Date of Award:

5-2013

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Committee Chair(s)

Joan M. Hevel

Committee

Joan M. Hevel

Committee

Lance C. Seefeldt

Committee

Sean J. Johnson

Committee

Tim Gilbertson

Committee

Alvan C. Hengge

Abstract

Protein enzymes perform a vast array of functions within living organisms, catalyzing various metabolic reactions including DNA replication, DNA repair, protein synthesis, etc. In order to maintain proper cellular functions, enzymes need to be accurately regulated under different circumstances. Specifically, enzymes can be modified after their creation to give them additional functions. These modifications can do a variety of things including activating (turning on) or inactivating (turning off) an enzyme, changing what proteins or molecules can interact with the enzyme, changing the enzyme’s location in the cell, and/or targeting the enzyme for destruction. This dissertation focuses on a single class of enzymes, protein arginine methyltransferases (PRMTs), which transfer one or two methyl groups to a specific amino acid, arginine, in the target protein (substrate).

Arginine methylation is a small but significant modification involved in cellular processes such as transcriptional regulation, DNA repair, subcellular localization, signal transduction, and nuclear transport. Moreover, irregular expression and malfunction of PRMTs, which lead to altered amount and/or type of the methylation products, are broadly observed in cancer and cardiovascular disease. Thus, detailed study of PRMTs is essential for the development of therapeutic drugs for diseases associated with arginine methylation. This dissertation presents continuous studies with broad insight into the product specificity and catalytic mechanism of PRMT1 by addressing how PRMT1 is regulated to maintain its specificity and activity to generate the desired amount and type of methylation products.

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