Utilization of N-acetylglucosamine by Streptococcus mutans and its regulation

 描述（由申请人提供）：人类口腔中定植着极其复杂的微生物群落，与患有龋齿或牙周疾病的个体相比，健康人中的群落的组成和生物化学活性不同。口腔生物膜和宿主环境之间的相互作用需要广泛的研究，以更好地了解疾病的发生和发展。人类饮食中的碳水化合物以及由宿主分泌物、宿主细胞和微生物提供的碳水化合物为定殖于人类牙齿表面的许多细菌分类群提供必需的碳和能量来源。对于乳酸菌（LAB）来说尤其如此，它们几乎完全依赖碳水化合物来产生能量和酸。葡糖胺（GlcN）和N-乙酰葡糖胺（GlcNAc）是地球上最丰富的天然存在的糖之一，并且作为碳和氮的来源被许多细菌物种分解代谢。在不存在这些氨基糖的情况下，细菌还从果糖-6-P和谷氨酰胺合成GlcN-6-P用于细胞壁生物合成。尽管这些氨基糖在口腔中普遍存在，但关于它们被口腔微生物群，特别是龋齿病原体利用的研究很少。在这里，我们提出了新的数据的调节和作用，在生理稳态的GlcN和GlcNAc的利用和生物合成的主要龋齿病原体，变形链球菌。重要的是，我们表明，监管机制的GlcN-6-P的内源性生产是不同的范式模型，如枯草芽孢杆菌和大肠杆菌。具体而言，我们已经证明，负责编码GlcNAc-6-P脱乙酰酶（那牙）和GlcN-6-P脱氨酶（NagB）的GlcNAc催化剂的基因受到GntR/HutC家族调节因子NagR的负调控。虽然nagAB的NagR依赖性调节是相当常见的，但我们还发现编码负责产生GlcN-6-P的酶GlmS的基因也在NagR的直接控制下;这是一个非常不寻常的发现，因为NagB分解代谢，而GlmS产生GlcN-6-P。大肠杆菌中的表达或mRNA在B中的稳定性。subtilis似乎不存在于S.变异人基于这些观察结果，我们建议：1）开始剖析维持NagB和GlmS活性之间关键平衡的分子机制; 2）更详细地探索S消耗GlcNAc的生理和生态益处。变异人从这些研究中获得的知识将为了解S.变形菌和相关口腔细菌，这可以导致对口腔植物群的致病潜力的改进控制。此外，许多乳酸杆菌、A组链球菌和肺炎链球菌似乎与S.因此，这些研究对一组重要的人类病原体和细菌具有高度相关性。

 DESCRIPTION (provided by applicant): Remarkably complex microbial communities colonize human oral cavity, and the composition and biochemical activities of the communities differ in healthy humans compared with individuals with dental caries or periodontal diseases. Interactions between oral biofilms and host environment warrant extensive study to better understand the initiation and progression of diseases. Carbohydrates in the human diet, and those provided by host secretions, host cells and microorganisms provide essential carbon and energy sources to many bacterial taxa that colonize human tooth surface. This is especially true for the lactic acid bacteria (LAB), which depend almost entirely on carbohydrates for energy and acid production. Glucosamine (GlcN) and N- acetylglucosamine (GlcNAc) are among the most abundant naturally-occurring sugars on the planet, and are catabolized by many bacterial species as a source of both carbon and nitrogen. In the absence of these amino sugars, bacteria also synthesize GlcN-6-P from fructose-6-P and glutamine for cell wall biogenesis. Despite the ubiquity of these amino sugars in the oral cavity, there have been very few studies regarding their utilization by the oral microbiota, and in particular by dental caries pathogens. Here, we present new data on the regulation and role in physiologic homeostasis of GlcN and GlcNAc utilization and biosynthesis in the major dental caries pathogen, Streptococcus mutans. Importantly, we show that the regulatory mechanisms governing the endogenous production of GlcN-6-P are different from paradigm models, such as Bacillus subtilis and Escherichia coli. Specifically, we have demonstrated that the genes responsible for GlcNAc catabolism encoding GlcNAc-6-P deacetylase (NagA) and GlcN-6-P deaminase (NagB), are negatively regulated by the GntR/HutC-family regulator NagR. While NagR-dependent regulation of nagAB is fairly common, we also discovered that the gene encoding the enzyme responsible for producing GlcN-6-P, GlmS, is also under direct control of NagR; a highly unusual finding since NagB catabolizes, but GlmS produces, GlcN-6-P. Moreover, the RNA-based pathways for control of glmS translational efficiency in E. coli or of mRNA stability in B. subtilis do not appear to be present in S. mutans. On the basis of these observations, we propose 1) to begin to dissect the molecular mechanisms maintaining the critical balance between NagB and GlmS activities and 2) to explore in more detail the physiologic and ecological benefits of the consumption of GlcNAc by S. mutans. The knowledge gained from these studies will provide critical information needed to understand amino sugar metabolism by S. mutans and related oral bacteria, which could lead to improved control of the pathogenic potential of the oral flora. In addition, many lactobacilli, group A streptococci, and Streptococcus pneumoniae, appear to share some key features in glmS regulation with S. mutans, so these investigations are of high relevance to a group of important human pathogens and commensals.