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PMID: 17002273 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Biochemistry ·Vol. 45 ·No. 39 ·2006-10-03 ·Pages 11727-36

Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR

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.

MeSH Terms
Amidines/chemistry,therapeutic use Arginine/chemistry,metabolism Arthritis, Rheumatoid/drug therapy,enzymology Calcium/chemistry,metabolism Chronic Disease Citrulline/metabolism Enzyme Activation/drug effects Enzyme Inhibitors/chemistry,therapeutic use Humans Hydrocarbons, Fluorinated/chemistry,therapeutic use Hydrolases/antagonists & inhibitors,chemistry,metabolism Molecular Probes/chemistry Protein Processing, Post-Translational Protein Structure, Tertiary Protein-Arginine Deiminase Type 4 Protein-Arginine Deiminases
Chemicals
Amidines Enzyme Inhibitors F-amidine Hydrocarbons, Fluorinated Molecular Probes Citrulline Arginine Hydrolases PADI4 protein, human Protein-Arginine Deiminase Type 4 Protein-Arginine Deiminases Calcium
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Luo Yuan
Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA.
Arita Kyouhei
Bhatia Monica
Knuckley Bryan
Lee Young-Ho
Stallcup Michael R
Sato Mamoru
Thompson Paul R
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34 references, click to expand
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Article Info
Journal
Biochemistry
Abbr.
Biochemistry
ISSN
0006-2960
DOI
10.1021/bi061180d
Published
2006-10-03
Pages
11727-36
Language
English
Region
United States
NLM ID
0370623
PMCID
PMC1808342
Subset
IM
Grants
NIDDK NIH HHS · R01 DK055274 · United States
NIDDK NIH HHS · R37 DK055274 · United States
NIDDK NIH HHS · DK55274 · United States
Databases
PDB
2DW5
External Links
PubMed source DOI: 10.1021/bi061180d PMC Full Text View journal details
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