Oxidative detoxification of phosphonothiolates

Yang, Yu Chu; Szafraniec, Linda L.; Beaudry, William T.; Rohrbaugh, D. K.

doi:10.1021/ja00174a025

Cited by 165 publications

(152 citation statements)

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“…Cysteine reacts to form thioether linkages, whereas tagged peptides form a chemically distinct phosphate diester. This diester linkage is normally quite stable but it can be made to rapidly hydrolyze by oxidation of the sulfur atom (16,17). The resin is treated with the peroxide agent Oxone, resulting in oxidation of all sulfur atoms present (thiophosphate, cysteine, and methionine).…”

Section: Resultsmentioning

confidence: 99%

Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates

Blethrow

Glavy²,

Morgan³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

291

290

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We describe a method for rapid identification of protein kinase substrates. Cdk1 was engineered to accept an ATP analog that allows it to uniquely label its substrates with a bio-orthogonal phosphate analog tag. A highly specific, covalent capture-andrelease methodology was developed for rapid purification of tagged peptides derived from labeled substrate proteins. Application of this approach to the discovery of Cdk1-cyclin B substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as Cdk1-cyclin B substrates. This approach has the potential to expand our understanding of kinase-substrate connections in signaling networks.P rotein kinases regulate a vast array of biological processes through phosphorylation of protein substrates. A comprehensive map of all phosphorylation sites and kinase-substrate pairs would greatly facilitate the study of signaling networks. This goal faces two fundamental challenges. First, all protein kinases use ATP as a cofactor to phosphorylate their targets, and thus the direct substrates of a single kinase cannot be easily traced in protein mixtures containing multiple kinases. Second, phosphorylation often occurs at low stoichiometry and on low-abundance proteins. This makes substrate and phosphorylation site identification very challenging. Powerful methods have been developed to address these dual problems (1, 2). Kinase-substrate pairs can be tested in multiplexed phosphorylation assays by using immobilized arrays of purified proteins. These high-throughput chip-based assays have the added benefit of presenting low-abundance proteins at easily detectable levels and have provided a first-generation map of protein phosphorylation in Saccharomyces cerevisiae (3). However, these assays do not currently allow identification of phosphorylation sites and have not been adapted to organisms with more complex proteomes. Prediction of high-likelihood kinase substrates can sometimes be achieved by using knowledge of the substrate sequence motif preferences of individual kinases, but only when these preferences are strong (4, 5). Finally, thousands of in vivo phosphorylation sites from metazoan organisms have been identified in proteomic screens (6-9), but for most of these sites the responsible upstream kinases remain unknown.We have demonstrated a chemical and genetic solution to the common use of ATP by all kinases. Our approach relies on engineering a kinase to accept unnatural ATP analogs by modification of the ATP-binding pocket (10, 11). The analogs are very poor substrates for wild-type kinases; thus, an analog-sensitive kinase (or as-kinase) can be used to specifically radiolabel its substrates in cell extracts while preserving important aspects of biological context, such as the integrity of protein complexes. Coupling this approach with the use of libraries of genetically encoded affinity-tagged proteins has facilitated identification of low-abundanc...

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Section: Resultsmentioning

confidence: 99%

Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates

Blethrow

Glavy²,

Morgan³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

291

290

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“…45) Nerve gases can be also decomposed by oxidation. 46) Amines 47) and metals 48,49) show decomposing activity toward nerve gases by forming coordination bonding. In plant nerve gases are decomposed.…”

Section: Concept Of Decontaminationmentioning

confidence: 99%

Research and Development of On-site Decontamination System for Biological and Chemical Warfare Agents

Seto

2011

JOURNAL OF HEALTH SCIENCE

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Biological and chemical warfare agents (BCWAs) are diverse in nature including synthetic low molecular weight chemical warfare agents (gaseous choking and blood agents), volatile nerve gases and blister agents, nonvolatile vomit agents and lachrymators, biological toxins (polar low molecular weight toxins and proteinous toxins), and microorganisms (viruses, rickettsia, chlamydia and bacteria). In the consequence management against chemical and biological warfare terrorism, speedy decontamination of casualties, goods, items and equipments, buildings and field is required for the minimization of the terrorism damage. At present, washing casualties and contaminated materials with large volumes of water is the basic way, and hypochlorite solution is mainly used to decompose BCWAs. However, it still remains unsolved how to dispose the waste water contaminated with BCWAs, and decontaminating reagents have serious problems of high toxicity to human, despoiling nature to environment, long finishing time and non-durability. In addition, the present decontamination technologies are not effective, nonspecifically affecting the surrounding non-target materials. Therefore, it is the urgent matter to build up usable decontamination system surpassing the present system. The author introduces the joint project of research and development of the novel decontamination system against BCWAs, in the purpose of realizing non-dangerous, rapid, specific, effective and economical on-site decontamination. The project consists of establishment of the evaluation methods for decontamination, and verification of the present technologies and utilization of bacterial organophosphorus hydrolase, development of specific adsorptive elimination technologies using molecular recognition devices, and development of deactivation technologies using photocatalysis.

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“…Chemical shift assignments were based on literature values. 9 The acidic buffered alum solution was comparable to 1.0 M A1 2 (SO 4 ) 3 in reducing the concentration of VX initially, but as Figure 5 shows, it removes all phosphorus hydrolysis products including ethyl methylphosphonic acid (EMPA) from solution. Furthermore, there was no evidence for the production of EA-2192.…”

Section: 3mentioning

confidence: 98%

Potential Usage of Aqueous Alum for Decomposition of Chemical Warfare Agents. Part 2: Reactions with VX and QL

Williams¹,

Bevilacqua²,

Creasy³

et al. 2006

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Oxidative detoxification of phosphonothiolates

Cited by 165 publications

References 0 publications

Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates

Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates

Research and Development of On-site Decontamination System for Biological and Chemical Warfare Agents

Potential Usage of Aqueous Alum for Decomposition of Chemical Warfare Agents. Part 2: Reactions with VX and QL

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