Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization.
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.
Luo
Yuan
Y
Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA.
Arita
Kyouhei
K
Bhatia
Monica
M
Knuckley
Bryan
B
Lee
Young-Ho
YH
Stallcup
Michael R
MR
Sato
Mamoru
M
Thompson
Paul R
PR
D000578:Amidines / Q000737:chemistry* / Q000627:therapeutic use; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D002908:Chronic Disease; D002956:Citrulline / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry* / Q000627:therapeutic use; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015335:Molecular Probes / Q000737:chemistry*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
D000578:Amidines; D004791:Enzyme Inhibitors; C509292:F-amidine; D006845:Hydrocarbons, Fluorinated; D015335:Molecular Probes; D002956:Citrulline; D001120:Arginine; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D002118:Calcium