Mutagenicity of aliphatic epoxides

Wade, Dean; Airy, Subhash C.; Sinsheimer, Joseph E.

doi:10.1016/0165-1218(78)90012-5

Cited by 152 publications

(66 citation statements)

References 16 publications

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“…Therefore, their synthesis and subsequent degradation must be tightly controlled. The detoxification of epoxides is accomplished by a series of reactions involving ring opening via nucleophilic attack of either glutathione or water to form covalent adducts by the activities of glutathione S-transferase and epoxide hydrolases (31,(63)(64)(65). While these detoxification strategies are nonproductive in some organisms, other organisms couple these processes to energy generation in reactions that require CoM (16,17).…”

Section: Com In Propylene Metabolismmentioning

confidence: 99%

Getting a Handle on the Role of Coenzyme M in Alkene Metabolism

Krishnakumar

Sliwa

Endrizzi

et al. 2008

Microbiol Mol Biol Rev

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SUMMARY Coenzyme M (2-mercaptoethanesulfonate; CoM) is one of several atypical cofactors discovered in methanogenic archaea which participate in the biological reduction of CO2 to methane. Elegantly simple, CoM, so named for its role as a methyl carrier in all methanogenic archaea, is the smallest known organic cofactor. It was thought that this cofactor was used exclusively in methanogenesis until it was recently discovered that CoM is a key cofactor in the pathway of propylene metabolism in the gram-negative soil microorganism Xanthobacter autotrophicus Py2. A four-step pathway requiring CoM converts propylene and CO2 to acetoacetate, which feeds into central metabolism. In this process, CoM is used to activate and convert highly electrophilic epoxypropane, formed from propylene epoxidation, into a nucleophilic species that undergoes carboxylation. The unique properties of CoM provide a chemical handle for orienting compounds for site-specific redox chemistry and stereospecific catalysis. The three-dimensional structures of several of the enzymes in the pathway of propylene metabolism in defined states have been determined, providing significant insights into both the enzyme mechanisms and the role of CoM in this pathway. These studies provide the structural basis for understanding the efficacy of CoM as a handle to direct organic substrate transformations at the active sites of enzymes.

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Section: Com In Propylene Metabolismmentioning

confidence: 99%

Getting a Handle on the Role of Coenzyme M in Alkene Metabolism

Krishnakumar

Sliwa

Endrizzi

et al. 2008

Microbiol Mol Biol Rev

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“…Most toxicological research concerning epoxides has centered on the evaluation of mutagenic activity and carcinogenic potential (e.g. Van Duuren et al, 1967a, b; Shimkin et al, .1966; Wade et al, 1978Wade et al, , 1979Hemminki and Vainio, 1984). The acute toxicity of epoxides, and alkylating agents in general, to aquatic organisms has hardly been investigated.…”

Section: Introductionmentioning

confidence: 99%

A quantitative structure-activity relationship for the acute toxicity of some epoxy compounds to the guppy

et al. 1988

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The 14 day LCso values of various epoxy compounds to the guppy (Poecilia reticulata) were determined, and investigated through the construction of a quantitative structure-activity relationship (QSAR). Both hydrophobicity and alkylating potency of the compounds are found to be necessary parameters for the satisfactory description of the LCs0 data. The findings of the present study are compared to results published for halogenated alkylating agents (Hermens, 1985), some of which are considerably more toxic than predicted on the basis of the QSAR established for the epoxy compounds.

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“…Aliphatic epoxides such as epoxypropane have toxic, mutagenic, and potential carcinogenic properties (6), and their metabolism in bacteria and mammalian systems has been the focus of considerable research in recent years. Epoxide carboxylation as described for Xanthobacter Py2 represents the most recently discovered biological epoxide transformation reaction, the others involving conjugation to glutathione, hydration to dihydrodiols (7), or isomerization to an aldehyde (8).…”

mentioning

confidence: 99%

Purification to Homogeneity and Reconstitution of the Individual Components of the Epoxide Carboxylase Multiprotein Enzyme Complex from Xanthobacter Strain Py2

Allen

Ensign

1997

Journal of Biological Chemistry

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Epoxide metabolism in the aerobic bacterium Xanthobacter strain Py2 proceeds by an NADPH-and NAD ؉ -dependent carboxylation reaction that forms ␤-keto acids as products. Epoxide carboxylase, the enzyme catalyzing this reaction, was resolved from the soluble fraction of cell-free extracts into four protein components that are obligately required for functional reconstitution of epoxide carboxylase activity. One of these components, component II, has previously been purified and characterized as an NADPH:disulfide oxidoreductase. In the present study, the three additional epoxide carboxylase components have been purified to homogeneity and characterized. Xanthobacter strain Py2 is one of several bacteria capable of growth with short chain aliphatic alkenes as carbon and energy sources (1). The first step in alkene metabolism involves an oxidative insertion of an oxygen atom into the olefin bond in a reaction that is catalyzed by an inducible (2), multiprotein (3) alkene monooxygenase as shown for the substrate propylene and product epoxypropane in Equation 1.Epoxides formed in this manner are further metabolized via a novel ring opening and carboxylation reaction that requires CO 2 as a cosubstrate and forms a ␤-keto acid as product as shown in Equation 2 (4, 5).Aliphatic epoxides such as epoxypropane have toxic, mutagenic, and potential carcinogenic properties (6), and their metabolism in bacteria and mammalian systems has been the focus of considerable research in recent years. Epoxide carboxylation as described for Xanthobacter Py2 represents the most recently discovered biological epoxide transformation reaction, the others involving conjugation to glutathione, hydration to dihydrodiols (7), or isomerization to an aldehyde (8). Initial studies of the epoxide-carboxylating enzyme, designated an epoxide carboxylase, indicate that it has cofactor requirements, molecular properties, and a catalytic mechanism as unique as the epoxide carboxylation reaction itself.With respect to cofactor requirements, in vitro epoxide carboxylation requires a source of reductant (DTT, 1 other dithiols, or NADPH) and an oxidant (NAD ϩ ) (4, 9). These cofactor requirements are unprecedented for all other carboxylases that have been characterized. The requirement of oxidant and reductant is intriguing since there is no net redox chemistry involved in epoxide carboxylation. In the course of epoxide carboxylation, there is an apparent transhydrogenation reaction wherein the reductant becomes oxidized and NAD ϩ becomes reduced, although this has not to date been unequivocally demonstrated.With respect to molecular properties, epoxide carboxylase appears to function as a multiprotein complex (10, 11). Fractionation of Xanthobacter cell extracts by anion-exchange chromatography resolved epoxide carboxylase into three fractions, designated fractions I, II, and III based on their order of elution, that could be recombined with restoration of activity (11). The active component of one of these fractions was purified to homogeneity on the basi...

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Mutagenicity of aliphatic epoxides

Cited by 152 publications

References 16 publications

Getting a Handle on the Role of Coenzyme M in Alkene Metabolism

Getting a Handle on the Role of Coenzyme M in Alkene Metabolism

A quantitative structure-activity relationship for the acute toxicity of some epoxy compounds to the guppy

Purification to Homogeneity and Reconstitution of the Individual Components of the Epoxide Carboxylase Multiprotein Enzyme Complex from Xanthobacter Strain Py2

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