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


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.

SUBMITTER: Luo Y 

PROVIDER: S-EPMC1808342 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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

Luo Yuan Y   Arita Kyouhei K   Bhatia Monica M   Knuckley Bryan B   Lee Young-Ho YH   Stallcup Michael R MR   Sato Mamoru M   Thompson Paul R PR  

Biochemistry 20061001 39


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 stu  ...[more]

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