Title

Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2006-10-03

Document Type

Article

Subjects

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

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

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.

DOI of Published Version

10.1021/bi061180d

Source

Biochemistry. 2006 Oct 3;45(39):11727-36. Link to article on publisher's site

Journal/Book/Conference Title

Biochemistry

Comments

At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed

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