Patil Rachit S, Sharma Siddhant, Bhaskarwar Aditya V, Nambiar Souparnika, Bhat Niharika A, Koppolu Mani Kanta, Bhukya Hussain
Department of Biology, Indian Institute of Science Education and Research, Tirupati, India.
Proteins. 2025 Jan;93(1):38-71. doi: 10.1002/prot.26621. Epub 2023 Oct 24.
This article provides a comprehensive review and sequence-structure analysis of transcription regulator (TR) families, TetR and OmpR/PhoB, involved in specialized secondary metabolite (SSM) biosynthesis and resistance. Transcription regulation is a fundamental process, playing a crucial role in orchestrating gene expression to confer a survival advantage in response to frequent environmental stress conditions. This process, coupled with signal sensing, enables bacteria to respond to a diverse range of intra and extracellular signals. Thus, major bacterial signaling systems use a receptor domain to sense chemical stimuli along with an output domain responsible for transcription regulation through DNA-binding. Sensory and output domains on a single polypeptide chain (one component system, OCS) allow response to stimuli by allostery, that is, DNA-binding affinity modulation upon signal presence/absence. On the other hand, two component systems (TCSs) allow cross-talk between the sensory and output domains as they are disjoint and transmit information by phosphorelay to mount a response. In both cases, however, TRs play a central role. Biosynthesis of SSMs, which includes antibiotics, is heavily regulated by TRs as it diverts the cell's resources towards the production of these expendable compounds, which also have clinical applications. These TRs have evolved to relay information across specific signals and target genes, thus providing a rich source of unique mechanisms to explore towards addressing the rapid escalation in antimicrobial resistance (AMR). Here, we focus on the TetR and OmpR family TRs, which belong to OCS and TCS, respectively. These TR families are well-known examples of regulators in secondary metabolism and are ubiquitous across different bacteria, as they also participate in a myriad of cellular processes apart from SSM biosynthesis and resistance. As a result, these families exhibit higher sequence divergence, which is also evident from our bioinformatic analysis of 158 389 and 77 437 sequences from TetR and OmpR family TRs, respectively. The analysis of both sequence and structure allowed us to identify novel motifs in addition to the known motifs responsible for TR function and its structural integrity. Understanding the diverse mechanisms employed by these TRs is essential for unraveling the biosynthesis of SSMs. This can also help exploit their regulatory role in biosynthesis for significant pharmaceutical, agricultural, and industrial applications.
本文对参与特殊次级代谢产物（SSM）生物合成及抗性的转录调节因子（TR）家族TetR和OmpR/PhoB进行了全面综述和序列-结构分析。转录调控是一个基本过程，在协调基因表达以赋予细菌在频繁的环境应激条件下生存优势方面发挥着关键作用。这个过程与信号感知相结合，使细菌能够对各种细胞内和细胞外信号做出反应。因此，主要的细菌信号系统使用一个受体结构域来感知化学刺激，同时使用一个输出结构域通过DNA结合来负责转录调控。单条多肽链上的传感和输出结构域（单组分系统，OCS）通过变构作用对刺激做出反应，即根据信号的存在与否调节DNA结合亲和力。另一方面，双组分系统（TCSs）允许传感和输出结构域之间进行相互作用，因为它们是分开的，并通过磷酸化传递信息以做出反应。然而，在这两种情况下，TR都起着核心作用。包括抗生素在内的SSM的生物合成受到TR的严格调控，因为它将细胞资源转移用于生产这些也具有临床应用价值的消耗性化合物。这些TR已经进化到能够跨特定信号和靶基因传递信息，从而为探索应对抗菌药物耐药性（AMR）快速上升的独特机制提供了丰富来源。在这里，我们重点关注分别属于OCS和TCS的TetR和OmpR家族TR。这些TR家族是次级代谢中调节因子的著名例子，在不同细菌中普遍存在，因为它们除了参与SSM生物合成和抗性外，还参与无数细胞过程。因此，这些家族表现出更高的序列差异，这从我们分别对TetR和OmpR家族TR的158389个和77437个序列进行的生物信息学分析中也很明显。对序列和结构的分析使我们除了确定负责TR功能及其结构完整性的已知基序外，还发现了新的基序。了解这些TR所采用的多种机制对于阐明SSM的生物合成至关重要。这也有助于利用它们在生物合成中的调节作用，实现重要的制药、农业和工业应用。
