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Tankyrases as drug targets
Abstract Tankyrase 1 and tankyrase 2 are poly(ADP-rTankyrase 1 and tankyrase 2 are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile α-motif multimerization domain and an ankyrin repeat protein-interaction domain. Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt-β-catenin signaling, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly(ADP-ribosyl)ation, and regulate protein interactions and stability. The proposed roles of tankyrases in disease-relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified. The selectivity and potency of these small molecules can be rationalized by how they fit within the NAD+-binding groove of the catalytic domain. Some molecules bind to the nicotinamide subsite, such as generic diphtheria toxin-like ADP-ribosyltransferase inhibitors, whereas others bind to a distinct adenosine subsite that diverges from other diphtheria toxin-like ADP-ribosyltransferases and confers specificity. A highly potent dual-site inhibitor is also available. Within the last few years, tankyrase inhibitors have proved to be useful chemical probes and potential lead compounds, especially for specific cancers. This review describes the biochemical and cellular functions of the tankyrase subfamily of human ADP-ribosyltransferases. Tankyrases use NAD+ as a substrate to covalently modify acceptor proteins leading to dissociation of macromolecular complexes and protein degradation. Existing tankyrase inhibitors target the nicotinamide and/or the adenine pocket of the donor NAD+-binding cleft of the catalytic domain.AD+-binding cleft of the catalytic domain.
Abstractsub Tankyrase 1 and tankyrase 2 are poly(ADP-rTankyrase 1 and tankyrase 2 are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile α-motif multimerization domain and an ankyrin repeat protein-interaction domain. Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt-β-catenin signaling, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly(ADP-ribosyl)ation, and regulate protein interactions and stability. The proposed roles of tankyrases in disease-relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified. The selectivity and potency of these small molecules can be rationalized by how they fit within the NAD+-binding groove of the catalytic domain. Some molecules bind to the nicotinamide subsite, such as generic diphtheria toxin-like ADP-ribosyltransferase inhibitors, whereas others bind to a distinct adenosine subsite that diverges from other diphtheria toxin-like ADP-ribosyltransferases and confers specificity. A highly potent dual-site inhibitor is also available. Within the last few years, tankyrase inhibitors have proved to be useful chemical probes and potential lead compounds, especially for specific cancers. This review describes the biochemical and cellular functions of the tankyrase subfamily of human ADP-ribosyltransferases. Tankyrases use NAD+ as a substrate to covalently modify acceptor proteins leading to dissociation of macromolecular complexes and protein degradation. Existing tankyrase inhibitors target the nicotinamide and/or the adenine pocket of the donor NAD+-binding cleft of the catalytic domain.AD+-binding cleft of the catalytic domain.
Bibtextype article  +
Doi 10.1111/febs.12320  +
Has author Lehtio L. + , Chi N.-W. + , Krauss S. +
Has extra keyword 1 + , 2 + , 4 triazole derivative + , 3 aminobenzamide + , 3 aminobenzamidine + , Ankyrin + , Beta catenin + , Flavone + , G 007 lk + , G 007lk + , Glucose transporter 4 + , Glycosyltransferase inhibitor + , Iwr 1 + , Jw 55 + , Jw 74 + , N (5 + , 6 dihydro 6 oxo 2 phenanthridinyl) 2 dimethylaminoacetamide + , Nicotinamide + , Nicotinamide adenine dinucleotide + , Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1 + , Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 2 + , Oxazolidinone + , Phenanthridinone + , Proteasome + , Quinazolinone derivative + , Small interfering RNA + , Tankyrase + , Tankyrase 1 + , Tankyrase 2 + , Tankyrase inhibitor + , Tiq a + , Unclassified drug + , Unindexed drug + , Wiki 4 + , Xav 939 + , Cell vacuole + , Cellular distribution + , Drug potency + , Drug protein binding + , Drug selectivity + , Drug structure + , Drug targeting + , Enzyme active site + , Enzyme inhibition + , Enzyme localization + , Enzyme structure + , Human + , IC 50 + , Mitosis + , Nonhuman + , Priority journal + , Protein function + , Protein transport + , Review + , Telomere + , Cancer + , Diphtheria toxin-like ADP-ribosyltransferase (ARTD) + , Drug discovery + , Poly(ADP-ribose) polymerase (PARP) + , Vesicle trafficking + , Wnt signalling + , Adenosine Diphosphate Ribose + , Amino Acid Motifs + , Animals + , Antineoplastic Agents + , Catalytic Domain + , Humans + , Models + , Molecular + , Neoplasms + , Proteasome Endopeptidase Complex + , Protein Processing + , Post-Translational + , Protein Transport + , Tankyrases + , Telomere Homeostasis +
Has keyword Cancer + , Diphtheria toxin-like ADP-ribosyltransferase (ARTD) + , Drug discovery + , Mitosis + , Poly(ADP-ribose) polymerase (PARP) + , Tankyrase + , Telomere + , Vesicle trafficking + , Wnt signalling +
Issn 1742464X  +
Issue 15  +
Language English +
Number of citations by publication 0  +
Number of references by publication 0  +
Pages 3576–3593  +
Published in FEBS Journal +
Pubmed 23648170  +
Title Tankyrases as drug targets +
Type literature review  +
Volume 280  +
Year 2013 +
Creation dateThis property is a special property in this wiki. 6 November 2014 18:28:47  +
Categories Publications without license parameter  + , Publications without remote mirror parameter  + , Publications without archive mirror parameter  + , Publications without paywall mirror parameter  + , Literature reviews  + , Publications without references parameter  + , Publications  +
Modification dateThis property is a special property in this wiki. 6 November 2014 18:28:47  +
DateThis property is a special property in this wiki. 2013  +
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