Metabolism of Aromatic Ring Precursors in Coenzyme Q Biosynthesis

辅酶 Q 生物合成中芳环前体的代谢

• 批准号: 1330803
• 负责人: Catherine Clarke
• 金额: $ 83.35万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1330803&HistoricalAwards=false
• 关键词: Metabolism; Aromatic; Ring; Precursors; Coenzyme

Scientific Merit:The controlled burn of carbohydrates (sugars) or lipids (fat) generates ATP, the cell's energy currency. Coenzyme Q (also known as ubiquinone, CoQ or Q) is an organic molecule essential for production of ATP. CoQ is also a crucial antioxidant that can protect cell membrane lipids from damage mediated by free radicals. From a chemical standpoint, the CoQ molecule has two parts: (1) a long carbon containing "tail" that anchors it in the membrane, and (2) an aromatic ring structure (benzoquinone) with properties that allow it to ferry electrons and protons essential to its function in ATP formation, and also donate H atoms essential to its function as an antioxidant. Cells are generally thought to produce the benzoquinone ring from the precursor 4-hydroxybenzoic acid (4-HB). The investigators identified a new pathway for biological formation of CoQ in baker's yeast, emanating from para-aminobenzoic acid or pABA, long thought to be dedicated exclusively to the biosynthesis of folate. Interestingly, unlike folate, CoQ is devoid of nitrogen in its chemical composition. Elucidating the biological steps or sequence by which the amino group that contains the nitrogen is removed is a key goal of this project. New evidence indicates that certain plant metabolites may also serve as potential ring precursors of CoQ, suggesting there are even more routes to generate CoQ. This project will investigate these new possible pathways and also determine whether they operate in other organisms.Broader Impacts:In this project graduate and undergraduate students are trained as researchers, and graduate students are also trained in the art and teaching of science. Graduate students have the opportunity to teach and mentor undergraduate students, and undergraduate students are active participants in the scientific discovery process. Instead of learning about metabolism as previously characterized textbook pathways that must be memorized, students learn that there are many unsolved problems and other routes yet to be discovered. This leads them to question the textbook pathways, and ask, "How do we know? How do these pathways differ? Why have more than one pathway?". Undergraduate students, including underrepresented minority students, learn to characterize mutants, use isotopes in metabolic labeling experiments, and prepare and analyze lipid extracts in the laboratory and learn science by doing. Students also see how interdisciplinary interactions among the project faculty with interdisciplinary expertise in organic synthetic chemistry, biochemistry and cell biology advances scientific research. Students present their research findings at undergraduate conferences, UCLA symposia, and at national and international meetings. This project identifies new pathways required for energy generating processes in living cells. Besides enhancing knowledge regarding the biosynthesis of the essential molecule CoQ, results may also lead to applications in agriculture, as the enzymes involved in this pathway are potential targets for herbicides.

科学价值：碳水化合物（糖）或脂质（脂肪）的受控燃烧产生ATP，细胞的能量货币。辅酶Q（也称为泛醌，CoQ或Q）是生产ATP所必需的有机分子。辅酶Q也是一种重要的抗氧化剂，可以保护细胞膜脂质免受自由基介导的损伤。从化学的角度来看，辅酶Q分子有两个部分：（1）一个长的含碳“尾巴”，将其锚定在膜上，和（2）一个芳香环结构（苯醌），其特性允许它运送电子和质子，这对它在ATP形成中的功能至关重要，并且还提供H原子，这对它作为抗氧化剂的功能至关重要。细胞通常被认为从前体4-羟基苯甲酸（4-HB）产生苯醌环。研究人员发现了一种新的途径，用于生物形成辅酶Q在面包酵母，从对氨基苯甲酸或pABA，长期以来被认为是专门用于叶酸的生物合成。有趣的是，与叶酸不同，辅酶Q的化学组成中没有氮。阐明去除含氮氨基的生物步骤或顺序是该项目的关键目标。新的证据表明，某些植物代谢物也可能作为辅酶Q的潜在环前体，这表明有更多的途径来产生辅酶Q。该项目将调查这些新的可能途径，并确定它们是否在其他生物中运作。更广泛的影响：在该项目中，研究生和本科生被培训为研究人员，研究生也接受科学艺术和教学方面的培训。研究生有机会教授和指导本科生，本科生是科学发现过程的积极参与者。学生们不再像以前那样学习必须记住的教科书途径，而是学习有许多未解决的问题和其他尚未发现的途径。这导致他们质疑教科书上的路径，并问：“我们怎么知道？这些途径有何不同？为什么有不止一条路？".本科生，包括代表性不足的少数民族学生，学习表征突变体，在代谢标记实验中使用同位素，在实验室中制备和分析脂质提取物，并通过实践学习科学。学生们还将看到项目教师之间的跨学科互动如何在有机合成化学，生物化学和细胞生物学方面具有跨学科的专业知识，从而推动科学研究。学生在本科生会议，加州大学洛杉矶分校研讨会，并在国家和国际会议上提出他们的研究成果。该项目确定了活细胞中能量产生过程所需的新途径。除了增强有关必需分子辅酶Q生物合成的知识外，研究结果还可能导致农业应用，因为参与这一途径的酶是除草剂的潜在靶标。