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Lisa A. Peterson – One of the best experts on this subject based on the ideXlab platform.

  • Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans.
    Chemical research in toxicology, 2015
    Co-Authors: Alexander E Grill, Thaddeus Schmitt, Leah A. Gates, Dipankar Bandyopadhyay, Jian-min Yuan, Sharon E. Murphy, Lisa A. Peterson

    Abstract:

    Furan, a possible human carcinogen, is found in heat treated foods and tobacco smoke. Previous studies have shown that humans are capable of converting furan to its reactive metabolite, cis-2-butene-1,4-dial (BDA), and therefore may be susceptible to furan toxicity. Human risk assessment of furan exposure has been stymied because of the lack of mechanism-based exposure biomarkers. Therefore, a sensitive LC-MS/MS assay for six furan metabolites was applied to measure their levels in urine from furan-exposed rodents as well as in human urine from smokers and nonsmokers. The metabolites that result from direct reaction of BDA with lysine (BDA-Nα-Acetyllysine) and from cysteine-BDA-lysine cross-links (N-acetylcysteine-BDA-lysine, N-acetylcysteine-BDA-Nα-Acetyllysine, and their sulfoxides) were targeted in this study. Five of the six metabolites were identified in urine from rodents treated with furan by gavage. BDA-Nα-Acetyllysine, N-acetylcysteine-BDA-lysine, and its sulfoxide were detected in most human uri…

  • Abundant Rodent
    Furan-Derived Urinary Metabolites
    Are Associated with Tobacco Smoke Exposure in Humans
    , 2015
    Co-Authors: Alexander E Grill, Thaddeus Schmitt, Leah A. Gates, Dipankar Bandyopadhyay, Jian-min Yuan, Sharon
    E. Murphy, Lisa A. Peterson

    Abstract:

    Furan, a possible human carcinogen,
    is found in heat treated foods
    and tobacco smoke. Previous studies have shown that humans are capable
    of converting furan to its reactive metabolite, cis-2-butene-1,4-dial (BDA), and therefore may be susceptible to furan
    toxicity. Human risk assessment of furan exposure has been stymied
    because of the lack of mechanism-based exposure biomarkers. Therefore,
    a sensitive LC-MS/MS assay for six furan metabolites was applied to
    measure their levels in urine from furan-exposed rodents as well as
    in human urine from smokers and nonsmokers. The metabolites that result
    from direct reaction of BDA with lysine (BDA-Nα-Acetyllysine) and from cysteine-BDA-lysine cross-links
    (N-acetylcysteine-BDA-lysine, N-acetylcysteine-BDA-Nα-Acetyllysine, and their sulfoxides)
    were targeted in this study. Five of the six metabolites were identified
    in urine from rodents treated with furan by gavage. BDA-Nα-Acetyllysine, N-acetylcysteine-BDA-lysine,
    and its sulfoxide were detected in most human urine samples from three
    different groups. The levels of N-acetylcysteine-BDA-lysine
    sulfoxide were more than 10 times higher than that of the corresponding
    sulfide in many samples. The amount of this metabolite was higher
    in smokers relative to that in nonsmokers and was significantly reduced
    following smoking cessation. Our results indicate a strong relationship
    between BDA-derived metabolites and smoking. Future studies will determine
    if levels of these biomarkers are associated with adverse health effects
    in humans

Anthony A. Sauve – One of the best experts on this subject based on the ideXlab platform.

  • Sirtuins: NAD(+)-dependent deacetylase mechanism and regulation.
    Current opinion in chemical biology, 2012
    Co-Authors: Anthony A. Sauve, Dou Yeon Youn

    Abstract:

    Sirtuins are NAD(+)-dependent deacetylases involved in chemical reversal of Acetyllysine modifications of cellular proteins. Deacetylation catalyzed by sirtuins is implicated in regulating diverse biological processes, including energy homeostasis. The mechanism of NAD(+)-dependent deacetylation is proposed to occur via an ADPR-peptidyl-imidate intermediate, resulting from reaction of NAD(+) and an Acetyllysine residue. This mechanism enables sirtuins to respond dynamically to intracellular fluctuations of NAD(+) and nicotinamide. Chemical probes such as nicotinamide antagonists and thioacetyl compounds provide key support for the imidate mechanism of sirtuin deacetylation catalysis. Novel new directions include chemical probes to study sirtuins in cells, and the discovery of novel post-translational modifications besides acetyl, such as succinyl and malonyl, that are regulated by sirtuins.

  • transition state of adp ribosylation of Acetyllysine catalyzed by archaeoglobus fulgidus sir2 determined by kinetic isotope effects and computational approaches
    Journal of the American Chemical Society, 2010
    Co-Authors: Yana Cen, Anthony A. Sauve

    Abstract:

    Sirtuins are protein-modifying enzymes distributed throughout all forms of life. These enzymes bind NAD+, a universal metabolite, and react it with Acetyllysine residues to effect deacetylation of protein side chains. This NAD+-dependent deacetylation reaction has been observed for sirtuin enzymes derived from archaeal, eubacterial, yeast, metazoan, and mammalian species, suggesting conserved chemical mechanisms for these enzymes. The first chemical step of deacetylation is the reaction of NAD+ with an Acetyllysine residue which forms an enzyme-bound ADPR−peptidylimidate intermediate and nicotinamide. In this manuscript, the transition state for the ADP-ribosylation of Acetyllysine is solved for an Archaeoglobus fulgidus sirtuin (Af2Sir2). Kinetic isotope effects (KIEs) were obtained by the competitive substrate method and were [1N-15N] = 1.024(2), [1′N-14C] = 1.014(4), [1′N-3H] = 1.300(3), [2′N-3H] = 1.099(5), [4′N-3H] = 0.997(2), [5′N-3H] = 1.020(5), [4′N-18O] = 0.984(5). KIEs were calculated for candid…

  • Sirtuin Chemical Mechanisms
    Biochimica et biophysica acta, 2010
    Co-Authors: Anthony A. Sauve

    Abstract:

    Sirtuins are ancient proteins widely distributed in all lifeforms of earth. These proteins are universally able to bind NAD(+), and activate it to effect ADP-ribosylation of cellular nucleophiles. The most commonly observed sirtuin reaction is the ADP-ribosylation of Acetyllysine, which leads to NAD(+)-dependent deacetylation. Other types of ADP-ribosylation have also been observed, including protein ADP-ribosylation, NAD(+) solvolysis and ADP-ribosyltransfer to 5,6-dimethylbenzimidazole, a reaction involved in eubacterial cobalamin biosynthesis. This review broadly surveys the chemistries and chemical mechanisms of these enzymes.

Yingming Zhao – One of the best experts on this subject based on the ideXlab platform.

  • Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain.
    Molecular cell, 2016
    Co-Authors: Benjamin R. Sabari, Hong Wen, Tatyana Panchenko, Dan Zhao, Haipeng Guan, Liling Wan, He Huang, Zhanyun Tang, Yingming Zhao

    Abstract:

    Recognition of histone covalent modifications by chromatin-binding protein modules (“readers”) constitutes a major mechanism for epigenetic regulation, typified by bromodomains that bind Acetyllysine. Non-acetyl histone lysine acylations (e.g., crotonylation, butyrylation, propionylation) have been recently identified, but readers that prefer these acylations have not been characterized. Here we report that the AF9 YEATS domain displays selectively higher binding affinity for crotonyllysine over Acetyllysine. Structural studies revealed an extended aromatic sandwiching cage with crotonyl specificity arising from π-aromatic and hydrophobic interactions between crotonyl and aromatic rings. These features are conserved among the YEATS, but not the bromodomains. Using a cell-based model, we showed that AF9 co-localizes with crotonylated histone H3 and positively regulates gene expression in a YEATS domain-dependent manner. Our studies define the evolutionarily conserved YEATS domain as a family of crotonyllysine readers and specifically demonstrate that the YEATS domain of AF9 directly links histone crotonylation to active transcription.

  • SILAC-Based Quantification of Sirt1-Responsive Lysine Acetylome
    Methods in molecular biology (Clifton N.J.), 2013
    Co-Authors: Yue Chen, Gozde Colak, Yingming Zhao

    Abstract:

    Stable Isotope Labeling by Amino acids in Cell culture (SILAC) is one of the in vivo metabolic labeling methods widely used for dynamic analysis of protein modifications. Here, we describe a general approach to applying SILAC, in combination with affinity enrichment of Acetyllysine peptides and mass spectrometry, to study the dynamic changes of the Lysine acetylome in response to Sirt1. The method should be applicable to quantify changes to other post translational modifications in diverse cellular systems.