Steinchen Wieland, Zegarra Victor, Bange Gert
Department of Chemistry, Center for Synthetic Microbiology (SYNMIKRO), Philipps-University Marburg, Marburg, Germany.
Front Microbiol. 2020 Sep 7;11:2072. doi: 10.3389/fmicb.2020.02072. eCollection 2020.
When bacteria experience growth-limiting environmental conditions, the synthesis of the hyperphosphorylated guanosine derivatives (p)ppGpp is induced by enzymes of the RelA/SpoT homology (RSH)-type protein family. High levels of (p)ppGpp induce a process called "stringent response", a major cellular reprogramming during which ribosomal RNA (rRNA) and transfer RNA (tRNA) synthesis is downregulated, stress-related genes upregulated, messenger RNA (mRNA) stability and translation altered, and allocation of scarce resources optimized. The (p)ppGpp-mediated stringent response is thus often regarded as an all-or-nothing paradigm induced by stress. Over the past decades, several binding partners of (p)ppGpp have been uncovered displaying dissociation constants from below one micromolar to more than one millimolar and thus coincide with the accepted intracellular concentrations of (p)ppGpp under non-stringent (basal levels) and stringent conditions. This suggests that the ability of (p)ppGpp to modulate target proteins or processes would be better characterized as an unceasing continuum over a concentration range instead of being an abrupt switch of biochemical processes under specific conditions. We analyzed the reported binding affinities of (p)ppGpp targets and depicted a scheme for prioritization of modulation by (p)ppGpp. In this ranking, many enzymes of e.g., nucleotide metabolism are among the first targets to be affected by rising (p)ppGpp while more fundamental processes such as DNA replication are among the last. This preference should be part of (p)ppGpp's "magic" in the adaptation of microorganisms while still maintaining their potential for outgrowth once a stressful condition is overcome.
当细菌处于限制生长的环境条件下时，超磷酸化鸟苷衍生物（p）ppGpp的合成由RelA / SpoT同源性（RSH）型蛋白家族的酶诱导。高水平的（p）ppGpp会引发一个称为“严谨反应”的过程，这是一种主要的细胞重编程过程，在此过程中核糖体RNA（rRNA）和转运RNA（tRNA）的合成被下调，应激相关基因被上调，信使RNA（mRNA）的稳定性和翻译发生改变，并且稀缺资源的分配得到优化。因此，（p）ppGpp介导的严谨反应通常被视为由应激诱导的全或无模式。在过去几十年中，已经发现了几种（p）ppGpp的结合伴侣，其解离常数从低于一微摩尔到超过一毫摩尔不等，因此与非严谨（基础水平）和严谨条件下公认的（p）ppGpp细胞内浓度一致。这表明（p）ppGpp调节靶蛋白或过程的能力在浓度范围内更适合被描述为一个连续的过程，而不是特定条件下生化过程的突然转变。我们分析了已报道的（p）ppGpp靶标的结合亲和力，并描绘了一个（p）ppGpp调节优先级的方案。在这个排名中例如许多核苷酸代谢酶是最早受到（p）ppGpp水平升高影响的靶标之一，而诸如DNA复制等更基本的过程则是最后受到影响的。这种偏好应该是（p）ppGpp在微生物适应过程中的“魔力”的一部分，同时在压力条件被克服后仍保持其生长潜力。
