6.20 - RNA Modifying Enzymes

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Approximately 100 chemically distinct, modified nucleosides occur in nucleic acids, with the vast majority seen in RNA. According to estimates, 5% of the Escherichia coli genome codes for the enzymes responsible for RNA modification. After the discovery of pseudouridine (pseudoU) in 1957, progress has been made to chemically identify the modified nucleosides themselves, their occurrence in RNA, and more recently to probe the enzymes responsible for their biosynthesis and incorporation into RNA.

The chapter briefly touches the history of many aspects of RNA modification (referring to previous reviews); however, it focuses on progress made during the past decade. There has been significant success in the determination of the X-ray crystal structures of many modification enzymes, often with their RNA and cofactor substrates bound. These structures have helped to clarify mechanisms, substrate recognition, and have provided insights regarding the evolutionary origins of modern RNA modifying enzymes. Comparative genomics in concert with careful enzymological characterization has elucidated the biochemical pathways for a number of the more complex modified nucleosides. Detailed studies have clarified mechanistic issues for a number of enzymes and, in one case, have actually caused a re-consideration of a mechanism that was previously thought to be understood. As technology advances, it seems likely that, a large number of nucleoside modifications will be found in a more diverse set of RNA species. It will become increasingly more important to characterize both the mechanism and substrate recognition for the enzymes responsible for generating these interesting natural products.

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George A. Garcia received his Ph.D. in pharmaceutical chemistry from the University of California, San Francisco in 1988, where he worked with Professor George L. Kenyon on the enzymology of benzoylformate decarboxylase and inhibitor design for tyrosine kinase. He was an NIH-sponsored postdoctoral fellow in the lab of Professor Alan R. Fersht in Cambridge, England in 1988 and 89. There he worked on tyrosyl-tRNA synthetase. He joined the faculty of the University of Michigan, College of Pharmacy in 1990 and presently works as associate professor of medicinal chemistry. Professor Garcia’s research interests are in the area of the enzymology of RNA modification and in novel antibiotic drug discovery. He has served on the NIH Bioorganic and Natural Products Chemistry Study Section. Professor Garcia’s research study has been supported by grants from NIH and from NSF. He has authored approximately 45 papers, reviews, and book chapters.

Julie K. (Cutcher) Hurt received a B.A. in chemistry (biology minor) from Kalamazoo College in 2004. She is completing her Ph.D. under the guidance of Professor George A. Garcia in the Department of Medicinal Chemistry, University of Michigan. Her research involves the primary virulence factor in Shigella flexneri, VirF, a member of the AraC family of transcriptional activators. Ms. Hurt is studying the link between VirF expression and activity as it relates to post-transcriptional RNA modification by TGT.

Yi-Chen Chen, a native of Taiwan, received his B.S. in pharmacy and M.S. in pharmaceutics with Professor Wen-Jen Lin (on the topic of developing novel drug carriers via biocompatible polymers) from the National Taiwan University. He is currently a Ph.D. candidate working under the guidance of Professor George A. Garcia in the Department of Medicinal Chemistry, University of Michigan. His research project is to characterize a human tRNA-modifying enzyme, TGT in order to gain further insight into the biological significance of queuosine modification.

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