A novel family of conserved glyoxal toxicity response proteins.

一个新的保守乙二醛毒性反应蛋白家族。

• 批准号: 10365682
• 负责人: ANDREW T ULIJASZ
• 金额: $ 44.59万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365682
• 关键词: Aging; Amino Acids; Anabolism; Antibiotics; Area; Arginine; Assimilations; Atherosclerosis; Bacteria; Binding; Binding Proteins; Biological Assay; Calcium-Binding Proteins; Cells; Cellular Stress; Cellular Structures; Complex; Crystallography; Cysteine; Data; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Enzymes; Eukaryota; Excision; Family; Fluorescence Resonance Energy Transfer; Gene Expression Regulation; Generations; Genes; Genetic; Glycolysis; Glyoxal; Goals; Grant; Growth; Health; Heart Diseases; Heme; Heme Iron; Histidine; Homeostasis; Human; Hypertension; Image; Iron; Knowledge; Life; Light; Literature; Longevity; Lysine; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Membrane; Metabolic; Metabolism; Methods; Microscopy; Mixed Function Oxygenases; Modification; Molecular; Mutation; Names; Nature; Nerve Degeneration; Neurons; Nuclear Magnetic Resonance; Nutrient; Operon; Organism; Oxidative Stress; Pathway interactions; Pattern; Planet Earth; Play; Polysaccharides; Predisposition; Process; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pyruvaldehyde; Quinolones; Regulation; Research; Resolution; Role; Side; Signal Pathway; Signal Transduction; Stress; Structure; System; Techniques; Time; Toxic effect; Toxin; Vesicle; Virulence Factors; Work; antimicrobial; biological adaptation to stress; cell envelope; experimental study; heme-binding protein; human disease; mutant; nervous system disorder; novel; novel antibiotic class; pathogenic bacteria; protein function; quorum sensing; remediation; response; stem; transcriptome sequencing; uptake; virtual

Advanced Glycan End Products (AGEs) are toxic and highly reactive dicarbonyl molecules produced by most life on earth from routine metabolic processes. As such, conserved and dedicated detoxifying systems have emerged for dicarbonyl removal. Owing to their importance, these removal systems are required to maintain longevity, thereby emphasizing the importance of dicarbonyl detoxification in maintaining health. One of the most prominent dicarbonyl species is glyoxal, which is predominantly produced as a byproduct of glycolysis. Glyoxal acts by mounting specific attacks on certain amino acids, namely arginines, cysteines, histidines and lysines in key proteins, thereby adversely altering protein function. In humans, these modifications can result in many diseased states, including: cancer, diabetes, nervous system disorders, heart disease, hypertension, atherosclerosis and aging. Unfortunately, although dicarbonyl stress-related toxicity is now regarded as important as oxidative stress, knowledge about how cells are able to detect and respond to glyoxal buildup is, by comparison, severely lacking. Our lab has discovered a novel class of Antibiotic Monooxygenase (ABM) domains that we hypothesize sense and respond to glyoxal and related dicarbonyls from bacteria to humans. This project proposes to elucidate the mechanism by which one of these ABM domains, we named Glyoxal-ABM Domain 1 (GAD1) responds to glyoxal in the bacterial pathogen Pseudomonas aeruginosa. We have thus far shown that GAD1 from P. aeruginosa, which is co- transcribed with the glyoxal detoxification enzyme GloA2, binds heme directly and is also covalently modified by glyoxal on a conserved arginine residue (Arg49). We hypothesize that GAD1 and its many homologs are specifically modified on conserved residues, which, in turn, signals to switch cellular metabolic flux away from glycolysis other pathways unable to produce the glyoxal toxin. Our studies here will Aim to (1) map GAD1 regulation, (2) determine its cellular distribution and its interactome and (3) solve the structures of its apo and holo forms, and in complex with interacting partners in P. aeruginosa. Studying GAD1 in P. aeruginosa is expected to reveal novel pathways that have potential as new antimicrobial targets, and at the same time advance our basic understanding of glyoxal toxicity sensing in humans and other multicellular organisms.

高级聚糖终产物（年龄）是有毒且高反应性的双骨分子 由地球上的大多数生命从常规代谢过程中产生。因此，保守和 专用的排毒系统已出现用于去除双骨的去除。由于它们的重要性， 这些拆除系统需要保持寿命，从而强调了重要性 维持健康方面的双骨解毒。最杰出的双龙酮物种之一 是乙醇，主要作为糖酵解的副产品产生。甘氨酸作用 对某些氨基酸的特定攻击，即精氨酸，半胱氨酸，组氨酸和 关键蛋白质中的赖氨酸，从而不利地改变了蛋白质功能。在人类中，这些 修改可能导致许多患病状态，包括：癌症，糖尿病，神经系统 疾病，心脏病，高血压，动脉粥样硬化和衰老。不幸的是，虽然 现在认为与毒胁迫相关的毒性与氧化应激一样重要，知识很重要 相比之下，关于细胞如何检测和响应乙二醛的堆积是严重的 缺乏。我们的实验室发现了一种新型的抗生素单加氧酶（ABM）域， 我们假设感官并对从细菌到人类的乙二醛和相关的双骨反应反应。 该项目建议阐明这些ABM域之一的机制，我们 名为乙二醇-ABM结​​构域1（GAD1）对细菌病原体中的乙二醛反应 铜绿假单胞菌。到目前为止，我们已经表明了来自铜绿假单胞菌的GAD1，这是 用乙二醛解毒酶GloA2转录，直接结合血红素，也是 通过乙二醛在保守的精氨酸残基上共价修饰（ARG49）。我们假设这一点 GAD1及其许多同源物是针对保守残留物进行的，而保守残留物又是 信号将细胞代谢通量转移到糖酵解其他途径无法产生的信号 乙二醇毒素。我们在这里的研究将旨在（1）MAP GAD1调节，（2）确定其细胞 分布及其相互作用组，（3）解决其apo和holo形式的结构，以及 与铜绿假单胞菌中的相互作用伙伴的复合物。预计在铜绿假单胞菌中研究GAD1 揭示具有新的抗菌靶标的潜力的新型途径，同时 促进我们对人类和其他多细胞的乙糖毒性感应的基本理解 有机体。