通过与HK的相互作用参与信号级联[ 32]。
3.6. Aor1 (SCO2281) 3.6.主动脉1（SCO2281）
This oRR acts as a positive regulator of antibiotic production (ACT, RED, and CDA) and the morphological differentiation process [65]. Transcriptomic studies have revealed that Aor1 is also involved in other cellular processes such as the protein secretion pathway via sigma factor SigU and in the osmotic stress response via the sigma factor SigB pathway [65]. The high number of altered genes in these studies suggests that Aor1 could be a master regulator within the physiology of this organism, although its signaling cascade has not yet been elucidated.
这种oRR作为抗生素生产（ACT，RED和CDA）和形态分化过程的正调节剂[ 65]。转录组学研究表明，Aor1还参与其他细胞过程，例如通过sigma因子SigU的蛋白质分泌途径和通过sigma因子SigB途径的渗透应激反应[ 65]。在这些研究中，大量的改变基因表明，Aor1可能是这种生物体生理学中的主要调节因子，尽管其信号级联尚未阐明。
3.7. BldM (SCO4768) 3.7.宝马（SCO 4768）
This oRR was initially called WhiK [66,67]. This protein acts as a central regulator of the morphological development and differentiation of aerial mycelium [66,67,68,69]. BldM is regulated by the extracytoplasmic function (ECF) sigma factor BldN [68].
这种oRR最初被称为WhiK [ 66，67]。这种蛋白质作为气生菌丝体形态发育和分化的中心调节因子[ 66，67，68，69]。BldM受细胞质外功能（ECF）σ因子BldN调节[ 68]。
Although BldM presents a typical phosphorylation site, it has been observed that the phosphorylation of this RR is not required for its function, so it may present alternative activation mechanisms such as aRR [66].
尽管BldM存在典型的磷酸化位点，但已观察到该RR的磷酸化对其功能不是必需的，因此其可能存在替代激活机制，如aRR [ 66]。
BldM shows different mechanisms of action. On the one hand, BldM can form homodimers that regulate a certain set of genes independently of the whi regulation pathway (involved in the sporulation process). On the other hand, BldM can form heterodimers with the oRR WhiI (which will be discussed later) and regulate a different set of genes. The second mechanism takes place after the first, which agrees with the stages of the life cycle (sporulation takes place once the aerial mycelium is developed) and allows the integration of key regulatory routes in the process of development and morphological differentiation [70].
BldM显示不同的作用机制。一方面，BldM可以形成同源二聚体，其独立于whi调节途径（参与孢子形成过程）调节某组基因。另一方面，BldM可以与oRR WhiI形成异源二聚体（将在后面讨论），并调节不同的基因组。第二种机制发生在第一种机制之后，这与生命周期的阶段一致（气生菌丝体发育后发生孢子形成），并允许在发育和形态分化过程中整合关键调控途径[ 70]。
3.8. ChiS/R (SCO5378/77) 3.8.中文（中华人民共和国）
This system is involved in the regulation of the chitinase enzyme ChiC in response to the presence of chitin [71,72]. However, the deletion of ChiR does not have an overall effect on chitinase activity, which may be due to the presence of multiple chitinases in this organism [72].
该系统参与几丁质酶ChiC响应几丁质存在的调节[ 71，72]。然而，ChiR的缺失对几丁质酶活性没有总体影响，这可能是由于该生物体中存在多种几丁质酶[ 72]。
3.9. CseC/B (SCO3359/58) 3.9. CseC/B（SCO3359/58）
This system is essential for maintaining cell wall integrity through the ECF sigma factor SigE [73,74]. The deletion of sigE or cseB produces a similar effect, consisting of increased sensitivity of the cell wall to lytic enzymes (due to an altered peptidoglycan profile), increased production of the antibiotic ACT, and a sporulation deficit, dependent on magnesium levels in the medium [74]. At the genomic level, although SigE (SCO3356) presents a monocistronic transcription, it can also be transcribed as part of the cseA (SCO3357), cseB, and cseC operon, through a positive self-regulation process mediated by the CseB RR [74].
该系统对于通过ECF sigma因子SigE维持细胞壁完整性至关重要[ 73，74]。sigE或cseB的缺失产生类似的效果，包括细胞壁对溶解酶的敏感性增加（由于肽聚糖谱改变），抗生素ACT的产生增加，以及孢子形成缺陷，这取决于培养基中的镁水平[ 74]。在基因组水平，虽然SigE（SCO3356）呈现单顺反子转录，但它也可以通过CseB RR介导的正性自我调节过程作为cseA（SCO3357）、cseB和cseC操纵子的一部分转录[ 74]。
To determine the activation signals of CseC/B, the construction of a bioassay system based on the regulation of this operon was carried out [73,75], which identified inducer compounds of this TCS that affect the integrity of the cell wall such as glycopeptide antibiotics, β-lactam antibiotics, and lysozymes. Based on these results, it has been proposed that the CseC/B TCS is activated by the accumulation of the intermediate products of peptidoglycan synthesis/degradation [73]. The perception of these signals by this system also involves the lipoprotein CseA, which is anchored to the plasma membrane and oriented towards the extracytoplasmic space, and probably modulates the activity of the CseC HK through interaction with its sensor domain, although the mechanism of action is unclear [76].
为了确定CseC/B的活化信号，进行了基于该操纵子调节的生物测定系统的构建[ 73，75]，其鉴定了影响细胞壁完整性的该TCS的诱导物化合物，例如糖肽抗生素、β-内酰胺抗生素和溶菌酶。基于这些结果，提出CseC/B TCS通过肽聚糖合成/降解的中间产物的积累而被激活[ 73]。该系统对这些信号的感知还涉及脂蛋白CseA，其锚定在质膜上并朝向胞质外空间，并可能通过与其传感器结构域的相互作用调节CseC HK的活性，尽管作用机制尚不清楚[ 76]。
3.10. CssS/R (SCO4155/56)
3.10. CssS/R（SCO4155/56）
It is important to note that this system has been described in S. lividans, a species extremely close to S. coelicolor, and has been included in this review for this reason.
值得注意的是，该系统已在S. lividans，与S. coelicolor，并已列入这一审查的原因。
The CssS/R TCS is involved in the secretion stress response that is caused by the accumulation of misfolded proteins on the outside of the plasmatic membrane which can interfere with the secretion machinery. It has been observed that the CssS/R system is induced by the overproduction of α-amylase, which causes secretion stress; in response to this, CssR regulates the proteases of the HtrA family for the elimination of misfolded proteins [77].
CssS/R TCS参与分泌应激反应，所述分泌应激反应是由质膜外部的错误折叠蛋白质的积累引起的，所述错误折叠蛋白质可以干扰分泌机制。已经观察到CssS/R系统由α-淀粉酶的过度产生诱导，这导致分泌应激;作为对此的响应，CssR调节HtrA家族的蛋白酶以消除错误折叠的蛋白[ 77]。
3.11. CutS/R (SCO5863/62)
3.11.切割S/R（SCO 5863/62）
This system acts as a negative regulator of the production of the antibiotic ACT, although it seems to be indirect as it does not bind to the specific regulator of the actII-ORF4 pathway [78].
该系统作为抗生素ACT产生的负调节剂，尽管它似乎是间接的，因为它不结合actII-ORF 4途径的特异性调节剂[ 78]。
3.12. Cvn (Conservons) 3.12. Cvn（保守党）
When the genome of S. coelicolor was described [25], 13 conservons were identified and called Cvn1 to 13 (the name derives from conserved operons). All conservons have a similar organization, consisting of four or five genes with specific functions: CvnA is an oHK, CvnB is a protein of the roadblock/LC7 family, CvnC is a protein of unknown function, CvnD is a GTP/GDP-binding protein, and CvnE is a cytochrome P450. These proteins can form complexes similar to eukaryotic G-protein-coupled receptors (GPCRs).
当S. [ 25]，鉴定了13个保守子，并将其称为Cvn 1至13（该名称来自保守操纵子）。所有保守子都有类似的组织，由四个或五个具有特定功能的基因组成：CvnA是oHK，CvnB是roadblock/LC 7家族的蛋白质，CvnC是功能未知的蛋白质，CvnD是GTP/GDP结合蛋白，CvnE是细胞色素P450。这些蛋白质可以形成类似于真核G蛋白偶联受体（GPCR）的复合物。
The oHK CvnA1 (SCO5544) acts as a positive regulator of antibiotic production (ACT and RED) and the development of aerial mycelium through sigma factor SigU [79].
oHK CvnA1（SCO5544）通过sigma因子SigU作为抗生素生产（ACT和RED）和气生菌丝体发育的正调节因子[ 79]。
The oHK CvnA9 (SCO1630) acts as a negative regulator of the production of the antibiotic ACT and the development of aerial mycelium through the bld pathway [80]. It has been determined that this oHK interacts with CvnB9 and CvnC9, which in turn interact with CvnD9 [80].
oHK CvnA9（SCO1630）作为抗生素ACT的产生和气生菌丝体通过bld途径的发育的负调节剂[ 80]。已经确定该oHK与CvnB9和CvnC9相互作用，CvnB9和CvnC9又与CvnD9相互作用[ 80]。
The oHK CvnA10 (SCO7422) exhibits similar behavior to CvnA9 and acts as a negative regulator of the production of the antibiotic ACT and the development of aerial mycelium [80].
oHK CvnA10（SCO7422）表现出与CvnA9相似的行为，并作为抗生素ACT产生和气生菌丝体发育的负调节剂[ 80]。
3.13. DraK/R (SCO3062/63)
3.13.德拉克/R（SCO 3062/63）
This system has been described as a regulator of antibiotic production, morphological differentiation, and primary metabolism [81,82]. Regarding the production of antibiotics, DraK/R acts as a positive regulator of ACT synthesis (controls directly the actII-ORF4 regulator) and a negative regulator of RED synthesis under conditions of high levels of different nitrogen sources (such as glutamine, glutamate, or glycine among others) [81]. The DraK/R TCS can self-regulate its expression since it acts as a negative regulator of its own operon [81]. The regulation of antibiotic production exerted by DraK/R is conserved in other Streptomycetes, such as Streptomyces avermitilis, where it acts as a negative regulator of avermectin synthesis and a positive regulator of oligomycin synthesis [81].
该系统被描述为抗生素生产、形态分化和初级代谢的调节剂[ 81，82]。关于抗生素的产生，DraK/R在高水平的不同氮源（例如谷氨酰胺、谷氨酸盐或甘氨酸等）的条件下充当ACT合成的正调节剂（直接控制actII-ORF 4调节剂）和RED合成的负调节剂[ 81]。DraK/R TCS可以自我调节其表达，因为它充当其自身操纵子的负调节剂[ 81]。DraK/R对抗生素产生的调节在其他链霉菌中是保守的，例如阿维链霉菌，它作为阿维菌素合成的负调节剂和寡霉素合成的正调节剂[ 81]。
The study of the sensor domain of the DraK HK, to try to determine the detection and signaling mechanism of this regulation system, is noteworthy [83,84,85]. The study of the biochemical and biophysical properties of this domain has revealed that it undergoes pH-dependent conformational changes that could be key in the signal transduction process of this TCS [83]. In addition, the structure of this domain (PDB ID: 2MJ6) has been obtained and led to the identification of the key residues that drive conformational changes in response to variations in pH [84]. Based on these studies, it has been proposed that the DraK/R TCS could play a key role in regulating the pH of the medium which S. coelicolor grows in [84].
对DraK HK的传感器域的研究，试图确定该调节系统的检测和信号传导机制，值得注意[ 83，84，85]。对该结构域的生物化学和生物物理特性的研究表明，它经历了pH依赖性构象变化，这可能是该TCS信号转导过程的关键[ 83]。此外，已经获得了该结构域（PDB ID：2 MJ 6）的结构，并鉴定了响应pH变化驱动构象变化的关键残基[ 84]。在此基础上，提出了DraK/R TCS对S. [ 84]第84话
3.14. EcrA1/A2 (SCO2518/17)
3.14. ECrA1/A2（SCO2518/17）
This system has been described as a positive regulator of the antibiotic RED [86].
该系统被描述为抗生素RED的正调节剂[ 86]。
3.15. EcrE1/E2 (SCO6421/22)
3.15. EcrE1/E2（SCO6421/22）
This system acts as a positive regulator of the production of the antibiotic RED, through the specific pathway regulators redD and redZ [87].
该系统通过特定途径调节剂redD和redZ作为抗生素RED生产的正调节剂[ 87]。
3.16. GlnR (SCO4159) 3.16. GlnR（SCO4159）
This oRR acts as a central regulator of nitrogen metabolism and is one of the most extensively studied RRs of S. coelicolor [88,89,90,91,92,93,94,95,96,97,98]. Besides its role in this key cellular process, GlnR is involved in many other directly or indirectly associated processes, such as carbon metabolism [93,99], antibiotic synthesis [93,100], or osmotic stress response [101].
该oRR作为氮代谢的中心调节器，是S. coelicolor [ 88，89，90，91，92，93，94，95，96，97，98].除了在这一关键细胞过程中的作用外，GlnR还参与许多其他直接或间接相关的过程，如碳代谢[ 93，99]，抗生素合成[ 93，100]或渗透胁迫反应[ 101]。
GlnR controls the expression of many key genes at different stages of nitrogen metabolism such as glutamine synthesis [90,96,97], ammonium assimilation [91,94], nitrate/nitrite assimilation [89], nitrite reduction [94], nitrate reduction [95], urea degradation [94], and amino acid biosynthesis [93]. All of these studies have made it possible to identify the target DNA sequences to which GlnR binds.
GlnR在氮代谢的不同阶段控制许多关键基因的表达，如谷氨酰胺合成[ 90，96，97]，铵同化[ 91，94]，硝酸盐/亚硝酸盐同化[ 89]，亚硝酸盐还原[94]，硝酸盐还原[ 95]，尿素降解[ 94]和氨基酸生物合成[ 93]。所有这些研究使得有可能鉴定GlnR结合的靶DNA序列。
The oRR GlnR interacts in cross-regulation with other TCSs, such as MtrB/A [102], AfsQ2/Q1 [48], and PhoR/P [103,104,105,106], of which GLnR competes in the regulation of the main genes involved in nitrogen metabolism. This in turn allows GLnR to participate in other key processes such as phosphate metabolism.
oRR GlnR与其他TCS（如MtrB/A [ 102]、AfsQ 2/Q1 [ 48]和PhoR/P [ 103，104，105，106]）相互作用，交叉调节，其中GLnR竞争参与氮代谢的主要基因的调节。这反过来又允许GLnR参与其他关键过程，如磷酸盐代谢。
Several reviews on nitrogen metabolism in S. coelicolor and its relationship with other primary metabolic processes have been published [107,108,109].
对S. coelicolor及其与其他主要代谢过程的关系已经发表[ 107，108，109]。
Regarding the mechanism of action at the molecular level of GlnR, certain alterations have been observed at the phosphorylation site as compared to the canonical structure of its RR. Furthermore, it has been determined that GlnR can form homodimers in the absence of the phosphorylation of the aspartate residue, a structure that is stabilized through electrostatic interactions established by this aspartate with other residues [92]. GlnR is modified post-translationally by the phosphorylation of the serine and threonine residues, as well as the acetylation of lysine residues [88]. These modifications vary depending on the levels of nitrogen and other nutrients in the medium (the higher the nitrogen levels in the medium, the greater the degree of phosphorylation in Ser/Thr of GlnR) and modulate the binding affinity of this RR to DNA, which affects the transcriptional response generated by it [88].
关于GlnR分子水平的作用机制，与其RR的典型结构相比，在磷酸化位点观察到某些改变。此外，已确定GlnR可在不存在天冬氨酸残基磷酸化的情况下形成同源二聚体，该结构通过该天冬氨酸与其他残基建立的静电相互作用而稳定[ 92]。GlnR通过丝氨酸和苏氨酸残基的磷酸化以及赖氨酸残基的乙酰化进行后修饰[ 88]。这些修饰根据培养基中氮和其他营养物质的水平而变化（培养基中氮水平越高，GlnR的Ser/Thr磷酸化程度越大），并调节该RR与DNA的结合亲和力，从而影响其产生的转录反应[ 88]。
3.17. GluK/R (SCO5779/78)
3.17. GluK/R（SCO 5779/78）
This system is involved in the detection and uptake of glutamate, since it regulates the gluABCD operon (SCO5774-77) that is adjacent at the genomic level and encodes the glutamate uptake system, under conditions of high levels of this compound [110].
该系统参与谷氨酸的检测和摄取，因为它调节在基因组水平上相邻的gluABCD操纵子（SCO 5774 -77），并在高水平该化合物的条件下编码谷氨酸摄取系统[ 110]。
In addition, GluK/R acts as a negative regulator of ACT synthesis, and a positive regulator of RED synthesis. However, the role of this TCS in regulating antibiotic production is independent of its role in glutamate uptake [110].
此外，GluK/R作为ACT合成的负调节剂和RED合成的正调节剂。然而，该TCS在调节抗生素产生中的作用与其在谷氨酸摄取中的作用无关[ 110]。
This TCS is one of the few cases in which the HK activation signal has been determined. A biolayer interferometry (BLI) assay has shown that it is the glutamate molecule that interacts with the GluK HK and acts as its activation signal [110]. Structurally similar compounds, such as glutamine, are not recognized by this HK.
该TCS是已确定HK激活信号的少数情况之一。生物层干涉法（BLI）试验表明，谷氨酸分子与GluK HK相互作用，并作为其激活信号[ 110]。结构相似的化合物，如谷氨酰胺，不被本HK认可。
3.18. MacS/R (SCO2121/20)
3.18. * MacS/R（SCO 2121/20）：
This system has been described as a positive regulator of antibiotic production (ACT, RED, and CDA) and a negative regulator of morphological differentiation [111,112]. Multiple direct targets of MacR have been identified, i.e., membrane proteins and lipoproteins which seem to act as morphogenetic factors that participate in the development of aerial mycelium. In addition, the binding consensus sequence of this RR has been established and validated [112].
该系统已被描述为抗生素生产（ACT，RED和CDA）的正调节剂和形态分化的负调节剂[ 111，112]。已经确定了MacR的多个直接靶点，即，膜蛋白和脂蛋白，它们似乎是参与气生菌丝体发育的形态发生因子。此外，该RR的结合共有序列已经确立并得到验证[ 112]。
3.19. MtrB/A (SCO3012/13)
3.19.地铁B/A（SCO 3012/13）
Much interest is focused on this TCS, owing to the orthologous system present in Mycobacterium tuberculosis, which seems to be involved in the regulation of the osmotic stress response, the homeostasis of cell envelopes, and the progression of the cell cycle (coordinating DNA replication with cell division) [113].
由于结核分枝杆菌中存在的邻位系统，许多兴趣都集中在这种TCS上，该邻位系统似乎参与了渗透压应激反应的调节、细胞包膜的稳态和细胞周期的进展（协调DNA复制与细胞分裂）[ 113]。
In S. coelicolor, it has been described that the MtrB/A TCS is essential in the development of aerial mycelium, as it acts as a positive regulator of many key genes in the differentiation process of the chp, rdl, ram, bld, and whi families [114].
In S.在coelicolor中，已经描述了MtrB/ATCS在气生菌丝体的发育中是必不可少的，因为它在chp、rdl、ram、bld和whi家族的分化过程中充当许多关键基因的正调节因子[ 114]。
In addition, this system acts as a key regulator in the production of antibiotics, as well as a negative regulator of the synthesis of ACT and RED and as a positive regulator of the synthesis of CDA. In all cases, MtrB/A exerts direct regulation on the specific regulators of the synthesis pathways of these antibiotics such as actII-ORF4, redZ, and cdaR [115,116]. The implication of MtrB/A in the regulation of antibiotic production is well preserved in other Streptomycetes, as it is involved in the control of biosynthetic clusters of chloramphenicol and jadomycin in Streptomyces venezuelae, avermectin, and oligomycin in S. avermitilis, and validamycin in Streptomyces hygroscopicus [116].
此外，该系统作为抗生素生产的关键调节剂，以及ACT和RED合成的负调节剂和CDA合成的正调节剂。在所有情况下，MtrB/A对这些抗生素合成途径的特定调节剂（如actII-ORF 4、redZ和cdaR）发挥直接调节作用[ 115，116]。在其他链霉菌中，MtrB/A在抗生素生产调节中的意义得到了很好的保留，因为它参与了委内瑞拉链霉菌中氯霉素和雅多霉素、S.阿维菌素和井冈霉素[ 116]。
The MtrB/A TCS has also been associated with nitrogen metabolism [102] and phosphate metabolism [117] in S. coelicolor. It has been described that MtrA represses nitrogen assimilation genes in nitrogen-rich media, and GlnR (key regulator in nitrogen metabolism) under limiting conditions. In addition, MtrB/A competes with this latter oRR in binding to its target sequences [102]. Thus, MtrA and GlnR compete in the control of genes involved in nitrogen metabolism, with priority placed on regulation by GlnR under nitrogen-limiting conditions, and a predominating regulation by MtrA in nutrient-rich conditions [102]. MtrA also regulates the key genes of phosphate metabolism, including the PhoP/R TCS, under different conditions (both in limiting and phosphate-rich situations); this regulation is similar to that of PhoP [117]. In addition, nitrogen metabolism is directly related to phosphate metabolism through these regulation systems, as it has been observed that the MtrB/A and PhoP/R systems regulate different nitrogen metabolism genes, including GlnR, under different phosphate availability conditions [117]. In summary, a clear phenomenon of the cross-regulation between the MtrB/A, PhoP/R, and GlnR systems can be observed concerning nitrogen and phosphate metabolism.
MtrB/A TCS还与S.天蓝色。已经描述了MtrA在富氮培养基中抑制氮同化基因，并且在限制条件下抑制GlnR（氮代谢中的关键调节因子）。此外，MtrB/A与后者oRR竞争结合其靶序列[ 102]。因此，MtrA和GlnR在参与氮代谢的基因的控制中竞争，在氮限制条件下优先考虑GlnR的调节，而在营养丰富的条件下主要由MtrA调节[ 102]。MtrA还在不同条件下（限制和富磷情况下）调节磷酸盐代谢的关键基因，包括PhoP/R TCS;这种调节与PhoP类似[ 117]。 此外，氮代谢通过这些调节系统与磷酸盐代谢直接相关，因为已经观察到MtrB/A和PhoP/R系统在不同的磷酸盐可用性条件下调节不同的氮代谢基因，包括GlnR [ 117]。总之，关于氮和磷酸盐代谢，可以观察到MtrB/A、PhoP/R和GlnR系统之间的交叉调节的明显现象。
3.20. OhkA (SCO1596) and OrrA (SCO3008)
3.20. OhkA（SCO1596）和OrrA（SCO3008）
The oHK OhkA has been described as a negative regulator of antibiotic production (ACT, RED, and CDA) and a positive regulator of aerial mycelium formation and the sporulation process [118,119].
oHK OhkA被描述为抗生素生产的负调节剂（ACT、RED和CDA）和气生菌丝体形成和孢子形成过程的正调节剂[ 118，119]。
Recent studies have identified the RR related to OhkA, which forms part of its signal transduction pathway, and have determined that it is the oRR encoded by the SCO3008 gene called OrrA [42]. The identification of OrrA as an OhkA-associated RR has been conducted through phenotypic, transcriptomic, and double-hybrid experiments. In fact, the removal of OrrA produces an effect similar to the deletion of OhkA [42]. Moreover, previous studies have linked oRR OrrA to the regulation of antibiotic synthesis [120].
最近的研究已经确定了与OhkA相关的RR，其形成其信号转导途径的一部分，并确定其是由称为OrrA的SCO3008基因编码的oRR [ 42]。OrrA作为OhkA相关RR的鉴定已经通过表型、转录组和双杂交实验进行。事实上，去除OrrA会产生类似于删除OhkA的效果[ 42]。此外，以前的研究将oRR OrrA与抗生素合成的调节联系起来[ 120]。
This signal transduction system comprising OhkA and OrrA also involves the pleiotropic regulator WblA (SCO3579). It has been determined that the expression of WblA is directly regulated by OrrA [121]. The role described for WblA is similar to that of OrrA, known to be a negative regulator of antibiotic production and a positive regulator of morphological development process [122,123,124].
这种包含OhkA和OrrA的信号转导系统还涉及多效性调节剂WblA（SCO3579）。已经确定WblA的表达直接受OrrA调节[ 121]。WblA的作用与OrrA相似，已知OrrA是抗生素产生的负调节剂和形态发育过程的正调节剂[ 122，123，124]。
3.21. OsaA/B (SCO5748/49)
3.21. OSAA/B（SCO5748/49）
This system is involved in the osmotic stress response since the OsaB RR is required for the osmoadaptation needed during the differentiation process. In addition, it is involved in the production of antibiotics acting as a negative regulator of the synthesis of ACT and RED [125].
该系统参与渗透胁迫反应，因为OsaB RR是分化过程中所需的细胞适应所必需的。此外，它还参与抗生素的生产，作为ACT和RED合成的负调节剂[ 125]。
The osaB gene has been determined to have its own promoter, independent of osaA [125].
已确定osaB基因具有独立于osaA的自身启动子[ 125]。
The OsaC regulator (SCO5747), which acts as an anti-sigma factor, is related to the regulation of the OsaB RR. OsaC is induced after exposure to osmotic stress by sigma factor SigB (a key factor in the response to osmotic stress and oxidative stress, as well as in the processes of differentiation and production of antibiotics) and is required to restore the expression levels of OsaB and SigB once the response to osmotic stress has taken place [126].
OsaC调节因子（SCO5747）作为抗σ因子，与OsaB RR的调节相关。OsaC在暴露于渗透应激后由sigma因子SigB（对渗透应激和氧化应激反应以及抗生素分化和生产过程中的关键因子）诱导，并且需要恢复OsaB和SigB的表达水平一旦对渗透应激的反应已经发生[ 126]。
A noteworthy feature of the OsaA and OsaB proteins is their atypical architecture. OsaA has been classified as a hybrid HK because it has a REC domain (with a phosphorylable aspartate residue). Another interesting structural characteristic is the presence of more than ten HAMP domains (this protein is very large, with a length of 1829 aa). In the case of the OsaB RR, its effector domain does not belong to any of the canonical families; this domain has a supercoiled helix structure (coiled coil) that is believed to interact with similar motifs of other proteins. 重试 错误原因
3.22. OsdK/R—DevS/R (SCO0203/04) 重试 错误原因
The name of the TCS encoded by SCO0203/04 presents certain discrepancies in the literature; some authors have named this system OsdK/R [127,128], while others refer to it as DevS/R [129,130].
由SCO 0203/04编码的TCS的名称在文献中存在一定的差异;一些作者将该系统命名为OsdK/R [ 127，128]，而其他人则将其称为DevS/R [ 129，130]。
The initial interest in this system arose because it is an ortholog of the DevS/R TCS (also called DosS/R) of the human pathogen M. tuberculosis, involved in the activation of the dormancy state after hypoxia conditions [131]. The state of dormancy consists of a cessation of growth, which is hugely important in pathogenic bacteria. This condition allows these bacteria to resist the defense system of the host, as well as antibiotic treatment, playing a central role in latent infections. Moreover, it has been described that the OsdK/R TCS of S. coelicolor controls a regulon associated with a state of dormancy as it includes a multitude of genes related to stress response and development [128].
对该系统的最初兴趣是因为它是人类病原体M的DevS/R TCS（也称为DoS/R）的直系同源物。结核病，参与缺氧条件后休眠状态的激活[ 131]。休眠状态包括停止生长，这对病原菌非常重要。这种情况使这些细菌能够抵抗宿主的防御系统以及抗生素治疗，在潜伏感染中发挥核心作用。此外，还描述了S. coelicolor控制与休眠状态相关的调节子，因为它包括与应激反应和发育相关的大量基因[ 128]。
In addition to this role, OsdK/R participates in the cycle of nitric oxide of S. coelicolor (gas that acts as an important signaling molecule in the control of bacterial metabolism, although it is toxic at high levels), which allows the interconversion of nitrates, nitrites, and nitric oxide through a dioxygenase (Fhb) and a nitrate reductase (Nar), the latter of which is regulated by this TCS. This cycle regulates endogenous nitric oxide levels, ACT antibiotic production, and morphological differentiation [130]. In this situation, OsdR acts as a positive regulator of ACT production, through the direct regulation of the specific regulator pathway actII-ORF4 [129].
OsdK/R还参与S. coelicolor（在控制细菌代谢中作为重要信号分子的气体，尽管其在高水平下是有毒的），其允许硝酸盐、亚硝酸盐和一氧化氮通过双加氧酶（Fhb）和硝酸还原酶（Nar）相互转化，后者由TCS调节。该循环调节内源性一氧化氮水平、ACT抗生素产生和形态分化[ 130]。在这种情况下，OsdR通过直接调节特定的调节途径actII-ORF 4作为ACT产生的正调节剂[ 129]。
The role of OsdK/R In both processes is not incompatible, especially considering that oxygen is one of the major determinants of nitric oxide metabolism. In fact, it has been described that the synthesis of NarG2 nitrate reductase is induced by hypoxia conditions through OsdK/R in the mycelium of S. coelicolor [127]. It has been proposed that the stimuli perceived by OsdK could be precisely the levels of oxygen and nitric oxide, which would be detected through a heme group, similar to its DevS ortholog in M. tuberculosis.
OsdK/R在这两个过程中的作用并不矛盾，特别是考虑到氧是一氧化氮代谢的主要决定因素之一。事实上，已经描述了NarG 2硝酸还原酶的合成是通过S. coelicolor [ 127].有人提出，OsdK感知的刺激可能正是氧气和一氧化氮的水平，这将通过血红素组检测到，类似于M中的DevS直系同源物。结核
Apart from this canonical signaling cascade, it has been determined that the OsdK HK is also able to phosphorylate the oRR SCO3818 (in addition to its associated RR, OsdR, and its autophosphorylation, as evidenced by in vitro phosphorylation assays). In addition, at the phenotypic level, it has been observed that OsdK and oRR SCO3818 could be involved in the downregulation of ACT antibiotic production under certain conditions [43].
除了这种典型的信号级联，已经确定OsdK HK还能够磷酸化oRR SCO 3818（除了其相关的RR、OsdR及其自磷酸化，如通过体外磷酸化测定所证明的）。此外，在表型水平，已经观察到OsdK和oRR SCO 3818在某些条件下可能参与ACT抗生素产生的下调[ 43]。
3.23. PdtaS (SCO5239) and PdtaR (SCO2013)
3.23. PdtaS（SCO5239）和PdtaR（SCO2013）
This signal transduction pathway consists of the oHK PdtaS and the oRR PdtaR. PdtaS/R acts as a negative regulator of antibiotic production (ACT and RED) and a positive regulator of the process of differentiation [41,132].
该信号转导通路由oHK PdtaS和oRR PdtaR组成。PdtaS/R作为抗生素生产的负调节剂（ACT和RED）和分化过程的正调节剂[ 41，132]。
The identification of PdtaR as the RR associated with PdtaS was initially established through bioinformatics but was later confirmed using in vitro phosphotransfer and phenotypic assays [41].
最初通过生物信息学确定PdtaR为与PdtaS相关的RR，但后来使用体外磷酸转移和表型测定法进行了确认[ 41]。
Interesting features of oRR PdtaR include its architecture, whose effector domain belongs to the AmiR family, and its ability to regulate RNA (transcriptional antiterminator).
oRR PdtaR的有趣特征包括其结构，其效应结构域属于AmiR家族，以及其调节RNA（转录抗终止子）的能力。
3.24. PhoR/P (SCO4229/30)
3.24. PhoR/P（SCO4229/30）
This system acts as a central regulator of phosphate metabolism and is one of the most extensively studied TCSs in S. coelicolor [28,103,104,105,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147]. Phosphate metabolism has a huge impact on many other cellular processes. Consequently, PhoR/P is also directly and indirectly involved in these processes which include the production of antibiotics [133,139,140,142,143,144], nitrogen metabolism [103,105,106,133,139], carbon metabolism [133,139], and morphological differentiation [133,139,140], among others.
该系统作为磷酸盐代谢的中心调节器，是S. coelicolor [ 28，103，104，105，133，134，135，136，137，138，139，140，141，142，143，144，145，146，147].磷酸盐代谢对许多其他细胞过程有巨大影响。因此，PhoR/P也直接和间接参与这些过程，包括抗生素的产生[ 133，139，140，142，143，144]，氮代谢[ 103，105，106，133，139]，碳代谢[ 133，139]和形态分化[ 133，139，139]。140.除其他外
The PhoR/P TCS responds to the phosphate-limiting conditions and controls the expression of many key genes at different stages of phosphate metabolism, such as phosphatases involved in phosphate recycling processes [105,134] or phosphate uptake systems [139,141,143,146]. In addition, this TCS is self-regulating, since it acts as an inducer of its operon [135,146], and presents a feedback control mechanism through PhoU (SCO4228), which acts as a negative regulator of the PHO regulon and is activated by PhoR/P [137].
PhoR/P TCS响应磷酸盐限制条件并控制磷酸盐代谢不同阶段的许多关键基因的表达，例如参与磷酸盐再循环过程的磷酸酶[ 105，134]或磷酸盐吸收系统[ 139，141，143，146]。此外，该TCS是自我调节的，因为它充当其操纵子的诱导物[ 135，146]，并通过PhoU（SCO 4228）呈现反馈控制机制，其充当PHO调节子的负调节剂并由PhoR/P激活[ 137]。
All of these studies have facilitated target DNA sequences to which PhoR binds to be identified, which are called PHO-Boxes. There are different types of these binding sequences, depending on the number of repetitions of the consensus motif (Dru) and its organization, which affect the type of regulation exercised by PhoP and its degree of affinity [145,148].
所有这些研究都有助于识别与PhoR结合的靶DNA序列，称为PHO-Box。根据共有基序（Dru）及其组织的重复数量，这些结合序列有不同类型，这影响了PhoP的调节类型及其亲和力程度[ 145，148]。
The PhoR/P TCS presents a cross-regulation with other TCSs such as GlnR [103,104,105,106].
PhoR/P TCS与GlnR等其他TCS存在交叉调节[ 103，104，105，106]。
It has recently been proposed that the difference in PhoR/P levels between closely related S. coelicolor and S. lividans (this TCS is less abundant in S. coelicolor) could explain the metabolic differences between these two species [136,138].
最近有人提出，密切相关的S之间PhoR/P水平的差异。coelicolor和S. lividans（该TCS在S. coelicolor）可以解释这两个物种之间的代谢差异[ 136，138]。
In summary, the PhoR/P TCS acts, under limited phosphate conditions (essential resource for proper cell functioning), as a central regulator of cellular processes, blocking much of the primary metabolism, secondary metabolism, and development and differentiation pathways until the phosphate levels recover, and so the growth and proper functioning of the organism can resume.
总之，PhoR/P TCS在有限的磷酸盐条件下（正常细胞功能的必要资源），作为细胞过程的中央调节剂，阻断大部分初级代谢，次级代谢以及发育和分化途径，直到磷酸盐水平恢复，因此生物体的生长和正常功能可以恢复。
Several reviews on phosphate metabolism in S. coelicolor and its relationship with other cellular processes have been carried out, as well as the PhoR/P transduction pathway [108,148,149,150,151].
对S.已经进行了腔棘鱼及其与其他细胞过程的关系，以及PhoR/P转导途径[ 108，148，149，150，151]。
3.25. RagK/R (SCO4073/72)
3.25. RagK/R（SCO 4073/72）
This system participates in the developmental processes of aerial mycelium and sporulation [152].
该系统参与气生菌丝体和孢子形成的发育过程[ 152]。
The process of morphological differentiation in S. coelicolor is complex and is largely controlled by the oRR RamR (which will later be discussed) and the morphogenic peptide SapB, which promotes the formation of the aerial mycelium by breaking the surface tension of the medium. One of the clusters regulated by RamR is rag, which contains the RagK/R TCS. The deletion of the rag cluster results in alterations in the morphology of the aerial mycelium, as well as in the processes of differentiation, septation, and sporogenesis. It has been proposed that RagK/R (together with the rest of the genes comprising the rag cluster) constitute a developmental pathway related to aerial mycelium and sporulation that is independent of SapB and which allows the integration of various morphogenic changes [152].
形态分化的过程。coelicolor是复杂的，并且主要由oRR RamR（稍后将讨论）和形态发生肽SapB控制，形态发生肽SapB通过打破培养基的表面张力促进气生菌丝体的形成。由RamR调节的簇之一是rag，其包含RagK/R TCS。抹布簇的缺失导致气生菌丝体形态的改变，以及分化、分隔和孢子发生过程的改变。已经提出RagK/R（与组成rag簇的其余基因一起）构成与气生菌丝体和孢子形成相关的发育途径，其独立于SapB并且允许各种形态发生变化的整合[ 152]。
3.26. RamR (SCO6685) 3.26. RamR（SCO6685）
This oRR acts as a central regulator of the process of morphogenesis during the development and differentiation of this organism [153,154]. RamR is kept within the bld signaling pathway of the development process and acts as a regulator of SapB, a morphogenetic peptide that is involved as a surfactant in the development of aerial mycelium [153,154].
这种oRR在该生物体的发育和分化期间充当形态发生过程的中央调节器[ 153，154]。RamR保持在发育过程的bld信号传导途径内，并作为SapB的调节剂，SapB是一种形态发生肽，作为表面活性剂参与气生菌丝体的发育[ 153，154]。
3.27. RapA2/A1 (SCO5404/03)
3.27. RapA2/A1（SCO5404/03）
This system acts as a positive regulator of the antibiotic ACT and coelimycin through pathway-specific regulators (actII-ORF4 and kasO) [155].
该系统通过途径特异性调节剂（actII-ORF 4和kasO）作为抗生素ACT和coelimycin的正调节剂[ 155]。
3.28. RedZ (SCO5881) 3.28. RedZ（SCO5881）
RedZ is an atypical oRR that presents a series of functional and structural peculiarities. It is part of the biosynthetic red cluster and acts together with RedD as a pathway-specific regulator. RedZ acts as a positive regulator of RedD, which in turn activates the biosynthetic genes of the cluster and therefore the production of the antibiotic RED. In addition, RedZ presents negative self-regulation [156]. The dependence of the growth process presented by the production of the antibiotic RED seems to be given by the regulation of RedZ, which contains a rare codon of leucine UUA, and requires bldA (which encodes the only tRNA of this codon) for translation [156,157].
RedZ是一种非典型的oRR，具有一系列功能和结构特点。它是生物合成的红色簇的一部分，并与RedD一起作为途径特异性调节剂。RedZ作为RedD的正调节因子，反过来激活簇的生物合成基因，从而产生抗生素RED。此外，RedZ呈现负自我调节[ 156]。抗生素RED的产生对生长过程的依赖性似乎是由RedZ的调节引起的，RedZ含有亮氨酸UUA的罕见密码子，并且需要bldA（编码该密码子的唯一tRNA）进行翻译[ 156，157]。
On a structural level, RedZ is an atypical RR and lacks the phosphorylation site of the REC domain [157]. The alternative control mechanism presented by RedZ seems to be given by its interaction with the molecule of the antibiotic RED, i.e., the final product of its signaling pathway [158].
在结构水平上，RedZ是一种非典型RR，缺乏REC结构域的磷酸化位点[ 157]。RedZ呈现的替代控制机制似乎是由其与抗生素RED分子的相互作用给出的，即，其信号通路的最终产物[ 158]。
3.29. SatK/R (SCO3390/89)
3.29. SatK/R（SCO3390/89）
This TCS acts as a regulator of the sporulation process and morphological development [159].
该TCS作为孢子形成过程和形态发育的调节剂[ 159]。
In S. coelicolor, as in other organisms, chromosomal topology plays a critical role in gene regulation; this is determined by chromosomal supercoiling (controlled primarily by TopA topoisomerase) and nucleoid-associated proteins (NAPs). In this organism, TopA is essential, and the decrease in its levels produces an increase in the supercoiling of DNA and the alteration of the expression of many genes (among them, the supercoiling hypersensitive clusters (SHCs) stand out), giving rise to a significant reduction in growth and blocked sporulation. The SatKR TCS was discovered because mutations in this system were able to suppress the blocking of sporulation associated with the high supercoiling of DNA by reduced levels of TopA [159].
In S.与其他生物一样，在腔棘鱼中，染色体拓扑结构在基因调控中起着关键作用;这是由染色体超螺旋（主要由TopA拓扑异构酶控制）和类核相关蛋白（NAP）决定的。在这种生物体中，TopA是必不可少的，其水平的降低导致DNA超螺旋的增加和许多基因表达的改变（其中，超螺旋过敏簇（SHC）突出），导致生长显著减少和孢子形成受阻。发现SatKR TCS是因为该系统中的突变能够通过降低TopA水平来抑制与DNA的高超螺旋相关的孢子形成的阻断[ 159]。
When SatR levels are low, e.g., due to the absence of SatK, this RR inhibits supercooling-dependent SHC activation. However, when SatR levels are high through SatK activation, SHC transcription is induced independently of supercooling, resulting in blocked sporulation and growth [159].
当SatR水平较低时，例如，由于不存在SatK，该RR抑制过冷依赖性SHC激活。然而，当SatR水平通过SatK激活而升高时，SHC转录被诱导而不依赖于过冷，导致孢子形成和生长受阻[ 159]。
3.30. SenS/R (SCO4275/76)
3.30.上一篇：SenS/R（SCO 4275/76）
This system is involved in the oxidative stress response [160].
该系统参与氧化应激反应[ 160]。
The SenS/R TCS acts in conjunction with HbpS (SCO4274), a secreted protein. The signaling pathway formed by these three components appears to be modulated by post-translational modifications due to redox stress. The genes regulated by this system have been identified and form the non-enzymatic response against the effects of oxidative stress, since they intervene in the synthesis of compounds that act as redox buffers and scavengers of reactive oxygen species, although enzymes with catalase or superoxide dismutase activity are not involved [160].
SenS/R TCS与分泌蛋白HbpS（SCO 4274）结合起作用。由这三种组分形成的信号通路似乎受到氧化还原应激引起的翻译后修饰的调节。已鉴定出受该系统调节的基因，并形成针对氧化应激效应的非酶促反应，因为它们干预作为氧化还原缓冲剂和活性氧清除剂的化合物的合成，尽管不涉及具有过氧化氢酶或超氧化物歧化酶活性的酶[ 160]。
3.31. SitK/R (SCO4667/68)
3.31. SitK/R（SCO 4667/68）
This system was described in parallel with the SatKR TCS (previously discussed), as it is part of the supercoiling hypersensitive cluster (SHC) and is involved in the inhibition of sporulation [159]. It has been observed that the removal of SitKR can restore blocked sporulation due to DNA supercoiling conditions [159].
该系统与SatKR TCS（先前讨论）平行描述，因为它是超螺旋过敏簇（SHC）的一部分，并参与抑制孢子形成[ 159]。已经观察到，去除SitKR可以恢复由于DNA超螺旋条件而被阻断的孢子形成[ 159]。
3.32. VanS/R (SCO3589/90)
3.32. VNS/R（SCO 3589/90）
This system controls resistance to the antibiotic vancomycin [161] and is one of the most extensively studied TCS in S. coelicolor.
该系统控制对抗生素万古霉素的耐药性[ 161]，是S.天蓝色。
Vancomycin is a glycopeptide antibiotic that inhibits cell wall synthesis by binding to peptidoglycan precursors (binds to the D-Ala-D-Ala end of Lipid II), blocking the formation of cross-links necessary to generate a functional cell wall. Vancomycin only affects Gram-positive bacteria (it cannot cross the outer membrane present in Gram-negative bacteria), and its clinical importance is key, as it is the only effective treatment against S. aureus MRSA. The vancomycin resistance cluster (van) is present in multiple human pathogens (S. aureus, E. faecium, etc.) and in several actinomycetes (glycopeptide antibiotic producers such as Amycolatopsis orientalis, Streptomyces toyocaensis, etc., and non-producers such as S. coelicolor) [162].
万古霉素是一种糖肽类抗生素，通过与肽聚糖前体结合（与脂质II的D-Ala-D-Ala末端结合）抑制细胞壁合成，阻断生成功能性细胞壁所需的交联形成。万古霉素只影响革兰氏阳性菌（它不能穿过革兰氏阴性菌的外膜），其临床重要性是关键，因为它是唯一有效的治疗链球菌。金黄色葡萄球菌万古霉素耐药簇（货车）存在于多种人类病原体（S. aureus、E.粪便等）以及在几种放线菌（糖肽抗生素生产者如东方拟无枝酸菌属（Amycolatopsis orientalis），丰冈链霉菌（Streptomyces toyocaensis）等，和非生产者如S. coelicolor）[ 162].
In S. coelicolor, the van cluster consists of seven genes, vanSRJKHAX (SCO3589/90; SCO3592-96), and is controlled by the VanSR TCS which forms part of the cluster [161]. The VanS activation signal is the vancomycin molecule itself, and not intermediates of peptidoglycan synthesis, as in other organisms. In addition, it has been determined that the binding sites of vancomycin to VanS and Lipid II are distinct, and the antibiotic molecules recognized by the VanS HK must be bound to this peptidoglycan precursor for the activation of the signaling cascade [163,164,165,166,167]. VanS autophosphorylates His150 and catalyzes the phosphorylation/dephosphorylation of VanR in Asp51. In the absence of vancomycin, VanS acts as VanR phosphatase (which can be phosphorylated via acetyl-phosphate under these conditions). In the presence of vancomycin, VanS goes on to act as a kinase, allowing the activation of VanR, which in turn activates the entire vancomycin resistance cluster [163]. The interaction between VanS and VanR seems to require additional residues of the RR beyond the REC domain [167].
In S. coelicolor中，货车簇由七个基因vanSRJKHAX（SCO 3589/90; SCO 3592 -96）组成，并且由形成簇的一部分的VanSR TCS控制[ 161]。VanS激活信号是万古霉素分子本身，而不是肽聚糖合成的中间体，如在其他生物体中。此外，已确定万古霉素与VanS和脂质II的结合位点不同，VanS HK识别的抗生素分子必须与该肽聚糖前体结合，以激活信号级联[ 163，164，165，166，167]。VanS自磷酸化His 150并催化Asp 51中VanR的磷酸化/去磷酸化。在不存在万古霉素的情况下，VanS充当VanR磷酸酶（其可在这些条件下经由乙酰磷酸被磷酸化）。在存在万古霉素的情况下，VanS继续充当激酶，允许VanR活化，进而活化整个万古霉素耐药簇[ 163]。 VanS和VanR之间的相互作用似乎需要REC结构域以外的RR的额外残基[ 167]。
Vancomycin resistance is achieved by modifying cell wall synthesis, replacing the D-Ala-D-Ala end of lipid II with D-Ala-D-Lac, which is not recognized by this antibiotic. This substitution is carried out by VanHAX. VanH is a lactate dehydrogenase enzyme that transforms pyruvate into D-lactate, VanX is a dipeptidase that breaks down D-Ala-D-Ala peptides, and VanA is a ligase that binds D-Ala and D-Lac. In S. coelicolor, the cluster also contains VanJ, whose function is unknown, and VanK, which is an enzyme responsible for binding a glycine branch to the modified precursor Lipid II (in the unmodified precursor, the reaction is catalyzed by FemX) [161,168].
万古霉素耐药性是通过改变细胞壁合成，用D-Ala-D-Lac取代脂质II的D-Ala-D-Ala末端来实现的，D-Ala-D-Lac不被这种抗生素识别。该取代由VanHAX进行。VanH是将丙酮酸转化为D-乳酸的乳酸脱氢酶，VanX是分解D-Ala-D-Ala肽的二肽酶，VanA是结合D-Ala和D-Lac的连接酶。In S. coelicolor，该簇还包含VanJ，其功能未知，和VanK，其是负责将甘氨酸分支结合至修饰的前体脂质II的酶（在未修饰的前体中，该反应由FemX催化）[ 161，168]。
Recently, it has been possible to obtain the structure of the VanR RR by X-ray diffraction, both in its inactive form (PDB ID: 7LZ9) and in its active form (PDB ID: 7LZA). The structural analysis of this protein has made it possible to identify the conformational changes produced by its activation via phosphorylation, which enables the dimerization of the REC domain. Although the inactive conformation seems able to bind to DNA, it has been proposed that the dimer of this RR presents a greater affinity for binding [169].
最近，已经可以通过X射线衍射获得非活性形式（PDB ID：7LZ9）和活性形式（PDB ID：7LZA）的VanRR RR的结构。这种蛋白质的结构分析已经使得有可能确定其通过磷酸化激活产生的构象变化，这使得REC结构域的二聚化成为可能。尽管非活性构象似乎能够与DNA结合，但已提出该RR的二聚体具有更大的结合亲和力[ 169]。
This system presents a cross-regulation with the AbrB1/B2 TCS [46] and CseC/B [161].
该系统与AbrB 1/B2 TCS [ 46]和CseC/B [ 161]存在交叉调节。
Finally, it should be noted that resistance to vancomycin in S. coelicolor is dependent on phosphate levels in the medium; this process is independent of the PhoR/P TCS and seems to be related to the phosphate content of the polymers present in the cell wall [170,171,172,173].
最后，应该指出的是，万古霉素耐药的S。coelicolor依赖于培养基中的磷酸盐水平;这一过程与PhoR/P TCS无关，似乎与细胞壁中存在的聚合物的磷酸盐含量有关[ 170，171，172，173]。
3.33. WhiI (SCO6029) 3.33. WhiI（SCO6029）
This oRR is one of the central regulators of the sporulation process and seems to play a key role in the process of septation of the aerial mycelium required for sporulation, as well as spore maturation [174,175,176,177]. WhiI is regulated by WhiG, the specific sigma factor of sporulation; in addition, it has been determined that this oRR is negatively self-regulated [178].
该oRR是孢子形成过程的中心调节因子之一，并且似乎在孢子形成所需的气生菌丝体的分隔过程以及孢子成熟过程中发挥关键作用[ 174，175，176，177]。WhiI受WhiG（孢子形成的特异性sigma因子）调节;此外，已确定该oRR是负自我调节的[ 178]。
On a structural level, WhiI is an aRR since it lacks the phosphorylation site of the REC domain [176,178].
在结构水平上，WhiI是一种aRR，因为它缺乏REC结构域的磷酸化位点[ 176，178]。
As previously mentioned, WhiI can form functional heterodimers with the oRR BldM, which integrates the development processes of aerial mycelium and sporulation [70].
如前所述，WhiI可与oRR BldM形成功能性异源二聚体，其整合气生菌丝体和孢子形成的发育过程[ 70]。
3.34. SCO5282/83
This system is involved in the regulation of different processes related to extracellular metabolism (protein secretion, carbon metabolism, and the metabolism of cell envelopes, among others) [179].
该系统参与调节与细胞外代谢相关的不同过程（蛋白质分泌，碳代谢和细胞包膜代谢等）[ 179]。
The initial interest in this TCS is given because certain mutations in the HK give rise to significant morphological changes in liquid medium, which could be favorable for its growth in industrial fermenters [179].
对这种TCS的最初兴趣是因为HK中的某些突变引起液体培养基中的显著形态变化，这可能有利于其在工业发酵罐中的生长[ 179]。
3.35. SCO5351
This oRR acts as a positive regulator of antibiotic production (ACT and CDA) and the processes of aerial mycelium development and sporulation [180]. In addition, some key residues in the oligomerization process of this oRR, whose mutation blocks its action, have been identified [180].
这种oRR作为抗生素生产（ACT和CDA）以及气生菌丝体发育和孢子形成过程的正调节剂[ 180]。此外，已经确定了该oRR寡聚化过程中的一些关键残基，其突变阻断了其作用[ 180]。
3.36. SCO5784/85
This system acts as a positive regulator of the production of ACT and RED antibiotics, the sporulation process, and secreted proteins [181].
该系统作为ACT和RED抗生素生产、孢子形成过程和分泌蛋白的正调节剂[ 181]。
4. Conclusions 4.结论
4.1. Regulation Systems Involved in all Cellular Processes
4.1.参与所有细胞过程的调节系统
As seen throughout the previous section, TCSs are involved and play a key role in virtually all cellular processes of S. coelicolor. This includes morphological development and differentiation (BldM [66,67,68,69,70], WhiI [70,174,175,176,177,178], and RamR [153,154], among others), primary metabolism (PhoR/P [28,103,104,105,106,108,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151] and GlnR [48,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109], among others), and secondary metabolism (RedZ [156,157,158], AbsA1/A2 [51,52,53,54,55,56,57,58,59,60,61], and EcrA1/A2 [86], among others), as well as in the response to different types of stress such as oxidative stress (SenS/R [160]), osmotic stress (OsaA/B [125,126]), and secretion stress (CssS/R [77]), to give some examples. The importance of TCSs in the physiology of this organism is predictable, especially considering they are one of the main prokaryotic transduction systems.
如前所述，TCS参与并在几乎所有的S细胞过程中发挥关键作用。天蓝色。这包括形态发育和分化（BldM [ 66，67，68，69，70]，WhiI [ 70，174，175，176，177，178]和RamR [ 153，154]等），初级代谢（PhoR/P [ 28，103，104，105，106，108，133，134，135，136，137，138，139，140，141，142，143，144，145，146，147，148，149，150，151]和GlnR [ 48，88，89，90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109]等）和次级代谢（RedZ [ 156，157，158]，AbsA 1/A2 [ 51，52，53，54，55，56，57，58，59，60，61]和EcrA 1/A2 [ 86]等），以及对不同类型的应激如氧化应激的应答（SenS/R [ 160]）、渗透胁迫（OsaA/B [ 125，126]）和分泌胁迫（CssS/R [ 77]），以给出一些实例。 TCS在该生物体的生理学中的重要性是可预测的，特别是考虑到它们是主要的原核转导系统之一。
Although some of the TCSs described are involved in a single cellular process, such as VanS/R in resistance to vancomycin [161] and ChiS/R in the regulation of ChiC chitinase [71,72], most of them are frequently involved in a multitude of biological processes, acting as pleiotropic regulators and essential pillars for their integration and coordination. In this sense, it is important to highlight that the signaling cascades of many of these regulatory systems overlap since they share target genes. This association allows the same process to be differentially regulated based on the various environmental conditions that the organism encounters (e.g., MtrB/A controls the assimilation of nitrogen in media rich in this element, while GlnR does so in limiting conditions). Furthermore, the most necessary cellular processes in different situations can be prioritized (for example in the case of PhoR/P, which can block much of the metabolism and development of the organism in phosphate-limiting situations). It should also be mentioned that most of the cross-regulation events described occur for those TCSs involved in the control of primary metabolism such as PhoP/R, GlnR, MtrB/A, and AfsQ2/Q1 [48,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117].
尽管所描述的一些TCS参与单个细胞过程，例如万古霉素抗性中的VanS/R [ 161]和ChiC几丁质酶调节中的ChiS/R [ 71，72]，但它们中的大多数经常参与多种生物过程，作为多效性调节剂和其整合和协调的重要支柱。在这个意义上，重要的是要强调，许多这些调控系统的信号级联重叠，因为它们共享靶基因。这种关联允许基于生物体遇到的各种环境条件（例如，MtrB/A在富含该元素的培养基中控制氮的同化，而GlnR在限制条件下这样做）。 此外，可以优先考虑不同情况下最必要的细胞过程（例如，在PhoR/P的情况下，它可以在磷酸盐限制的情况下阻止生物体的大部分代谢和发育）。还应该提到的是，所描述的大多数交叉调节事件发生在参与初级代谢控制的那些TCS中，例如PhoP/R、GlnR、MtrB/A和AfsQ 2/Q1 [ 48，102，103，104，105，106，107，108，109，110，111，112，113，114，115，116，118，119，1119，11119，117]。
The complex regulatory network formed by these systems and other cellular regulators, as well as their dependence on environmental conditions, makes the study and understanding of TCSs at a more global level significantly difficult.
这些系统和其他细胞调节因子形成的复杂调节网络，以及它们对环境条件的依赖，使得在更全球水平上研究和理解TCS变得非常困难。
4.2. Molecular Mechanism of Action and its Modulation
4.2.分子作用机制及其调控
Many of the TCSs of this organism have a canonical organization and architecture, as well as a typical molecular mechanism of action. However, some exceptions may be of great interest from a more general point of view, regarding how this type of regulatory system works, and from a more specific point of view, regarding the manipulation and handling of this organism and others that are similar.
这种生物体的许多TCS具有典型的组织和结构，以及典型的分子作用机制。然而，从更一般的角度来看，关于这种类型的调节系统如何工作，以及从更具体的角度来看，关于这种生物体和其他类似生物体的操纵和处理，一些例外可能非常有趣。
In S. coelicolor, there are three hybrid HKs (OsaA [125,126], SCO4009, and SCO7327) whose signaling cascades are unclear. In all three cases, they have REC domains that contain a phosphorylatable Asp residue. Moreover, the existence of accessory HPt proteins acting as intermediates in the phosphotransfer process toward the RR are common. However, in principle, there are no proteins of this type in S. coelicolor. The reason for this may involve an alternative signaling pathway for these systems, perhaps interacting with other signaling cascades or forming oligomers with certain RRs to modulate their action. Hence, it would be interesting to study these systems in more depth. Additionally, it is noteworthy that in all three cases, the HK lacks a transmembrane helix (so they might be cytosolic). Moreover, similar to OsaA, the associated OsaB RR has a peculiar effector domain (coiled coil) that does not belong to any of the classical families and whose mechanism of action has not yet been fully elucidated [125,126].
In S. coelicolor中，有三种杂交HK（OsaA [ 125，126]，SCO4009和SCO7327），其信号级联尚不清楚。在所有三种情况下，它们都具有含有可磷酸化的Asp残基的REC结构域。此外，存在的辅助HPt蛋白作为中间体的磷酸转移过程中向RR是常见的。然而，原则上，在S.天蓝色。其原因可能涉及这些系统的替代信号通路，可能与其他信号级联相互作用或与某些RR形成寡聚体以调节其作用。因此，更深入地研究这些系统将是有意义的。此外，值得注意的是，在所有三种情况下，HK缺乏跨膜螺旋（因此它们可能是胞质的）。 此外，与OsaA相似，相关OsaB RR具有不属于任何经典家族的特殊效应结构域（卷曲螺旋），其作用机制尚未完全阐明[ 125，126]。
Additional HKs of potential interest are those belonging to conservons. These oHKs can interact with other proteins of these operons to give rise to complexes similar to eukaryotic GPCRs. Although several of these proteins (CvnA1, CvnA9, and CvnA10) have been studied [79,80], their biological role and their involvement in processes such as antibiotic production or morphological development, their molecular mechanism of action, and their signaling cascade, which could be of great interest, have not yet been analyzed in depth.
潜在利益的其他HK是属于保护区的HK。这些oHK可以与这些操纵子的其他蛋白质相互作用，产生类似于真核GPCR的复合物。虽然这些蛋白质（CvnA1，CvnA9和CvnA10）中的几个已经被研究[ 79，80]，但它们的生物学作用和它们在抗生素生产或形态发育等过程中的参与，它们的分子作用机制，以及它们的信号级联，这些可能是非常有趣的，尚未被深入分析。
The different TCSs described exhibit a wide variety of mechanisms for regulating the activation state of the RR beyond the canonical phosphorylation of its Asp residue. This is relatively evident in atypical RRs, which lack key residues from the phosphorylation site, justifying additional modulation mechanisms such as the end product that regulates its own signaling pathway (such as RedZ by the RED molecule [157,158]), which can be useful in these signal transduction pathways. However, this is more significant in those RRs that, despite having a canonical phosphorylation site, present alternative mechanisms, as is the case of BldM [66] and GlnR [92]. In the case of BldM, it may be related to its differential oligomerization capacity (formation of homodimers or heterodimers with WhiI), which allows it to act on different sets of genes at different times of the life cycle. In the case of GlnR, post-translational modifications, such as the phosphorylation of Ser and Thr residues, as well as the acetylation of Lys, have been described, which vary depending on the levels of nutrients in the medium and modulate the binding affinity to DNA, that is, the response generated [88]. Regarding this mode of regulation, it would be interesting to see if it is present in other RRs, especially those related to cellular metabolism.
所描述的不同TCS表现出多种机制，用于调节RR的活化状态，超出其Asp残基的典型磷酸化。这在非典型RR中相对明显，其缺乏来自磷酸化位点的关键残基，证明了额外的调节机制，例如调节其自身信号传导途径的终产物（例如RED分子的RedZ [ 157，158]），其可用于这些信号转导途径。然而，这在那些尽管具有典型磷酸化位点但存在替代机制的RR中更显著，如BldM [ 66]和GlnR [ 92]的情况。在BldM的情况下，它可能与其差异寡聚化能力（与WhiI形成同源二聚体或异源二聚体）有关，这使得它能够在生命周期的不同时间作用于不同的基因组。 在GlnR的情况下，已经描述了翻译后修饰，例如Ser和Thr残基的磷酸化以及Lys的乙酰化，其根据培养基中营养素的水平而变化，并调节与DNA的结合亲和力，即产生的反应[ 88]。关于这种调节模式，看看它是否存在于其他RR中，特别是那些与细胞代谢相关的RR中，将是有趣的。
Regarding orphan systems, oHK and oRR that are associated with each other have been described such as OhkA/Orra [42] and PdtaS/R [41], but there are also others that can intervene in the signaling cascades of other TCSs. This is especially relevant in some cases where completely different cellular responses are generated, which is an additional point of regulation; an example of this is OsdK. In its signaling cascade involving OsdR (its associated RR), it acts as a positive regulator of ACT production [129], while in the one involving oRR SCO3818, it acts as a negative regulator of ACT production [43].
关于孤儿系统，已经描述了彼此相关的oHK和oRR，例如OhkA/Orra [ 42]和PdtaS/R [ 41]，但也有其他系统可以干预其他TCS的信号级联。这在某些情况下特别相关，其中产生完全不同的细胞反应，这是一个额外的调节点; OsdK就是一个例子。在其涉及OsdR（其相关RR）的信号级联中，它充当ACT产生的正调节剂[ 129]，而在涉及oRR SCO 3818的信号级联中，它充当ACT产生的负调节剂[ 43]。
Finally, it should be noted that the modulation of the signaling cascades of TCSs is essential for the organism, since a mismatch in these cascades could lead to serious problems in cell function, including cytotoxicity, as has been described, e.g., due to the accumulation of AbrA2 and AbrC3 RRs in their phosphorylated forms [45,49]. Therefore, there are many control mechanisms such as the self-regulation of TCSs AbrA1/A2 [45], AbsA1/A2 [53,55], CseC/B [74], DraK/R [81], PhoR/P [135,146], RedZ [156], and WhiI [178], among others.
最后，应该注意的是，TCS的信号传导级联的调节对于生物体是必需的，因为这些级联中的错配可能导致细胞功能的严重问题，包括细胞毒性，如已经描述的，例如，由于AbrA 2和AbrC 3 RR以其磷酸化形式积累[ 45，49]。因此，存在许多控制机制，例如TCS AbrA 1/A2 [ 45]、AbsA 1/A2 [ 53，55]、CseC/B [ 74]、DraK/R [ 81]、PhoR/P [ 135，146]、RedZ [ 156]和WhiI [ 178]等的自我调节。
4.3. Biotechnological Application
4.3.生物技术应用
One of the main interests in the study of S. coelicolor has been to elucidate the regulatory mechanisms of antibiotic production. As previously mentioned, most of the TCSs described in this organism participate in the control of the synthesis of these compounds (Figure 3), either directly through the control of pathway-specific regulators or genes of the biosynthetic cluster, or indirectly. In fact, some of these systems, such as RedZ and AbsA1/A2, are part of some of these biosynthetic clusters.
S. coelicolor一直致力于阐明抗生素生产的调节机制。如前所述，该生物体中描述的大多数TCS直接或间接通过控制生物合成簇的途径特异性调节剂或基因参与控制这些化合物的合成（图3）。事实上，其中一些系统，如RedZ和AbsA 1/A2，是这些生物合成集群的一部分。
The role of different TCSs in controlling the production of secondary metabolites of interest is highly conserved in other Streptomycetes. For example, DraK/R modulates the production of ACT and RED in S. coelicolor, as well as avermectin and oligomycin in S. avermitilis [81]. MtrB/A modulates the production of ACT, RED, and CDA in S. coelicolor; chloramphenicol and jadomycin in S. venezuelae; avermectin and oligomycin in S. avermitilis; and validamycin in S. hygroscopicus [116].
不同TCS在控制感兴趣的次级代谢产物的产生中的作用在其他链霉菌中是高度保守的。例如，DraK/R调节S中ACT和RED的产生。coelicolor、阿维菌素和寡霉素等。阿维菌素[ 81]。MtrB/A调节S. coelicolor;氯霉素和雅多霉素;阿维菌素和寡霉素;阿维菌素和井冈霉素。[ 116].
It has been widely shown that the biotechnological potential of these systems has two main applications. On the one hand, their manipulation can lead to host strains with an enhanced production capacity of compounds of interest. For example, the removal of the negative regulator AbrA1/A2 of antibiotic production represents a significant improvement in the heterologous production of oviedomycin in S. coelicolor [45]. On the other hand, its manipulation or expression in other strains may be key for activating cryptic biosynthetic clusters and for discovering new molecules of interest, as has been shown by the heterologous expression of the AbsA1 HK [61] and the AbrC3 RR in other species [182].
已经广泛表明，这些系统的生物技术潜力有两个主要应用。一方面，它们的操纵可以导致宿主菌株具有增强的感兴趣的化合物的生产能力。例如，去除抗生素生产的负调节因子AbrA 1/A2代表了在S. coelicolor [ 45].另一方面，其在其他菌株中的操纵或表达可能是激活隐蔽生物合成簇和发现新的目标分子的关键，如AbsA 1 HK [ 61]和AbrC 3 RR在其他物种中的异源表达所示[ 182]。
With respect to the use of Streptomyces strains in the production of compounds of interest on an industrial level, it is also essential to characterize the TCSs involved in primary metabolism, as well as in morphological development and differentiation, to optimize their growth in industrial fermenters (in fact, some systems such as SCO5282/83 have been described precisely for this purpose [179]), or in other situations, such as agricultural biocontrol agents.
关于链霉菌菌株在工业水平上生产感兴趣的化合物中的用途，还必须表征参与初级代谢以及形态发育和分化的TCS，以优化它们在工业发酵罐中的生长（事实上，一些系统，如SCO 5282/83已被精确地描述用于此目的[ 179]），或在其他情况下，如农业生物控制剂。
Recent research on TCSs has shown that some are involved in antibiotic resistance such as VanS/R [161], CsecC/B [73], and AbrB1/B2 [46]. This discovery has presented another potential application for this model species, as using the information obtained with their study not only improves the understanding of antibiotic resistance mechanisms in Streptomycetes, but also the highly relevant human pathogens such as S. aureus or E. faecium.
最近对TCS的研究表明，一些TCS涉及抗生素耐药性，如VanS/R [ 161]，CsecC/B [ 73]和AbrB 1/B2 [ 46]。这一发现为这种模式物种提供了另一种潜在的应用，因为使用他们的研究获得的信息不仅提高了对链霉菌抗生素耐药性机制的理解，而且还提高了对高度相关的人类病原体如S。aureus或E.屎室
Finally, another potential biotechnological application for S. coelicolor TCSs is to engineer proteins to obtain chimeric HKs (HKs resulting from the fusion of the domains of different HKs). The resulting proteins can therefore be used as biosensors in other organisms [183]. Furthermore, chimeric HKs could generate cellular responses of great biotechnological interest, such as LinR, i.e., the chimeric HK generated from AbrC1 and AbrC2 that confers resistance to lincomycin [50].
最后，S. coelicolor TCS是工程化蛋白质以获得嵌合HK（由不同HK的结构域融合产生的HK）。因此，所产生的蛋白质可以用作其他生物体中的生物传感器[ 183]。此外，嵌合HK可以产生具有重大生物技术意义的细胞应答，例如LinR，即，由AbrC1和AbrC2产生的嵌合HK赋予对林可霉素的抗性[ 50]。
4.4. Future Considerations
4.4.今后的考量
Despite the large number of studies that have been carried out in this field, much remains to be revealed regarding the TCSs discussed in this review, both in terms of the physiological role they play as well as the signaling cascades and mechanisms of action they present. The identification of the activation signals of these systems and the structural characterization of resulting proteins are some of the future tasks that must be undertaken.
尽管在这一领域已经进行了大量的研究，还有很多有待透露的TCS在本次审查中讨论，无论是在他们发挥的生理作用，以及他们提出的信号级联和机制的行动。这些系统的激活信号的识别和所产生的蛋白质的结构表征是未来必须进行的一些任务。
The complex regulatory network formed by the TCS in S. coelicolor is far from being unraveled. Many of the systems that have already been described still require further examination and the functions of approximately two-thirds of TCSs remain unknown. Nevertheless, the biotechnological potential of these bacteria has been shown to be enormous in recent decades and will continue to be in the future.
S.腔棘鱼还远未解开。许多已经描述过的系统仍然需要进一步研究，大约三分之二的TCS的功能仍然未知。尽管如此，近几十年来，这些细菌的生物技术潜力已被证明是巨大的，并将在未来继续下去。
Acknowledgments 致谢
The authors would like to thank Emma Keck for her help with the English language revisions.
作者要感谢Emma Keck在英语修订方面提供的帮助。
Funding Statement 资金报表
This work was funded by the project PID2019-107716RB-I00 (Spanish Ministry of Science and Innovation/State Research Agency/10.13039/501100011033). The work by R.S.d.l.N. was supported through an FPU fellowship (ref.: FPU17/02862) from the Spanish Ministry of Science, Innovation, and Universities. Furthermore, our institute (IBFG) was funded by the Program “Escalera de Excelencia” of the Junta de Castilla y León (ref.: CLU-2017-03), co-funded by the P.O. FEDER of Castilla y León 14–20, and the Internationalization Project “CL-EI-2021-08-IBFG Unit of Excellence” of the CSIC, funded by Junta de Castilla y León and co-financed by the European Union (ERDF “Europe drives our growth)”.
这项工作由项目PID 2019 - 107716 RB-I 00（西班牙科学和创新部/国家研究机构/10.13039/501100011033）资助。R.S.d.l.N.的作品通过FPU奖学金获得支持（参考：FPU 17/02862）从西班牙科学，创新和大学部。此外，我们的研究所（IBFG）由卡斯蒂利亚和莱昂委员会的“Escalera de Excelvent”计划资助（参考：CLU-2017-03），由P.O. FEDER of Castilla y León 14-20，以及CSIC的国际化项目“CL-EI-2021-08-IBFG Unit of Excellence”，由Junta de Castilla y León资助，由欧盟共同资助（ERDF“Europe drives our growth”）。
Author Contributions 作者贡献
R.S.d.l.N.: writing of the manuscript; M.D. and R.I.S.: writing and review of the manuscript; M.D. and R.I.S.: funding. All authors have read and agreed to the published version of the manuscript.
R.S.d.l.N.：手稿的写作;医学博士R.I.S.：写作和审查手稿;医学博士R.I.S.：经费所有作者都已阅读并同意手稿的出版版本。
Footnotes 脚注
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