Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Amidines; Arginine; Arthritis, Rheumatoid; Calcium; Chronic Disease; Citrulline; Enzyme Activation; Enzyme Inhibitors; Humans; Hydrocarbons, Fluorinated; Hydrolases; Molecular Probes; Protein Processing, Post-Translational; Protein Structure, Tertiary
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Protein arginine deiminase 4 (PAD4) is a transcriptional coregulator that catalyzes the calcium-dependent conversion of specific arginine residues in proteins to citrulline. Recently, we reported the synthesis and characterization of F-amidine, a potent and bioavailable irreversible inactivator of PAD4. Herein, we report our efforts to identify the steric and leaving group requirements for F-amidine-induced PAD4 inactivation, the structure of the PAD4-F-amidine x calcium complex, and in vivo studies with N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a PAD4 inactivator with enhanced potency. The PAD4 inactivators described herein will be useful pharmacological probes in characterizing the incompletely defined physiological role(s) of this enzyme. In addition, they represent potential lead compounds for the treatment of rheumatoid arthritis because a growing body of evidence supports a role for PAD4 in the onset and progression of this chronic autoimmune disorder.
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Citation: Biochemistry. 2006 Oct 3;45(39):11727-36. Link to article on publisher's site
Luo, Yuan; Arita, Kyouhei; Bhatia, Monica; Knuckley, Bryan; Lee, Young-Ho; Stallcup, Michael R.; Sato, Mamoru; and Thompson, Paul R., "Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization" (2006). Thompson Lab Publications. 78.