Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ADP-ribosylation is essential for cell function, yet there is a dearth of methods for detecting this post-translational modification in cells. Here, we describe a clickable aminooxy alkyne (AO-alkyne) probe that can detect cellular ADP-ribosylation on acidic amino acids following Cu-catalyzed conjugation to an azide-containing reporter. Using AO-alkyne, we show that PARP10 and PARP11 are auto-ADP-ribosylated in cells. We also demonstrate that AO-alkyne can be used to monitor stimulus-induced ADP-ribosylation in cells. Functional studies using AO-alkyne support a previously unknown mechanism for ADP-ribosylation on acidic amino acids, wherein a glutamate or aspartate at the initial C1'-position of ADP-ribose transfers to the C2' position. This new mechanism for ADP-ribosylation has important implications for how glutamyl/aspartyl-ADP-ribose is recognized by proteins in cells.
ACS Chem Biol 2015 Aug 21
PMID:A Clickable Aminooxy Probe for Monitoring Cellular ADP-Ribosylation. 2597 21

Poly-ADP-ribose polymerases (PARPs 1-16) have emerged as major regulators of diverse cellular processes. PARPs can be subclassified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While much is known about the cellular roles of PARPs that catalyze PARylation (e.g., PARP1), the function of PARPs that catalyze MARylation (e.g., PARP10) is substantially less understood. This is due in large part to the lack of small-molecule inhibitors that are selective for individual PARP family members that catalyze MARylation. Herein, we describe the rational design and synthesis of selective inhibitors of PARP10. Using structure-based design, we targeted a hydrophobic subpocket within the nicotinamide-binding site of PARP10. We synthesized a series of small molecules based on a 3,4-dihydroisoquinolin-1(2H)-one (dq, 1) scaffold that contain various substituents at the C-5 and C-6 positions designed to exploit this hydrophobic subpocket. We found a dq analogue (22) that contains a methyl group at the C-5 position and a substituted pyridine at the C-6 position that exhibits >10-fold selectivity for PARP10 over a large subset of other PARP family members. The results of this study will serve as a platform for future small-molecule probe development for PARP10 and other PARP family members that catalyze MARylation.
ACS Med Chem Lett 2019 Jan 10
PMID:Rational Design of Cell-Active Inhibitors of PARP10. 3065 50