Activity-based Protein Profiling Reagents for Protein Arginine Deiminase 4 (PAD4): Synthesis and in Vitro Evaluation of a Fluorescently Labeled Probe

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2006 Nov 9

PMID 17090024

Citations 33

Authors

Yuan Luo

Bryan Knuckley

Monica Bhatia

Perry J Pellechia

Paul R Thompson

Affiliations

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Abstract

Protein arginine deiminase 4 (PAD4), which catalyzes the post-translational conversion of peptidyl arginine to peptidyl citrulline, is widely regarded as one of the best new targets for the development of a novel rheumatoid arthritis therapeutic. In addition to its presumed role in this disease, PAD4 is also a calcium-dependent histone deiminase that acts as a transcriptional co-repressor. Herein we describe the design, synthesis, and in vitro evaluation of two fluorescently labeled activity-based protein profiling (ABPP) reagents that specifically and irreversibly modify the active, that is, calcium-bound, form PAD4 with equal affinity to previously described small molecule chemical probes of PAD4 function. These fluorescently tagged ABPPs will be useful for identifying the conditions under which this enzyme is activated in vivo and may prove to be useful RA diagnostics.

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