Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides<sup>1</sup>

Swain, C. Gardner; Scott, C. B.

doi:10.1021/ja01097a041

Cited by 623 publications

(201 citation statements)

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“…are some of the most potent mutagens in mammalian and microbial cells. They are S N l-type monofunctional alkylating agents with a low Swain-Scott substrate constant (s) (Swain and Scott 1953) and these agents have high reactivity towards centers of low nucleophilicity such as oxygen atom sites in DNA, while S N 2-type reagents such as EMS and dimethyl sulfate, have a higher s value than S N 1 reagents and primarily attack sites of high nucleophilicity, such as ring nitrogen atom sites in DNA; they cause little alkylation at the oxygen atom sites (Neale 1976). Mutations by S N 2 reagents are induced via the error-prone pathway depend on repair system, whereas S N 1 agents are capable to induce mutations independently from error-prone repair (Neale 1976).…”

Section: Chemical Properties Of Nitroso Compoundsmentioning

confidence: 99%

Use of N-methyl-N-nitrosourea treatment of fertilized egg cells for saturation mutagenesis of rice

2010

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The efficiency of N-methyl-N-nitrosourea (MNU) treatment of fertilized egg cells at the single-cell stage in rice (Oryza sativa L.) was about twice that of dry seeds. The proportion of recessive iso-chlorophyll mutants in the segregating progeny of M 1 plants decreased remarkably with treatment at later stages of embryonic development, perhaps because of the presence of diplontic selection and chimera formation when older, multicellular embryos were mutagenized. Panicle sterility of the M 1 plants showed a linear relationship with the frequency of chlorophyll mutations in the progeny. The mutagenicity of N-ethyl-N-nitrosourea was similar to that of MNU, but N-methyl-N′-nitro-N-nitrosoguanidine and N-ethyl-N′-nitro-N-nitrosoguanidine were less effective. Several thousand rice mutants affecting endosperm, culm length, heading date, and chlorophyll were obtained by MNU mutagenesis. The frequency of certain types of endosperm mutants seemed to differ according to the precise timing of treatment. The mutation rate was calculated as 7.4 × 10 −6 per nucleotide, and the mutations were evenly distributed over the gene regions examined. These results indicate that our rice mutant library, generated by MNU mutagenesis, is a promising resource for identifying mutations in any rice gene.

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Section: Chemical Properties Of Nitroso Compoundsmentioning

confidence: 99%

Use of N-methyl-N-nitrosourea treatment of fertilized egg cells for saturation mutagenesis of rice

2010

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“…Furthermore, a comparision of the hydrolysis rates (k 3 ) demonstrated that the H300N mutant was destabilized in the transition state of alkylenzyme hydrolysis by 29 kJ · mol −1 when compared with the wild-type enzyme ( Table 4). The rate decrease can be explained by an anticipated shift in reacting nucleophile from hydroxyl ion to water, which is several orders of magnitude less nucleophilic in carbonyl reactions when compared with the hydroxyl ion [37]. In addition, the positive charge of a protonated imidazole is expected to stabilize a formed hydroxyl ion as well as a negatively charged transition state within the apolar environment of the enzyme active site.…”

Section: Function Of His 300mentioning

confidence: 99%

Catalysis of potato epoxide hydrolase, StEH1

Elfström

Widersten

2005

Biochemical Journal

134

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The kinetic mechanism of epoxide hydrolase (EC 3.3.2.3) from potato, StEH1 (Solanum tuberosum epoxide hydrolase 1), was studied by presteady-state and steady-state kinetics as well as by pH dependence of activity. The specific activities towards the different enantiomers of TSO (trans-stilbene oxide) as substrate were 43 and 3 µmol · min −1 · mg −1 with the R,R-or S,S-isomers respectively. The enzyme was, however, enantioselective in favour of the S,S enantiomer due to a lower K m value. The pH dependences of k cat with R,R or S,S-TSO were also distinct and supposedly reflecting the pH dependences of the individual kinetic rates during substrate conversion. The rate-limiting step for TSO and cis-and trans-epoxystearate was shown by rapid kinetic measurements to be the hydrolysis of the alkylenzyme intermediate. Functional characterization of point mutants verified residues Asp 105 , Tyr 154 , Tyr 235 and His 300 as crucial for catalytic activity. All mutants displayed drastically decreased enzymatic activities during steady state. Presteady-state measurements revealed the base-deficient H300N (His 300 → Asn) mutant to possess greatly reduced efficiencies in catalysis of both chemical steps (alkylation and hydrolysis).

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“…Alkylating agents can be classified as monofunctional or bifunctional (i.e., single or double reactive groups), and they are electrophilic; thus, they react with electron-rich nucleophilic centers within DNA and proteins, with their specific targets depending upon the reactivity of the individual chemicals. The Swain Scott constant (s value) is used as a standard measure of the reactivity of alkylating agents (12). Compounds with high s values target highly nucleophilic centers (e.g., N 7 -G, N 3 -A), whereas low-s value alkylating agents are less sensitive to the level of nucleophilicity of their target; thus, they do not discriminate between centers of high and low nucleophilicity and so are able to alkylate O atoms (e.g., O…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

et al. 2007

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A mechanistic understanding of carcinogenic genotoxicity is necessary to determine consequences of chemical exposure on human populations and improve health risk assessments. Currently, linear dose-responses are assumed for DNA reactive compounds, ignoring cytoprotective processes that may limit permanent damage. To investigate the biological significance of low-dose exposures, human lymphoblastoid cells were treated with alkylating agents that have different mechanisms of action and DNA targets: methylmethane sulfonate (MMS), methylnitrosourea (MNU), ethylmethane sulfonate (EMS), and ethylnitrosourea (ENU). Chromosomal damage and point mutations were quantified with the micronucleus and hypoxanthine phosphoribosyltransferase forward mutation assays. MNU and ENU showed linear dose-responses, whereas MMS and EMS had nonlinear curves containing a range of nonmutagenic low doses. The lowest observed effect level for induction of chromosomal aberrations was 0.85 Mg/mL MMS and 1.40 Mg/mL EMS; point mutations required 1.25 Mg/mL MMS and 1.40 Mg/mL EMS before a mutagenic effect was detected. This nonlinearity could be due to homeostatic maintenance by DNA repair, which is efficient at low doses of compounds that primarily alkylate N 7 -G and rarely attack O atoms. A pragmatic threshold for carcinogenicity may therefore exist for such genotoxins. [Cancer Res 2007;67(8):3904-11]

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Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides¹

Cited by 623 publications

References 3 publications

Use of N-methyl-N-nitrosourea treatment of fertilized egg cells for saturation mutagenesis of rice

Use of N-methyl-N-nitrosourea treatment of fertilized egg cells for saturation mutagenesis of rice

Catalysis of potato epoxide hydrolase, StEH1

Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

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Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides1

Cited by 623 publications

References 3 publications

Use of N-methyl-N-nitrosourea treatment of fertilized egg cells for saturation mutagenesis of rice

Use of N-methyl-N-nitrosourea treatment of fertilized egg cells for saturation mutagenesis of rice

Catalysis of potato epoxide hydrolase, StEH1

Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

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Product

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Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides¹