Utilization of N-acetylglucosamine by Streptococcus mutans and its regulation

变形链球菌对N-乙酰氨基葡萄糖的利用及其调控

• 批准号: 8808938
• 负责人: Lin Zeng
• 金额: $ 11.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8808938
• 关键词: Acetylglucosamine; Acids; Amino Sugars; Anabolism; Bacillus subtilis; Bacteria; Biochemical; Biogenesis; Biological Assay; Carbohydrates; Carbon; Catabolism; Cell Wall; Cells; Communicable Diseases; Communities; Complex; Consumption; Coupled; Data; Deacetylase; Deaminase; Dental caries; Development; Diet; Disease Progression; Ecology; Energy-Generating Resources; Environment; Environmental Impact; Enzymes; Equilibrium; Escherichia coli; Family; Foundations; Fructose; Future; Gene Expression; Generations; Genes; Genetic; Glucosamine; Glucose; Glutamine; Goals; Growth; Homeostasis; Human; Individual; Investigation; Knowledge; Lactobacillus; Lead; Mannose; Metabolism; Microbial Biofilms; Modeling; Molecular; Molecular Biology; Molecular Profiling; Nitrogen; Oral; Oral cavity; Oral health; Organism; Pathway interactions; Peptidoglycan; Periodontal Diseases; Physiological; Physiology; Pilot Projects; Planets; Play; Principal Investigator; Process; Production; Property; Protein S; RNA; Regulation; Research; Role; Signal Transduction; Site; Source; Streptococcus mutans; Streptococcus pneumoniae; Streptococcus pyogenes; Taxon; Virulence; Virulence Factors; Work; base; career; cariogenic bacteria; combat; design; differential expression; fitness; gene discovery; improved; lactic acid bacteria; mRNA Stability; microbial; microbial community; microorganism; mutant; new therapeutic target; novel therapeutics; oral bacteria; oral biofilm; pH Homeostasis; pathogen; promoter; public health relevance; response; sugar; tool; tooth surface; trait

 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.

 描述（由申请人提供）：人类口腔中栖息着非常复杂的微生物群落，与患有龋齿或牙周病的个体相比，健康人的群落组成和生化活性有所不同。口腔生物膜与宿主环境之间的相互作用需要进行广泛的研究，以更好地了解疾病的发生和进展。人类饮食中的碳水化合物以及宿主分泌物、宿主细胞和微生物提供的碳水化合物为定植于人类牙齿表面的许多细菌类群提供了必需的碳和能量来源。对于乳酸菌（LAB）来说尤其如此，它几乎完全依赖碳水化合物来产生能量和酸。氨基葡萄糖 (GlcN) 和 N-乙酰氨基葡萄糖 (GlcNAc) 是地球上最丰富的天然糖类之一，被许多细菌种类分解代谢为碳和氮的来源。在缺乏这些氨基糖的情况下，细菌也会从果糖-6-P 和谷氨酰胺合成 GlcN-6-P，用于细胞壁生物发生。尽管这些氨基糖在口腔中普遍存在，但关于口腔微生物群，特别是龋齿病原体对它们的利用的研究却很少。在这里，我们提出了关于主要龋齿病原体变形链球菌中 GlcN 和 GlcNAc 利用和生物合成的生理稳态调节和作用的新数据。重要的是，我们表明控制 GlcN-6-P 内源性生产的调节机制不同于枯草芽孢杆菌和大肠杆菌等范式模型。具体来说，我们已经证明负责编码 GlcNAc-6-P 脱乙酰酶 (NagA) 和 GlcN-6-P 脱氨酶 (NagB) 的 GlcNAc 分解代谢的基因受到 GntR/HutC 家族调节因子 NagR 的负调控。虽然 nagAB 的 NagR 依赖性调节相当普遍，但我们还发现编码负责产生 GlcN-6-P 的酶 GlmS 的基因也受到 NagR 的直接控制；这是一个非常不寻常的发现，因为 NagB 会分解代谢，但 GlmS 会产生 GlcN-6-P。此外，用于控制大肠杆菌中glmS翻译效率或枯草芽孢杆菌中mRNA稳定性的基于RNA的途径似乎并不存在于变形链球菌中。基于这些观察，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) 更详细地探索变形链球菌消耗 GlcNAc 的生理和生态效益。从这些研究中获得的知识将为了解变形链球菌和相关口腔细菌的氨基糖代谢提供所需的关键信息，这可能有助于改善对口腔菌群致病潜力的控制。此外，许多乳酸杆菌、A 族链球菌和肺炎链球菌似乎与变形链球菌在 glmS 调节方面具有一些关键特征，因此这些研究与一组重要的人类病原体和共生菌具有高度相关性。