Sensing central metabolic stress

感知中枢代谢压力

• 批准号: 7919714
• 负责人: ALAN J WOLFE
• 金额: $ 31.77万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919714
• 关键词: Acetates; Acetyl Coenzyme A; Acetylation; Bacteria; Behavior; Biochemical Genetics; Biochemistry; Carbon; Cell physiology; Cells; Coenzyme A; Colon; Complex; Coupled; Development; Escherichia coli; Fermentation; Flagella; Gene Expression; Genetic; Glucose; Growth; Human; Individual; Learning; Link; Metabolic stress; Metabolism; Microbial Biofilms; Nutritional status; Pathogenesis; Pathway interactions; Phosphorylation; Pilum; Positioning Attribute; Process; Recycling; Regulation; Signal Transduction; Signaling Protein; Source; Swimming; Testing; Urinary tract infection; Variant; Virulence; acetyl phosphate; antimicrobial; base; carboxylate; design; experience; inorganic phosphate; member; metabolomics; novel; pathogen; promoter; public health relevance; response

DESCRIPTION (provided by applicant): In Escherichia coli -- and likely other bacteria -- high-energy intermediates of central metabolism [e.g. acetyl phosphate (acP) and acetyl-coenzyme A (acCoA)] appear to control global gene expression -- at least in part - through a subset of signaling proteins called two-component signal transduction (2CST) response regulators (RRs). The high-energy status of acP and acCoA makes each an excellent donor: acP can donate its phosphoryl group, while acCoA can donate its acetyl group. Coupled with their central position in metabolism, these abilities make acP and acCoA ideally suited to indicate nutritional status and thereby impact a variety of cellular processes. This proposal will test key aspects of the following hypothesis. Cells exposed to excess carbon experience a central metabolic stress associated with their inability to recycle coenzymeA (CoA) rapidly enough. Because CoA is present in limiting amounts, the acCoA:CoA ratio becomes large. To recycle the metabolically essential CoA, some of the excess acetyl groups pass from CoA to inorganic phosphate. This process results in the synthesis of acP, which has been proposed to donate its phosphoryl group to a subset of 2CSTRRs. Alternatively or simultaneously, other acetyl groups can be donated directly to a second subset of RRs, thereby altering their function. This hypothesis is broadly based on the following observations: (i) cells manipulate the ratio of acCoA and acP during growth and in response to the quality and quantity of carbon source. (ii) cells respond globally to variations in the concentrations of both high-energy central metabolites; (iii) the response to acP depends on the action of at least one RR and likely more; (iv) two promoters, each dependent on a different RR, appear to respond to the status of the acCoA pool; and (v) acCoA has been shown to donate its acetyl group to 2 purified RRs. 2CST pathways regulate diverse processes associated with biofilm development and pathogenesis. Because humans do not express 2CST pathways, the abilities of acP and acCoA to modify RRs represent a prime target for anti-microbial strategies. PUBLIC HEALTH RELEVANCE: This proposal will test the hypothesis that acetyl coenzyme A and acetyl phosphate, high-energy intermediates of central metabolism, can modify - by acetylation or phosphorylation, respectively - and thereby alter the function of signaling proteins that contribute to biofilm development by and virulence of diverse pathogens. Because humans do not express these signaling proteins, called response regulators, these interactions represent a prime target for anti-microbial strategies.

描述（由申请人提供）：在大肠杆菌-以及可能的其他细菌-中，中心代谢的高能中间体[例如乙酰磷酸（acP）和乙酰辅酶A（acCoA）]似乎通过称为双组分信号转导（2CST）反应调节因子（RR）的信号蛋白亚组控制全局基因表达-至少部分控制全局基因表达。acP和acCoA的高能量状态使其各自成为优秀的供体：acP可以捐赠其磷酰基，而acCoA可以捐赠其乙酰基。再加上它们在代谢中的中心地位，这些能力使acP和acCoA非常适合指示营养状态，从而影响各种细胞过程。本提案将检验以下假设的关键方面。暴露于过量碳的细胞经历与它们不能足够快地再循环辅酶A（CoA）相关的中心代谢应激。由于CoA以有限的量存在，因此acCoA：CoA比率变大。为了回收代谢必需的辅酶A，一些多余的乙酰基从辅酶A转移到无机磷酸盐。该过程导致acP的合成，acP已被提议将其磷酰基基团捐赠给2CSTRR的子集。可替代地或同时地，其他乙酰基可以直接提供给RR的第二子集，从而改变它们的功能。这一假设广泛地基于以下观察：（i）细胞在生长期间以及响应于碳源的质量和数量来操纵acCoA和acP的比率。(ii)细胞对两种高能中心代谢物浓度的变化有全局性的反应;（iii）对acP的反应取决于至少一种RR的作用，可能更多;（iv）两种启动子，每种依赖于不同的RR，似乎对acCoA库的状态有反应;（v）已显示acCoA将其乙酰基捐赠给2种纯化的RR。2CST通路调节与生物膜形成和发病相关的多种过程。由于人类不表达2CST途径，因此acP和acCoA修饰RR的能力代表了抗微生物策略的主要目标。公共卫生关系：该提案将测试的假设，乙酰辅酶A和乙酰磷酸，中央代谢的高能量中间体，可以修改-通过乙酰化或磷酸化，分别-从而改变信号蛋白的功能，有助于生物膜的发展和毒力的不同病原体。由于人类不表达这些称为反应调节剂的信号蛋白，这些相互作用代表了抗微生物策略的主要目标。