| Structural highlights
Disease
ADPRS_HUMAN The disease is caused by variants affecting the gene represented in this entry.
Function
ADPRS_HUMAN ADP-ribose glycohydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1 position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:21498885, PubMed:30045870, PubMed:29907568, PubMed:30401461, PubMed:33186521). Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:28650317, PubMed:29234005, PubMed:30045870, PubMed:33186521). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802, PubMed:33186521). Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds (PubMed:16278211). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:16278211). Also hydrolyzes free poly(ADP-ribose) in mitochondria (PubMed:22433848). Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (PubMed:17075046, PubMed:21498885). Specifically degrades 1-O-acetyl-ADP-D-ribose isomer, rather than 2-O-acetyl-ADP-D-ribose or 3-O-acetyl-ADP-D-ribose isomers (PubMed:21498885).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
Poly-ADP-ribosylation at sites of DNA damage, catalyzed by PARP enzymes, activates the DNA damage response, chromatin remodeling, and DNA repair. The modification is reversed by two enzymes in humans: PARG, which efficiently hydrolyzes the poly-ADP-ribose chains, and ARH3, which is the key enzyme for removing the last proximal mono-ADP-ribose from serine residues. While inhibitor development has largely focused on PARPs and PARG, no potent and selective inhibitors for ARH3 are currently available. We optimized a FRET-based competition assay for ARH3 and carried out high-throughput screening of small-molecule inhibitors. One hit compound, 1, with a potency of 22 muM was discovered, and through structure-activity relationship studies and synthesis, we improved its potency 10-fold to 2 muM (compound 27, MDOLL-0286). We demonstrate that the compound inhibits ARH3's poly-ADP-ribose hydrolytic activity on cellular substrates. Intriguingly, it does not effectively inhibit the hydrolysis of mono-ADP-ribosylation from natural protein substrates. This is despite the fact that the cocrystal structure of compound 1 bound to ARH3 reveals its overlap with the enzyme's ADP-ribose binding site, agreeing with the competition in the FRET assay. The first experimental ARH3 inhibitor complex provides a valuable starting point for developing more potent chemical probes to study DNA damage response mechanisms in the future.
Discovery and Structural Optimization of 2-Hydrazinopyrimidin-4-one Analogs Inhibiting Human ADP-Ribosylhydrolase ARH3.,Parviainen TAO, Duong MTH, Paakkonen J, Burdova K, Kuttichova B, Hanzlikova H, Lehtio L, Heiskanen JP ACS Chem Biol. 2025 Sep 15. doi: 10.1021/acschembio.5c00461. PMID:40952342[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Oka S, Kato J, Moss J. Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase. J Biol Chem. 2006 Jan 13;281(2):705-13. Epub 2005 Nov 8. PMID:16278211 doi:https://dx.doi.org/M510290200
- ↑ Ono T, Kasamatsu A, Oka S, Moss J. The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylases. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16687-91. doi:, 10.1073/pnas.0607911103. Epub 2006 Oct 30. PMID:17075046 doi:https://dx.doi.org/10.1073/pnas.0607911103
- ↑ Kasamatsu A, Nakao M, Smith BC, Comstock LR, Ono T, Kato J, Denu JM, Moss J. Hydrolysis of O-acetyl-ADP-ribose isomers by ADP-ribosylhydrolase 3. J Biol Chem. 2011 Jun 17;286(24):21110-7. doi: 10.1074/jbc.M111.237636. Epub 2011, Apr 17. PMID:21498885 doi:https://dx.doi.org/10.1074/jbc.M111.237636
- ↑ Niere M, Mashimo M, Agledal L, Dolle C, Kasamatsu A, Kato J, Moss J, Ziegler M. ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose). J Biol Chem. 2012 May 11;287(20):16088-102. doi: 10.1074/jbc.M112.349183. Epub, 2012 Mar 20. PMID:22433848 doi:https://dx.doi.org/10.1074/jbc.M112.349183
- ↑ Fontana P, Bonfiglio JJ, Palazzo L, Bartlett E, Matic I, Ahel I. Serine ADP-ribosylation reversal by the hydrolase ARH3. Elife. 2017 Jun 26;6. doi: 10.7554/eLife.28533. PMID:28650317 doi:https://dx.doi.org/10.7554/eLife.28533
- ↑ Abplanalp J, Leutert M, Frugier E, Nowak K, Feurer R, Kato J, Kistemaker HVA, Filippov DV, Moss J, Caflisch A, Hottiger MO. Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase. Nat Commun. 2017 Dec 12;8(1):2055. doi: 10.1038/s41467-017-02253-1. PMID:29234005 doi:https://dx.doi.org/10.1038/s41467-017-02253-1
- ↑ Palazzo L, Leidecker O, Prokhorova E, Dauben H, Matic I, Ahel I. Serine is the major residue for ADP-ribosylation upon DNA damage. Elife. 2018 Feb 26;7. pii: 34334. doi: 10.7554/eLife.34334. PMID:29480802 doi:https://dx.doi.org/10.7554/eLife.34334
- ↑ Pourfarjam Y, Ventura J, Kurinov I, Cho A, Moss J, Kim IK. Structure of human ADP-ribosyl-acceptor hydrolase 3 bound to ADP-ribose reveals a conformational switch that enables specific substrate recognition. J Biol Chem. 2018 Aug 10;293(32):12350-12359. doi: 10.1074/jbc.RA118.003586. Epub, 2018 Jun 15. PMID:29907568 doi:https://dx.doi.org/10.1074/jbc.RA118.003586
- ↑ Wang M, Yuan Z, Xie R, Ma Y, Liu X, Yu X. Structure-function analyses reveal the mechanism of the ARH3-dependent hydrolysis of ADP-ribosylation. J Biol Chem. 2018 Jul 25. pii: RA118.004284. doi: 10.1074/jbc.RA118.004284. PMID:30045870 doi:https://dx.doi.org/10.1074/jbc.RA118.004284
- ↑ Danhauser K, Alhaddad B, Makowski C, Piekutowska-Abramczuk D, Syrbe S, Gomez-Ospina N, Manning MA, Kostera-Pruszczyk A, Krahn-Peper C, Berutti R, Kovacs-Nagy R, Gusic M, Graf E, Laugwitz L, Roblitz M, Wroblewski A, Hartmann H, Das AM, Bultmann E, Fang F, Xu M, Schatz UA, Karall D, Zellner H, Haberlandt E, Feichtinger RG, Mayr JA, Meitinger T, Prokisch H, Strom TM, Ploski R, Hoffmann GF, Pronicki M, Bonnen PE, Morlot S, Haack TB. Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. Am J Hum Genet. 2018 Nov 1;103(5):817-825. doi: 10.1016/j.ajhg.2018.10.005. Epub , 2018 Oct 25. PMID:30401461 doi:https://dx.doi.org/10.1016/j.ajhg.2018.10.005
- ↑ Bonfiglio JJ, Leidecker O, Dauben H, Longarini EJ, Colby T, San Segundo-Acosta P, Perez KA, Matic I. An HPF1/PARP1-Based Chemical Biology Strategy for Exploring ADP-Ribosylation. Cell. 2020 Nov 12;183(4):1086-1102.e23. doi: 10.1016/j.cell.2020.09.055. PMID:33186521 doi:https://dx.doi.org/10.1016/j.cell.2020.09.055
- ↑ Parviainen TAO, Duong MTH, Pääkkönen J, Burdova K, Kuttichova B, Hanzlikova H, Lehtiö L, Heiskanen JP. Discovery and Structural Optimization of 2-Hydrazinopyrimidin-4-one Analogs Inhibiting Human ADP-Ribosylhydrolase ARH3. ACS Chem Biol. 2025 Sep 15. PMID:40952342 doi:10.1021/acschembio.5c00461
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