Spiroiminodihydantoin lesions derived from guanine oxidation: Structures, energetics, and functional implications

Lei Jia, Vladimir Shafirovich, Robert Shapiro, Nicholas Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

Reactive oxygen species present in the cell generate DNA damage. One of the major oxidation products of guanine in DNA, 8-oxo-7,8-dihydroguanine, formed by loss of two electrons, is among the most extensively studied base lesions. The further removal of two electrons from this product can yield spiroiminodihydantoin (Sp) R and S stereoisomers. Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G → T and G → C transversions. Hence, they are of interest as examples of endogenous DNA damage that may initiate cancer. To interpret the mutagenic properties of the Sp lesions, an understanding of their structural properties is needed. To elucidate these structural effects, we have carried out computational investigations at the level of the Sp-modified base and nucleoside. At the base level, quantum mechanical geometry optimization studies have revealed exact mirror image symmetry of the R and S stereoisomers, with a near-perpendicular geometry of the two rings. At the nucleoside level, an extensive survey of the potential energy surface by molecular mechanics calculations using AMBER has provided three-dimensional potential energy maps. These maps reveal that the range and flexibility of the glycosidic torsion angles are significantly more restricted in both stereoisomeric adducts than in unmodified 2′-deoxyguanosine. The structural and energetic results suggest that the unusual geometric, steric, and hydrogen bonding properties of these lesions underlie their mutagenicity. In addition, stereoisomer-specific differences indicate the possibility that their processing by cellular replication and repair enzymes may be differentially affected by their absolute configuration.

Original languageEnglish (US)
Pages (from-to)6043-6051
Number of pages9
JournalBiochemistry
Volume44
Issue number16
DOIs
StatePublished - Apr 26 2005

Fingerprint

Stereoisomerism
Guanine
Oxidation
Nucleosides
DNA Damage
DNA
Electrons
Potential energy surfaces
Deoxyguanosine
Molecular mechanics
Geometry
Hydrogen Bonding
Potential energy
Mechanics
Torsional stress
Structural properties
Reactive Oxygen Species
Hydrogen bonds
Mirrors
Repair

ASJC Scopus subject areas

  • Biochemistry

Cite this

Spiroiminodihydantoin lesions derived from guanine oxidation : Structures, energetics, and functional implications. / Jia, Lei; Shafirovich, Vladimir; Shapiro, Robert; Geacintov, Nicholas; Broyde, Suse.

In: Biochemistry, Vol. 44, No. 16, 26.04.2005, p. 6043-6051.

Research output: Contribution to journalArticle

@article{180a355ac93b4db991ac5193f4c3615a,
title = "Spiroiminodihydantoin lesions derived from guanine oxidation: Structures, energetics, and functional implications",
abstract = "Reactive oxygen species present in the cell generate DNA damage. One of the major oxidation products of guanine in DNA, 8-oxo-7,8-dihydroguanine, formed by loss of two electrons, is among the most extensively studied base lesions. The further removal of two electrons from this product can yield spiroiminodihydantoin (Sp) R and S stereoisomers. Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G → T and G → C transversions. Hence, they are of interest as examples of endogenous DNA damage that may initiate cancer. To interpret the mutagenic properties of the Sp lesions, an understanding of their structural properties is needed. To elucidate these structural effects, we have carried out computational investigations at the level of the Sp-modified base and nucleoside. At the base level, quantum mechanical geometry optimization studies have revealed exact mirror image symmetry of the R and S stereoisomers, with a near-perpendicular geometry of the two rings. At the nucleoside level, an extensive survey of the potential energy surface by molecular mechanics calculations using AMBER has provided three-dimensional potential energy maps. These maps reveal that the range and flexibility of the glycosidic torsion angles are significantly more restricted in both stereoisomeric adducts than in unmodified 2′-deoxyguanosine. The structural and energetic results suggest that the unusual geometric, steric, and hydrogen bonding properties of these lesions underlie their mutagenicity. In addition, stereoisomer-specific differences indicate the possibility that their processing by cellular replication and repair enzymes may be differentially affected by their absolute configuration.",
author = "Lei Jia and Vladimir Shafirovich and Robert Shapiro and Nicholas Geacintov and Suse Broyde",
year = "2005",
month = "4",
day = "26",
doi = "10.1021/bi0473657",
language = "English (US)",
volume = "44",
pages = "6043--6051",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "16",

}

TY - JOUR

T1 - Spiroiminodihydantoin lesions derived from guanine oxidation

T2 - Structures, energetics, and functional implications

AU - Jia, Lei

AU - Shafirovich, Vladimir

AU - Shapiro, Robert

AU - Geacintov, Nicholas

AU - Broyde, Suse

PY - 2005/4/26

Y1 - 2005/4/26

N2 - Reactive oxygen species present in the cell generate DNA damage. One of the major oxidation products of guanine in DNA, 8-oxo-7,8-dihydroguanine, formed by loss of two electrons, is among the most extensively studied base lesions. The further removal of two electrons from this product can yield spiroiminodihydantoin (Sp) R and S stereoisomers. Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G → T and G → C transversions. Hence, they are of interest as examples of endogenous DNA damage that may initiate cancer. To interpret the mutagenic properties of the Sp lesions, an understanding of their structural properties is needed. To elucidate these structural effects, we have carried out computational investigations at the level of the Sp-modified base and nucleoside. At the base level, quantum mechanical geometry optimization studies have revealed exact mirror image symmetry of the R and S stereoisomers, with a near-perpendicular geometry of the two rings. At the nucleoside level, an extensive survey of the potential energy surface by molecular mechanics calculations using AMBER has provided three-dimensional potential energy maps. These maps reveal that the range and flexibility of the glycosidic torsion angles are significantly more restricted in both stereoisomeric adducts than in unmodified 2′-deoxyguanosine. The structural and energetic results suggest that the unusual geometric, steric, and hydrogen bonding properties of these lesions underlie their mutagenicity. In addition, stereoisomer-specific differences indicate the possibility that their processing by cellular replication and repair enzymes may be differentially affected by their absolute configuration.

AB - Reactive oxygen species present in the cell generate DNA damage. One of the major oxidation products of guanine in DNA, 8-oxo-7,8-dihydroguanine, formed by loss of two electrons, is among the most extensively studied base lesions. The further removal of two electrons from this product can yield spiroiminodihydantoin (Sp) R and S stereoisomers. Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G → T and G → C transversions. Hence, they are of interest as examples of endogenous DNA damage that may initiate cancer. To interpret the mutagenic properties of the Sp lesions, an understanding of their structural properties is needed. To elucidate these structural effects, we have carried out computational investigations at the level of the Sp-modified base and nucleoside. At the base level, quantum mechanical geometry optimization studies have revealed exact mirror image symmetry of the R and S stereoisomers, with a near-perpendicular geometry of the two rings. At the nucleoside level, an extensive survey of the potential energy surface by molecular mechanics calculations using AMBER has provided three-dimensional potential energy maps. These maps reveal that the range and flexibility of the glycosidic torsion angles are significantly more restricted in both stereoisomeric adducts than in unmodified 2′-deoxyguanosine. The structural and energetic results suggest that the unusual geometric, steric, and hydrogen bonding properties of these lesions underlie their mutagenicity. In addition, stereoisomer-specific differences indicate the possibility that their processing by cellular replication and repair enzymes may be differentially affected by their absolute configuration.

UR - http://www.scopus.com/inward/record.url?scp=17644395664&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17644395664&partnerID=8YFLogxK

U2 - 10.1021/bi0473657

DO - 10.1021/bi0473657

M3 - Article

VL - 44

SP - 6043

EP - 6051

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 16

ER -