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Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes

Deubiquitinating enzymes (DUBs) function to remove or cleave ubiquitin from post-translationally modified protein substrates. There are about 100 known DUBs in the proteome, and their dysregulation has been implicated a number of disease states, but the specific function of many subclass members rem...

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Autores principales: Conole, Daniel, Mondal, Milon, Majmudar, Jaimeen D., Tate, Edward W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930156/
https://www.ncbi.nlm.nih.gov/pubmed/31921788
http://dx.doi.org/10.3389/fchem.2019.00876
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author Conole, Daniel
Mondal, Milon
Majmudar, Jaimeen D.
Tate, Edward W.
author_facet Conole, Daniel
Mondal, Milon
Majmudar, Jaimeen D.
Tate, Edward W.
author_sort Conole, Daniel
collection PubMed
description Deubiquitinating enzymes (DUBs) function to remove or cleave ubiquitin from post-translationally modified protein substrates. There are about 100 known DUBs in the proteome, and their dysregulation has been implicated a number of disease states, but the specific function of many subclass members remains poorly understood. Activity-based probes (ABPs) react covalently with an active site residue to report on specific enzyme activity, and thus represent a powerful method to evaluate cellular and physiological enzyme function and dynamics. Ubiquitin-based ABPs, such as HA-Ub-VME, an epitope-tagged ubiquitin carrying a C-terminal reactive warhead, are the leading tool for “DUBome” activity profiling. However, these probes are generally cell membrane impermeable, limiting their use to isolated enzymes or lysates. Development of cell-permeable ABPs would allow engagement of DUB enzymes directly within the context of an intact live cell or organism, refining our understanding of physiological and pathological function, and greatly enhancing opportunities for translational research, including target engagement, imaging and biomarker discovery. This mini-review discusses recent developments in small molecule activity-based probes that target DUBs in live cells, and the unique applications of cell-permeable DUB activity-based probes vs. their traditional ubiquitin-based counterparts.
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spelling pubmed-69301562020-01-09 Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes Conole, Daniel Mondal, Milon Majmudar, Jaimeen D. Tate, Edward W. Front Chem Chemistry Deubiquitinating enzymes (DUBs) function to remove or cleave ubiquitin from post-translationally modified protein substrates. There are about 100 known DUBs in the proteome, and their dysregulation has been implicated a number of disease states, but the specific function of many subclass members remains poorly understood. Activity-based probes (ABPs) react covalently with an active site residue to report on specific enzyme activity, and thus represent a powerful method to evaluate cellular and physiological enzyme function and dynamics. Ubiquitin-based ABPs, such as HA-Ub-VME, an epitope-tagged ubiquitin carrying a C-terminal reactive warhead, are the leading tool for “DUBome” activity profiling. However, these probes are generally cell membrane impermeable, limiting their use to isolated enzymes or lysates. Development of cell-permeable ABPs would allow engagement of DUB enzymes directly within the context of an intact live cell or organism, refining our understanding of physiological and pathological function, and greatly enhancing opportunities for translational research, including target engagement, imaging and biomarker discovery. This mini-review discusses recent developments in small molecule activity-based probes that target DUBs in live cells, and the unique applications of cell-permeable DUB activity-based probes vs. their traditional ubiquitin-based counterparts. Frontiers Media S.A. 2019-12-18 /pmc/articles/PMC6930156/ /pubmed/31921788 http://dx.doi.org/10.3389/fchem.2019.00876 Text en Copyright © 2019 Conole, Mondal, Majmudar and Tate. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Conole, Daniel
Mondal, Milon
Majmudar, Jaimeen D.
Tate, Edward W.
Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes
title Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes
title_full Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes
title_fullStr Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes
title_full_unstemmed Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes
title_short Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes
title_sort recent developments in cell permeable deubiquitinating enzyme activity-based probes
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930156/
https://www.ncbi.nlm.nih.gov/pubmed/31921788
http://dx.doi.org/10.3389/fchem.2019.00876
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