Cross Regulation and Central Metabolism in Bacteria

WANER 9730034交叉监管是发生在不同全球系统之间的监管互动。这些相互作用可能是关键的信息整合者，直接连接网络中的不同路径，以协调生长和新陈代谢。交叉调控最令人信服的证据是在大肠杆菌的磷酸(Pho)调节子中发现的。Pho调节子由大量共调控基因组成，编码各种环境磷(P)来源所需的摄取系统和降解酶。该系统主要由磷/磷双组分调节系统控制；它的控制响应于细胞外无机磷(PI)水平，并与PI转运体相连，而不是PI吸收本身，这是PI代谢的第一步。PHOB的交叉调节涉及两个额外的信号转导通路，这两个通路与PI与代谢中主要的磷酸供体ATP的结合有关。一条信号通路导致分解代谢调节传感器激酶CREC(以前称为Phom)激活Phob。CREC及其伙伴反应调节因子被认为控制着中枢代谢的基因，尽管之前还不知道有什么靶基因。另一种途径是通过底物水平的磷酸转移乙酰基酶-醋酸激酶(PTA-AckA)途径的中间产物乙酰磷酸来激活Phob，从而使PI进入ATP。因此，交叉调节将控制磷同化的基因与控制中枢碳和能量代谢的基因联系起来。已经开发出新的遗传工具来识别由未知功能的调节蛋白控制的基因。这些工具被用来识别CREC/CREB调控的基因。其中一个基因特别有趣，因为它编码一种在不同细菌(大肠杆菌、流感嗜血杆菌、枯草芽孢杆菌和詹纳斯基甲烷球菌)中高度保守的蛋白质，这表明了一种重要的功能，尽管尚未确定。最近的其他结果表明，除了乙酰磷酸外，高能化合物还参与了PHOB的体内激活。已经设计了新的研究来进一步调查这些结果。具体目标1是定义新发现的CREB调节(CBR)基因的遗传调控，并在可行的情况下，使用类似或新的策略，包括基于基因组技术的策略，识别更多的CBR基因。具体目标2是使用新开发的遗传和基因组技术来定义一个或多个CBR基因的功能。具体目标3是使用类似的方法确定一种或多种高能化合物在全球基因表达调控中的作用。这些研究对于深入理解细菌中心代谢途径中基因的交叉调控和调控，以及在细菌基因组学新时代研究基因表达的全球调控策略方面都具有重要意义。

Wanner 9730034 Cross regulation is the regulatory interactions that occur between different global systems. These interactions may be key information integrators, directly linking different pathways in a network to coordinate growth and metabolism. The most compelling evidence for cross regulation is found in the phosphate (Pho) regulon of E. coli. The Pho regulon is comprised of a large number of co-regulated genes encoding uptake systems and degradative enzymes required for the use of various environmental phosphorus (P) sources. This system is controlled primarily by the PhoR/PhoB two-component regulatory system; its control responds to the extracellular inorganic phosphate (Pi) level and is coupled to a Pi transporter but not Pi uptake per se, the first step of Pi metabolism. Cross regulation of PhoB involves two additional signal transduction pathways that are coupled to the incorporation of Pi into ATP, the primary phosphoryl donor in metabolism. One signaling pathway leads to activation of PhoB by the catabolite regulatory sensor kinase CreC (formerly called PhoM). CreC and its partner response regulator are thought to control genes of central metabolism, although no target gene was previously known. The other leads to activation of PhoB by acetyl phosphate, an intermediate of the phosphotransacetylase-acetate kinase (Pta-AckA) pathway of substrate level phosphorylation for entry of Pi into ATP. Accordingly, cross regulation links the control of genes for P assimilation with those for central carbon and energy metabolism. New genetic tools have been developed to identify genes controlled by a regulatory protein of unknown function. These tools were used to identify CreC/CreB-regulated genes. One such gene is especially interesting as it encodes a protein that is highly conserved in diverse bacteria (E. coli, Haemophilus influenzae, Bacillus subtilis, and Methanococcus jannaschii), suggesting an important, although unidentified, function. Other recent results suggest that high energy com pounds in addition to acetyl phosphate are involved in the in vivo activation of PhoB. New studies have been designed to further investigate these results. Specific Aim 1 is to define the genetic regulation of the newly identified CreB-regulated (cbr) genes and, as feasible, to identify additional cbr genes using similar or new strategies, including ones based on genomic techniques. Specific Aim 2 is to define the function of one or more cbr genes using newly developed genetic and genomic techniques. Specific Aim 3 is to define the role of one or more high energy compounds in global regulation of gene expression using similar approaches. These studies will be valuable both in gaining a deeper understanding of cross regulation and the control of genes in central metabolic pathways in bacteria and in developing strategies for studying global regulation of gene expression in the new era of bacterial genomics.