Quantum Theoretical Study of Cleavage of the Glycosidic Bond of 2′-Deoxyadenosine: Base Excision-Repair Mechanism of DNA by MutY

Tiwari, Saumya; Agnihotri, Neha; Mishra, P. C.

doi:10.1021/jp1109256

Cited by 17 publications

(33 citation statements)

References 73 publications

(145 reference statements)

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“…Further investigations into the transition state structure of MutY showed that the irreversible breakage of the N-glycosidic bond could not take place until a H 2 O atom was present and that the enzyme stabilized the excision site after excision (McCann and Berti, 2008). Recently, a two-step reaction was proposed to be the basis of the catalytic activity of MutY, as opposed to the three-step mechanism proposed before (Tiwari et al, 2011). …”

Section: Function Of Muty and Mutyhmentioning

confidence: 99%

MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA

Markkanen¹,

Dorn²,

Hübscher³

2013

Front. Genet.

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Maintenance of genetic stability is crucial for all organisms in order to avoid the onset of deleterious diseases such as cancer. One of the many proveniences of DNA base damage in mammalian cells is oxidative stress, arising from a variety of endogenous and exogenous sources, generating highly mutagenic oxidative DNA lesions. One of the best characterized oxidative DNA lesion is 7,8-dihydro-8-oxoguanine (8-oxo-G), which can give rise to base substitution mutations (also known as point mutations). This mutagenicity is due to the miscoding potential of 8-oxo-G that instructs most DNA polymerases (pols) to preferentially insert an Adenine (A) opposite 8-oxo-G instead of the appropriate Cytosine (C). If left unrepaired, such A:8-oxo-G mispairs can give rise to CG→AT transversion mutations. A:8-oxo-G mispairs are proficiently recognized by the MutY glycosylase homologue (MUTYH). MUTYH can remove the mispaired A from an A:8-oxo-G, giving way to the canonical base-excision repair (BER) that ultimately restores undamaged Guanine (G). The importance of this MUTYH-initiated pathway is illustrated by the fact that biallelic mutations in the MUTYH gene are associated with a hereditary colorectal cancer syndrome termed MUTYH-associated polyposis (MAP). In this review, we will focus on MUTYH, from its discovery to the most recent data regarding its cellular roles and interaction partners. We discuss the involvement of the MUTYH protein in the A:8-oxo-G BER pathway acting together with pol λ, the pol that can faithfully incorporate C opposite 8-oxo-G and thus bypass this lesion in a correct manner. We also outline the current knowledge about the regulation of MUTYH itself and the A:8-oxo-G repair pathway by posttranslational modifications (PTM). Finally, to achieve a clearer overview of the literature, we will briefly touch on the rather confusing MUTYH nomenclature. In short, MUTYH is a unique DNA glycosylase that catalyzes the excision of an undamaged base from DNA.

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Section: Function Of Muty and Mutyhmentioning

confidence: 99%

MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA

Markkanen¹,

Dorn²,

Hübscher³

2013

Front. Genet.

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“…[37][38][39][40][41] Hotokka et al 37 studied hydrolysis of adenosine and the 3-methyladenosinium ion m 3 Ado + using semiempirical and Hartree-Fock ab initio calculations. Tiwari et al 41 examined N-glycosidic bond cleavage of dAdo induced by glutamic acid with two water molecules using quantum chemical methods. Their results suggested that N7 protonation better facilitates glycosidic bond hydrolysis than N1 and N3 protonation.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms and energetics for N-glycosidic bond cleavage of protonated adenine nucleosides: N3 protonation induces base rotation and enhances N-glycosidic bond stability

Rodgers

2016

Phys. Chem. Chem. Phys.

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Our previous gas-phase infrared multiple photon dissociation action spectroscopy study of protonated 2'-deoxyadenosine and adenosine, [dAdo+H](+) and [Ado+H](+), found that both N3 and N1 protonated conformers are populated with the N3 protonated ground-state conformers predominant in the experiments. Therefore, N-glycosidic bond dissociation mechanisms of N3 and N1 protonated [dAdo+H](+) and [Ado+H](+) and the associated quantitative thermochemical values are investigated here using both experimental and theoretical approaches. Threshold collision-induced dissociation (TCID) of [dAdo+H](+) and [Ado+H](+) with Xe is studied using guided ion beam tandem mass spectrometry techniques. For both systems, N-glycosidic bond cleavage reactions are observed as the major dissociation pathways resulting in production of protonated adenine or elimination of neutral adenine. Electronic structure calculations are performed at the B3LYP/6-311+G(d,p) level of theory to probe the potential energy surfaces (PESs) for N-glycosidic bond cleavage of [dAdo+H](+) and [Ado+H](+). Relative energetics of the reactants, transition states, intermediates and products along the PESs for N-glycosidic bond cleavage are determined at the B3LYP/6-311+G(2d,2p), B3LYP-GD3BJ/6-311+G(2d,2p), and MP2(full)/6-311+G(2d,2p) levels of theory. The predicted N-glycosidic bond dissociation mechanisms for the N3 and N1 protonated species differ. Base rotation of the adenine residue enables formation of a strong N3H(+)O5' hydrogen-bonding interaction that stabilizes the N3 protonated species and its glycosidic bond. Comparison between experiment and theory indicates that the N3 protonated species determine the threshold energies, as excellent agreement between the measured and B3LYP computed activation energies (AEs) and reaction enthalpies (ΔHrxns) for N-glycosidic bond cleavage of the N3 protonated species is found.

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“…The amino acids are the building blocks of proteins and the protein synthesis is dictated by DNA structure. The interaction of the DNA bases with specific amino acids plays a crucial role in the repair of damaged DNA by proteins [3]. For example, the Ade-glutamic acid interaction is of great importance in the repair of damaged DNA by the protein MutY [3].…”

mentioning

confidence: 99%

“…The interaction of the DNA bases with specific amino acids plays a crucial role in the repair of damaged DNA by proteins [3]. For example, the Ade-glutamic acid interaction is of great importance in the repair of damaged DNA by the protein MutY [3]. In this regard, a thorough understanding of the interaction of nucleobases with amino acids is essential.…”

mentioning

confidence: 99%