Repair of DNA Methylphosphotriesters Through a Metalloactivated Cysteine Nucleophile

Myers, Lawrence C.; Terranova, Michael P.; Ferentz, Ann E.; Wagner, Gerhard; Verdine, Gregory L.

doi:10.1126/science.8395079

Cited by 177 publications

(185 citation statements)

References 24 publications

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“…The resulting Cd(II)-substituted N-Ada retained the ability to repair S p -methylphosphotriester, but the rate was one-fourth that of the native Zn(II)-containing protein. 46 This experiment suggested that metal is directly involved in the rate-determining step of the repair. To determine the ligands around the metal ion, 113 Cd-substituted N-Ada20 was prepared for 113 Cd nuclear magnetic resonance (NMR) investigations.…”

Section: N-ada Utilizes a Zinc(ii)-activated Cysmentioning

confidence: 99%

Direct Reversal of DNA Alkylation Damage

Mishina

Duguid

2006

ChemInform

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Section: N-ada Utilizes a Zinc(ii)-activated Cysmentioning

confidence: 99%

Direct Reversal of DNA Alkylation Damage

Mishina

Duguid

2006

ChemInform

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“…EaCoMT belongs to a subset of the family of alkyl transferases for which zinc is crucial in activation of a thiol for nucleophilic attack (17,42). Other examples of this family are the Ada protein, which is involved in DNA repair (44,45), betaine:homocysteine methyltransferase (10), cobalamin-independent methionine synthases (MetE) (24,42), and various methanogenic methyltransferases (MtaA, MtbA, and MtsA) (56).…”

Section: Eacomt: Zinc-mediated Activation Of the Com Thiol Reactions mentioning

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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“…The Ada protein removes methyl groups from the premutagenic lesions 06-methylguanine and 04-methylthymine, transferring them irreversibly to Cys-321, a cysteine located in its carboxylterminal domain (4-6), and also removes methyl groups from the S diastereoisomers of DNA methylphosphotriesters, transferring them irreversibly to Cys-69, which is located in its amino-terminal domain (7-10). Methylation at Cys-69 converts Ada into a strong transcriptional activator ofits own gene (ada) and also of several other genes (alkB, alkA, and aidW) (11)(12)(13)(14)(15) N-methyl-N'-nitro-N-nitrosoguanidine. …”

mentioning

confidence: 99%

The Ada protein acts as both a positive and a negative modulator of Escherichia coli's response to methylating agents.

Saget

Walker²

1994

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

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The adaptive response of Escherichia coli protects the cells against the toxic and mutagenic effects of ceilain alkylating agents. The major effector molecule regulating this response is the 39-kDa Ada protein, which functions as both a DNA repair protein and a transcriptional activator. Ada removes methyl groups from phosphotriester and 0P-methyluanine lesions in DNA, irreversibly transferring them to cystehie residues at positions 69 and 321, respectively. When methylated at Cys-69, Ada is converted into a potent activator ofada and alkA transcription and binds to a sequence (Ada box) present in both promoters. We have found that physiologically relevant higher concentrations of unmethylated Ada are able to inhibit the activation of ada transcription by methylated Ada, both in vitro and in vivo. In contrast, the same concentrations of unmethylated Ada do not inhibit the activation of aLkA transcription by methylated Ada, either in vitro or in vivo.Deletion of the carboxyl-trminal 67 amino acids of Ada abolished the ability of the unmethylated form of the protein to inhibit activation of ada transcription but not the ability of the methylated form to activate ada or alkA transcription. Our results suggest that the Ada protein plays a pivotal role in the negative modulation of Its own synthesis and therefore in the down-regulation of the adaptive response. Elements present in the carboxyl terminus of Ada appear to be necessary for this negative regulatory function.The adaptive response of Escherichia coli is an inducible DNA repair system that helps prevent the mutagenic and cytotoxic effects caused by exposure to alkylating agents, particularly methylating agents (1-3). The Ada protein removes methyl groups from the premutagenic lesions 06-methylguanine and 04-methylthymine, transferring them irreversibly to Cys-321, a cysteine located in its carboxylterminal domain (4-6), and also removes methyl groups from the S diastereoisomers of DNA methylphosphotriesters, transferring them irreversibly to Cys-69, which is located in its amino-terminal domain (7-10). Methylation at Cys-69 converts Ada into a strong transcriptional activator ofits own gene (ada) and also of several other genes (alkB, alkA, and aidW) (11)(12)(13)(14)(15) N-methyl-N'-nitro-N-nitrosoguanidine. 9730The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Repair of DNA Methylphosphotriesters Through a Metalloactivated Cysteine Nucleophile

Cited by 177 publications

References 24 publications

Direct Reversal of DNA Alkylation Damage

Direct Reversal of DNA Alkylation Damage

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

The Ada protein acts as both a positive and a negative modulator of Escherichia coli's response to methylating agents.

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