The Experts below are selected from a list of 1077 Experts worldwide ranked by ideXlab platform
Lisa A. Peterson - One of the best experts on this subject based on the ideXlab platform.
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Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans.
Chemical research in toxicology, 2015Co-Authors: Alexander E Grill, Thaddeus Schmitt, Leah A. Gates, Dipankar Bandyopadhyay, Jian-min Yuan, Sharon E. Murphy, Lisa A. PetersonAbstract: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...
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Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans
2015Co-Authors: Alexander E Grill, Thaddeus Schmitt, Leah A. Gates, Dipankar Bandyopadhyay, Jian-min Yuan, Sharon E. Murphy, Lisa A. PetersonAbstract: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.
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Sirtuins: NAD(+)-dependent deacetylase mechanism and regulation.
Current opinion in chemical biology, 2012Co-Authors: Anthony A. Sauve, Dou Yeon YounAbstract: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.
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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, 2010Co-Authors: Yana Cen, Anthony A. SauveAbstract: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...
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Sirtuin Chemical Mechanisms
Biochimica et biophysica acta, 2010Co-Authors: Anthony A. SauveAbstract: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.
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A SIR-tain Acetyl Complex Is Caught by a Sulfur Trap
Structure (London England : 1993), 2008Co-Authors: Anthony A. SauveAbstract:In this issue, Hawse et al. (2008) provide additional insight into the mechanistic properties of sirtuin enzymes by describing the structure of a thio-imidate in the active site of Thermatoga maritima Sir2, which strengthens the proposal that the enzyme directly couples NAD + and Acetyllysine oxygen to form a versatile ADPR-peptidyl-imidate intermediate.
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Plasmodium falciparum Sir2 is an NAD+-Dependent Deacetylase and an Acetyllysine-Dependent and Acetyllysine-Independent NAD+ Glycohydrolase†
Biochemistry, 2008Co-Authors: Jarrod B. French, Yana Cen, Anthony A. SauveAbstract:Sirtuins are NAD+-dependent enzymes that deacetylate a variety of cellular proteins and in some cases catalyze protein ADP-ribosyl transfer. The catalytic mechanism of deacetylation is proposed to involve an ADPR-peptidylimidate, whereas the mechanism of ADP-ribosyl transfer to proteins is undetermined. Herein we characterize a Plasmodium falciparum sirtuin that catalyzes deacetylation of histone peptide sequences. Interestingly, the enzyme can also hydrolyze NAD+. Two mechanisms of hydrolysis were identified and characterized. One is independent of Acetyllysine substrate and produces α-stereochemistry as established by reaction of methanol which forms α-1-O-methyl-ADPR. This reaction is insensitive to nicotinamide inhibition. The second solvolytic mechanism is dependent on acetylated peptide and is proposed to involve the imidate to generate β-stereochemistry. Stereochemistry was established by isolation of β-1-O-methyl-ADPR when methanol was added as a cosolvent. This solvolytic reaction was inhibited b...
Yingming Zhao - One of the best experts on this subject based on the ideXlab platform.
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Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain.
Molecular cell, 2016Co-Authors: Benjamin R. Sabari, Hong Wen, Tatyana Panchenko, Dan Zhao, Haipeng Guan, Liling Wan, He Huang, Zhanyun Tang, Yingming ZhaoAbstract: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.
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SILAC-Based Quantification of Sirt1-Responsive Lysine Acetylome
Methods in molecular biology (Clifton N.J.), 2013Co-Authors: Yue Chen, Gozde Colak, Yingming ZhaoAbstract: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.
Alexander E Grill - One of the best experts on this subject based on the ideXlab platform.
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Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans.
Chemical research in toxicology, 2015Co-Authors: Alexander E Grill, Thaddeus Schmitt, Leah A. Gates, Dipankar Bandyopadhyay, Jian-min Yuan, Sharon E. Murphy, Lisa A. PetersonAbstract: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...
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Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans
2015Co-Authors: Alexander E Grill, Thaddeus Schmitt, Leah A. Gates, Dipankar Bandyopadhyay, Jian-min Yuan, Sharon E. Murphy, Lisa A. PetersonAbstract: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
Xiaobing Shi - One of the best experts on this subject based on the ideXlab platform.
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af9 yeats domain links histone acetylation to dot1l mediated h3k79 methylation
Cell, 2014Co-Authors: Kaori Tanaka, Haibo Wang, Danni Peng, Xiaobing ShiAbstract:The recognition of modified histones by "reader" proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the great variety of readers for histone methylation, few protein modules that recognize histone acetylation are known. Here, we show that the AF9 YEATS domain binds strongly to histone H3K9 acetylation and, to a lesser extent, H3K27 and H3K18 acetylation. Crystal structural studies revealed that AF9 YEATS adopts an eight-stranded immunoglobin fold and utilizes a serine-lined aromatic "sandwiching" cage for Acetyllysine readout, representing a novel recognition mechanism that is distinct from that of known Acetyllysine readers. ChIP-seq experiments revealed a strong colocalization of AF9 and H3K9 acetylation genome-wide, which is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L. Together, our studies identified the evolutionarily conserved YEATS domain as a novel Acetyllysine-binding module and established a direct link between histone acetylation and DOT1L-mediated H3K79 methylation in transcription control.
