One Enzyme for Two Distinct Metabolisms

一种酶负责两种不同的代谢

• 批准号: 8324519
• 负责人: F ROBERT TABITA
• 金额: $ 28.53万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324519
• 关键词: Active Sites; Address; Aerobic; Animal Model; Apoptotic; Assimilations; Biochemical; Bordetella bronchiseptica; Cancer Cell Growth; Carbon; Catalysis; Cells; DNA; Enzymes; Eukaryotic Cell; Genetic; Goals; Growth; Health; Human; Investigation; Knowledge; Laboratories; Life Cycle Stages; Liver Cirrhosis; Lower Organism; Metabolic; Metabolic Pathway; Metabolism; Methionine; Mycobacterium tuberculosis; Organism; Oxygenases; Parasites; Pathology; Pathway interactions; Physiological Processes; Play; Post-Translational Protein Processing; Process; Production; Prokaryotic Cells; Protein Biosynthesis; Proteins; RNA; Reaction; Regimen; Regulation; Relative (related person); Rhodospirillum rubrum; Ribulose-Bisphosphate Carboxylase; Role; Route; Scheme; Structure-Activity Relationship; Sulfur; Sulfur Compounds; Sulfur Metabolism Pathway; System; Therapeutic Agents; Trypanosoma; analog; base; cell growth; enolase; experience; insight; microorganism; novel; oxidation; pathogen; protein structure function; ribulose

DESCRIPTION (provided by applicant): Sulfur-containing metabolites play significant roles in many important processes that define healthy cellular activity. To make sulfur precursor molecules available for subsequent metabolism, and for DNA and RNA metabolism and various protein posttranslational modifications, prokaryotic and eukaryotic cells have developed salvage or sparing pathways. When such pathways become compromised, there are many health-related effects that are noted. For example, disruption or reduced functioning of the methionine salvage pathway has consequences relative to cancer cell growth and liver cirrhosis. In addition, intermediates of this pathway have been shown to influence apoptotic processes, while analogs of these intermediates are promising therapeutic agents that selectively disrupt the life cycle of malarial and trypanosome parasites. Despite the importance of such pathways, the strategies by which microorganisms and higher organisms control their ability to salvage sulfur-containing metabolites is not well understood, nor is there good understanding of the variety of ways in which these metabolites may be produced. In this investigation, the overall goal is to better understand the mechanism and regulation of newly discovered and wide-spread novel sulfur salvage pathways. Based on recent studies, it is apparent that an important and surprising strategy taken by diverse organisms is to employ ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) or the RubisCO-like protein (RLP), or both RubisCO and RLP, as key reactions that anchor sulfur salvage pathways in the cell. Both enzymes catalyze absolutely essential reactions that are needed for the metabolism and salvage of sulfur-containing metabolites in the cell. Using a model organism (Rhodospirillum rubrum) that is amenable to genetic and biochemical manipulation, and employs both aerobic (RLP-anchored) and anaerobic (RubisCO-anchored) methionine/sulfur salvage pathways, we will seek to: (a) elucidate the involvement of novel reactions required for new pathways of sulfur salvage; (b) determine how the aerobic and anaerobic pathways are differentially controlled; and (c) establish how the active site region of RubisCO accommodates and enables catalysis of reactions crucial to both sulfur and carbon metabolism. The latter aim presents an unprecedented opportunity to provide new paradigms for integrating protein structure/function relationships to key and diverse physiological processes.

描述（由申请人提供）：含硫代谢物在定义健康细胞活性的许多重要过程中起着重要作用。为了使硫前体分子可用于随后的代谢，以及用于DNA和RNA代谢以及各种蛋白质后翻译后修饰，原核和真核细胞已经开发出挽救或保留途径。当这种途径被妥协时，有许多与健康相关的影响。例如，相对于癌细胞生长和肝肝硬化，蛋氨酸挽救途径的破坏或减少具有后果。此外，该途径的中间体已被证明会影响凋亡过程，而这些中间体的类似物是有前途的治疗剂，可有望选择性地破坏疟疾和锥虫寄生虫的生命周期。尽管这种途径很重要，但微生物和更高生物体控制其拯救含硫硫代谢的能力的策略尚不清楚，也没有很好地了解这些代谢物可以产生这些代谢物的各种方式。在这项调查中，总体目标是更好地了解新发现和广泛的新型硫磺拯救途径的机制和调节。根据最近的研究，很明显，多种生物体采取的重要且令人惊讶的策略是采用核糖1,5-双磷酸羧化酶/氧合酶（Rubisco）或Rubisco类蛋白（RLP），或Rubisco和Rubisco和RLP，或作为锚定硫磺溶液途径的关键反应。这两种酶都催化了绝对必要的反应，这些反应是细胞中代谢和挽救含硫代谢物的代谢所需的必不可少的反应。使用可与遗传和生化操纵相提并论的模型有机体（杜鹃花rubrum），并采用有氧和厌氧（RLP锚定）和厌氧（Rubisco锚定的）甲硫氨酸/硫酸硫氨酸/硫磺溶剂的途径，我们将寻求：（a）为新的反应介绍了新的反应，以供新的途径参与。 （b）确定有氧和厌氧途径如何差异控制； （c）建立Rubisco的活性部位区域如何适应对硫和碳代谢至关重要的反应的催化。后一个目标为提供新的范式提供了将蛋白质结构/功能关系与关键和多样化生理过程相结合的新范式。