Metabolism of Aromatic Ring Precursors in Coenzyme Q Biosynthesis

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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.