Development of activity-based probes for the protein deacylase Sirt1

Goetz, Christopher J.; Sprague, Daniel; Smith, Brian C.

doi:10.1016/j.bioorg.2020.104232

Cited by 8 publications

(5 citation statements)

References 49 publications

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“…Preliminary screening (Figure S1) showed little to no binding of bromodomains to the methane sulfonyllysine analogues, and despite seeing interactions with thioacetyllysine, we became concerned about the potential for unwanted covalent interactions in downstream cellular studies. 35 As an alternative, TfAcK (Figure 1A) also appeared to support interactions with several bromodomains. We further tested the bromodomain found in BAZ2B, a member of the ISWI chromatin remodeling complex, for its ability to bind the trifluoroacetyl modification.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

“…We synthesized arrays with histone H3 peptides modified with acetyl or an analogue at commonly occurring histone H3 acetylation sites. Preliminary screening (Figure S1) showed little to no binding of bromodomains to the methane sulfonyllysine analogues, and despite seeing interactions with thioacetyllysine, we became concerned about the potential for unwanted covalent interactions in downstream cellular studies . As an alternative, TfAcK (Figure A) also appeared to support interactions with several bromodomains.…”

Section: Resultsmentioning

confidence: 99%

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Trifluoroacetyl Lysine as a Bromodomain Binding Mimic of Lysine Acetylation

Miller¹,

Flynn²,

Tom³

et al. 2022

ACS Chem. Biol.

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Genetic code expansion has proven invaluable to the elucidation of functions of defined protein modifications through the site-specific incorporation of noncanonical amino acids. The use of nonhydrolyzable derivatives of post-translational modifications can greatly increase site stoichiometry and half-life. Investigating acetyllysine reader domain (bromodomain) interactions with acetylated nonhistone proteins is challenging due to the limited tools available and dynamic nature of this posttranslational modification. Here, we demonstrate that bromodomains bind acetyllysine peptides and those substituted with an acetyllysine derivative, trifluoroacetyllysine, with similar affinity and selectivity. Importantly, both trifluoroacetyllysine and acetyllysine can be site-specifically incorporated into proteins expressed in bacterial and mammalian cells, and the strong electron-withdrawing trifluoro substituent makes the latter resistant to deacetylation by sirtuins (SIRTs). The controlled expression of SIRT-resistant, site-specifically acetylated transcription factors expands the set of available tools for determining the function of acetylation, and it serves as a template for investigating bromodomain interactions with acetylated transcription factors.

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Section: ■ Results and Discussionmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Trifluoroacetyl Lysine as a Bromodomain Binding Mimic of Lysine Acetylation

Miller¹,

Flynn²,

Tom³

et al. 2022

ACS Chem. Biol.

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“…Several groups have developed thioacyllysine peptides as sirtuin inhibitors. 18,20,27,28 These peptides normally contain 5 to 20 amino acids (AAs). The sequences are based on the known sirtuin substrates.…”

Section: Design Of Three Generations Of Abpsmentioning

confidence: 99%

Multifunctional activity-based chemical probes for sirtuins

et al. 2023

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“…A significant body of literature indicates that Sirt1 is both modified and inhibited by S -nitrosation ( Table 3 ; Kornberg et al, 2010 ; Rodríguez-Ortigosa et al, 2014 ; Shinozaki et al, 2014 ; Kalous et al, 2016 , 2020 ; Nakazawa et al, 2017 ; Hoth et al, 2018 ; Kim et al, 2018 ; Sen et al, 2018 ). Recombinantly purified Sirt1 shows direct transnitrosation in vitro following treatment with GSNO ( Kornberg et al, 2010 ; Kalous et al, 2016 , 2020 ; Goetz et al, 2020 ) or nitrosated GAPDH ( Kornberg et al, 2010 ). Treatment with the transnitrosation donor S -nitroso- N -acetylpenicillamine (SNAP) ( Shinozaki et al, 2014 ; Kalous et al, 2020 ) or NO-donating compounds (NONOates) ( Kalous et al, 2016 , 2020 ) also yields S -nitrosated Sirt1.…”

Section: Protein Oxidative Post-translational Modificationsmentioning

confidence: 99%

Sirtuin Oxidative Post-translational Modifications

2021

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Increased sirtuin deacylase activity is correlated with increased lifespan and healthspan in eukaryotes. Conversely, decreased sirtuin deacylase activity is correlated with increased susceptibility to aging-related diseases. However, the mechanisms leading to decreased sirtuin activity during aging are poorly understood. Recent work has shown that oxidative post-translational modification by reactive oxygen (ROS) or nitrogen (RNS) species results in inhibition of sirtuin deacylase activity through cysteine nitrosation, glutathionylation, sulfenylation, and sulfhydration as well as tyrosine nitration. The prevalence of ROS/RNS (e.g., nitric oxide, S-nitrosoglutathione, hydrogen peroxide, oxidized glutathione, and peroxynitrite) is increased during inflammation and as a result of electron transport chain dysfunction. With age, cellular production of ROS/RNS increases; thus, cellular oxidants may serve as a causal link between loss of sirtuin activity and aging-related disease development. Therefore, the prevention of inhibitory oxidative modification may represent a novel means to increase sirtuin activity during aging. In this review, we explore the role of cellular oxidants in inhibiting individual sirtuin human isoform deacylase activity and clarify the relevance of ROS/RNS as regulatory molecules of sirtuin deacylase activity in the context of health and disease.

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Development of activity-based probes for the protein deacylase Sirt1

Cited by 8 publications

References 49 publications

Trifluoroacetyl Lysine as a Bromodomain Binding Mimic of Lysine Acetylation

Trifluoroacetyl Lysine as a Bromodomain Binding Mimic of Lysine Acetylation

Multifunctional activity-based chemical probes for sirtuins

Sirtuin Oxidative Post-translational Modifications

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