Kinetic, Mechanistic, and Inhibition Studies On the Deiminase Family of Enzymes

<p>Protein arginine deiminase (PAD) and agmatine deiminase (AgD) both belong to the guanidino-group modifying enzymes superfamily. Although these two enzymes catalyze a similar reaction, the conversion of a guanidinium to a ureido and ammonia, their substrates differ greatly, i.e., peptidyl-arginine versus agmatine (decarboxylated arginine). Interestingly, the dysregulation of these enzymes are involved in a number of diseases. Furthermore, it has been shown that the dysregulation of PAD2 as well as PAD4 are involved in a number of diseases including, rheumatoid arthritis, multiple sclerosis, and cancer. AgD is found in plants, viruses, and bacteria where it is involved in energy production, biosynthesis of polyamines, and biofilm formation. Thus, inhibitors for these enzymes could represent novel targets for the treatment of the associated diseases. Herein the kinetic characterization and mechanism of AgD will be discussed. Furthermore, it has been determined that the AgDs utilize a reverse protonation mechanism. These studies have led to the development of the two most potent inactivators of AgD described to date, ABFA and ABCA. Both ABFA and ABCA are mechanism based inactivators. Studies to determine the mechanism of inactivation have been performed and the data suggest proton donation from a histidine is vital in stabilizing the tetrahedral intermediate. Second generation inactivators of PAD4 will also be discussed. TDFA is a mechanism based inactivator that displays 15-fold selectivity for PAD4 compared to PADs 1-3.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Campus Access Dissertation

Discipline thesis:degree_discipline

Chemistry and Biochemistry

Year

2010

Author dc:creator

• Jones, Justin Edward

Contributors dc:contributor

• Paul R Thompson

• Chemistry
• Physical Sciences and Mathematics
• AgD
• Agmatine
• Deiminase
• PAD

Statement dc:rights

• © 2010, Justin Edward Jones

Repository record dc:identifier

https://scholarcommons.sc.edu/etd/693

OAI identifier oai:identifier

oai:scholarcommons.sc.edu:etd-1694