Rational Development of Novel Activity Probes for the Analysis of Human Cytochromes P450

Sellars, Jonathan D.; Skipsey, Mark; Sadr-ul-Shaheed,; Gravell, Sebastian; Abumansour, Hamza; Kashtl, Ghasaq; Irfan, Jawaria; Khot, M. Ibrahim; Pors, Klaus; Patterson, Laurence H.; Sutton, Chris W.

doi:10.1002/cmdc.201600134

Cited by 5 publications

(4 citation statements)

References 37 publications

(40 reference statements)

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“… 114 Cravatt and co-workers have demonstrated that metabolic oxidation of alkynes can form ketene ( Figure 5 c) and α,β-unsaturated ketone electrophiles, 115 , 116 resulting in the labeling of a range of CYP enzymes. In 2016, Sutton and co-workers 117 extended this work by examining 8-hydroxypsoralen analogues that underwent CYP oxidation to form electrophilic furan epoxides ( Figure 5 d). The benzofuran probe JDS-14 was found to effectively inhibit CYP3A4 in enzymatic assays, and labeling of the overexpressed enzyme in cell lysate was also demonstrated.…”

Section: Endogenous Inductionmentioning

confidence: 99%

Flipping the Switch: Innovations in Inducible Probes for Protein Profiling

2021

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Over the past two decades, activity-based probes have enabled a range of discoveries, including the characterization of new enzymes and drug targets. However, their suitability in some labeling experiments can be limited by nonspecific reactivity, poor membrane permeability, or high toxicity. One method for overcoming these issues is through the development of “inducible” activity-based probes. These probes are added to samples in an unreactive state and require in situ transformation to their active form before labeling can occur. In this Review, we discuss a variety of approaches to inducible activity-based probe design, different means of probe activation, and the advancements that have resulted from these applications. Additionally, we highlight recent developments which may provide opportunities for future inducible activity-based probe innovations.

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Section: Endogenous Inductionmentioning

confidence: 99%

Flipping the Switch: Innovations in Inducible Probes for Protein Profiling

2021

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“…epoxyfuran, which would be electrophilic enough to be attacked by protein nucleophiles (Figure 3). [33] Probe 8 exhibited the most effective NADPH‐dependent binding to CYP3A4, which is also the most abundant P450 in the human body.…”

Section: Activity‐based Protein Profiling Of Various Oxidoreductasesmentioning

confidence: 99%

Activity‐Based Protein Profiling (ABPP) of Oxidoreductases

Fuerst

Breinbauer

2020

ChemBioChem

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Over the last two decades, activity‐based protein profiling (ABPP) has been established as a tremendously useful proteomic tool for measuring the activity of proteins in their cellular context, annotating the function of uncharacterized proteins, and investigating the target profile of small‐molecule inhibitors. Unlike hydrolases and other enzyme classes, which exhibit a characteristic nucleophilic residue, oxidoreductases have received much less attention in ABPP. In this minireview, the state of the art of ABPP of oxidoreductases is described and the scope and limitations of the existing approaches are discussed. It is noted that several ABPP probes have been described for various oxidases, but none so far for a reductase, which gives rise to opportunities for future research.

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“…A P450 enzyme could convert the substrate into an epoxy‐furane, which would be electrophilic enough to be attacked by protein nucleophiles (Figure 1). [45] Probe 6 exhibited the most effective NADPH‐dependent binding against a panel of overexpressed CYP proteins to CYP3A4, which is also the most abundant P450 in the human body.…”

Section: Introductionmentioning

confidence: 99%