Activity-based proteomics

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Activity-based proteomics - Wikipedia

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Activity-based proteomics, or activity-based protein profiling (ABPP) is a functional proteomic technology that uses chemical probes that react with mechanistically related classes of enzymes.^[1]

Description

The basic unit of ABPP is the probe, which typically consists of two elements: a reactive group (RG, sometimes called a "warhead") and a tag. Additionally, some probes may contain a binding group which enhances selectivity. The reactive group usually contains a specially designed electrophile that becomes covalently-linked to a nucleophilic residue in the active site of an active enzyme. An enzyme that is inhibited or post-translationally modified will not react with an activity-based probe. The tag may be either a reporter such as a fluorophore or an affinity label such as biotin or an alkyne or azide for use with the Huisgen 1,3-dipolar cycloaddition (also known as click chemistry).^[2]

Advantages

A major advantage of ABPP is the ability to monitor the availability of the enzyme active site directly, rather than being limited to protein or mRNA abundance. With classes of enzymes such as the serine hydrolases^[3] and metalloproteases^[4] that often interact with endogenous inhibitors or that exist as inactive zymogens, this technique offers a valuable advantage over traditional techniques that rely on abundance rather than activity. Furthermore, ABPP could be used to target specific proteins which were previously viewed as undruggable targets.^[5]

Multidimensional protein identification technology

In-gel ABPP using probes with different fluorophores in the same lane to simultaneously profile differences in enzyme activities

In recent years ABPP has been combined with tandem mass spectrometry enabling the identification of hundreds of active enzymes from a single sample. This technique, known as ABPP-MudPIT (multidimensional protein identification technology) is especially useful for profiling inhibitor selectivity as the potency of an inhibitor can be tested against hundreds of targets simultaneously.^{[citation needed]}

ABPP were first reported in the 1990s in the study of proteases.^[6]^[7]

References

^ Berger AB, Vitorino PM, Bogyo M (2004). "Activity-based protein profiling: applications to biomarker discovery, in vivo imaging and drug discovery". American Journal of Pharmacogenomics. 4 (6): 371–81. doi:10.2165/00129785-200404060-00004. PMID 15651898. S2CID 18637390.
^ Speers AE, Adam GC, Cravatt BF (April 2003). "Activity-based protein profiling in vivo using a copper(i)-catalyzed azide-alkyne [3 + 2] cycloaddition". Journal of the American Chemical Society. 125 (16): 4686–7. doi:10.1021/ja034490h. PMID 12696868.
^ Liu Y, Patricelli MP, Cravatt BF (December 1999). "Activity-based protein profiling: the serine hydrolases". Proceedings of the National Academy of Sciences of the United States of America. 96 (26): 14694–9. Bibcode:1999PNAS...9614694L. doi:10.1073/pnas.96.26.14694. PMC 24710. PMID 10611275.
^ Saghatelian A, Jessani N, Joseph A, Humphrey M, Cravatt BF (July 2004). "Activity-based probes for the proteomic profiling of metalloproteases". Proceedings of the National Academy of Sciences of the United States of America. 101 (27): 10000–5. Bibcode:2004PNAS..10110000S. doi:10.1073/pnas.0402784101. PMC 454150. PMID 15220480.
^ Deng, Hui; Lei, Qian; Wu, Yangping; He, Yang; Li, Weimin (2020). "Activity-based protein profiling: Recent advances in medicinal chemistry". European Journal of Medicinal Chemistry. 191. doi:10.1016/j.ejmech.2020.112151. PMID 32109778.
^ Kam CM, Abuelyaman AS, Li Z, Hudig D, Powers JC (1993). "Biotinylated isocoumarins, new inhibitors and reagents for detection, localization, and isolation of serine proteases". Bioconjugate Chemistry. 4 (6): 560–7. doi:10.1021/bc00024a021. PMID 8305526.
^ Abuelyaman AS, Hudig D, Woodard SL, Powers JC (1994). "Fluorescent derivatives of diphenyl [1-(N-peptidylamino)alkyl]phosphonate esters: synthesis and use in the inhibition and cellular localization of serine proteases". Bioconjugate Chemistry. 5 (5): 400–5. doi:10.1021/bc00029a004. PMID 7849068.

v t e Genomics
Fields	Cognitive genomics Computational genomics Comparative genomics Functional genomics Genome project Human Genome Project Metagenomics Human Microbiome Project Pangenomics Personal genomics Population genomics Sociogenomics Structural genomics
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Structural biology	Proteomics Human proteome project Call-map proteomics Structure-based drug design Expression proteomics
Research tools	2-D electrophoresis Mass spectrometer Electrospray ionization Matrix-assisted laser desorption ionization Matrix-assisted laser desorption ionization-time of flight mass spectrometer Microfluidic-based tools Isotope affinity tags Chromosome conformation capture
Organizations	DNA Data Bank of Japan (JP) European Molecular Biology Laboratory (EU) National Institutes of Health (USA) Wellcome Sanger Institute (UK)
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Advantages

Multidimensional protein identification technology

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References