Principles Governing Conformations in Stereoisomeric Adducts of Bay Region Benzo[<i>a</i>]pyrene Diol Epoxides to Adenine in DNA:  Steric and Hydrophobic Effects Are Dominant

Tan, Jian Jun; Geacintov, Nicholas E.; Broyde, Suse

doi:10.1021/ja993624h

Cited by 24 publications

(50 citation statements)

References 47 publications

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“…The torsion angle β' adopts values of ~ −90° for the 1S (−) and ~ +90° for the 1R (+)-trans-anti isomer (Table 1). Thus, the α', β' combination, computed in nucleosides and observed in duplexes, gives rise to the opposite orientations of the B[c]Ph, relative to the modified deoxyadenosyl residues.These results are consistent with our previous studies on R and S benzo[c]phenanthrene diol epoxide guanine adducts (25), and on a number of R and S nucleoside adducts of diol epoxide metabolites derived from the planar bay region PAH, benzo[a]pyrene (19)(20)(21)(22). In all cases symmetric potential energy surfaces are manifested in nucleosides and opposite orientations are observed in NMR solution structures of DNA duplexes (18,(32)(33)(34)(35).…”

supporting

confidence: 92%

“…Parameters added to the AMBER 5.0 force field for the B[c]Ph-N 6 -dA adducts are the same as those given previously (21), except for the partial charges for the modified nucleosides; these were computed with Gaussian 94 (29) at the 6-31G* basis set level which is compatible with the rest of the Cornell et al force field and parm96 parameter set; the least squares charge fitting algorithm RESP (30) provided with AMBER 5.0 was then used to fit the charge to each atomic center. Partial charges, atom types and topology information are given in Table A2, Appendix.…”

Section: Energy Computationmentioning

confidence: 99%

“…The opposite orientation phenomenon of R versus S adducts has been extensively documented for the planar, non-hindered bay region PAH benzo[a]pyrene (6,(19)(20)(21)(22) in both trans and cis opened guanine and adenine DNA adducts. However, the analogous adducts derived from the fjord region PAH B[c]Ph metabolites, which have remarkably different structural features (6) and biochemical functions (2)(3)(4)(5)23) due to the non-planar topology of the aromatic ring system (24), have not been fully investigated (25).…”

Section: Introductionmentioning

confidence: 99%

“…In guanine adducts, the R isomer is 3'-directed while the S isomer is 5'-directed (18). Distorted Watson-Crick base pairing is retained in both cases.The opposite orientation phenomenon of R versus S adducts has been extensively documented for the planar, non-hindered bay region PAH benzo[a]pyrene (6,(19)(20)(21)(22) …”

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confidence: 99%

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Conformational searches elucidate effects of stereochemistry on structures of deoxyadenosine covalently bound to tumorigenic metabolites of benzo[C] phenanthrene

Wu¹

2004

Front Biosci

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Remarkably different conformations can result when DNA binds with stereoisomeric compounds containing differing absolute configurations of substituents about chiral carbon atoms. Furthermore, the biochemical functions of covalent adducts with DNA are strongly affected by the stereochemistry of the ligands. Such stereochemical effects are manifested by DNA covalent adducts derived from metabolites of the non-planar fjord region environmental chemical carcinogen benzo [c]phenanthrene. To analyze these phenomena, an extensive conformational investigation for R and S stereoisomeric adducts to deoxyadenosine, derived from trans addition of enantiomeric anti diol epoxide metabolites of benzo [c]phenanthrene, has been carried out. We have surveyed the potential energy surface of the two adducts by varying systematically at 5° intervals in combination, the three important torsion angles that govern conformational flexibility of the carcinogen bulk with respect to the linked nucleoside. We carried out a grid search by creating 373, 248 structures for each isomer, and evaluated their molecular mechanical energies. This has permitted us to map the potential energy surface of each adduct in these three variables, and to delineate their low energy regions. The maps have a symmetric relationship which stems from the near mirror-image stereochemistry in the R and S isomers. This produces near mirrorimage low energy structures in the nucleoside adducts. The limited sets of stereoisomer-dependent conformational domains delineated are determined by steric effects. Moreover, these features have been experimentally demonstrated to play governing structural roles in such carcinogen-damaged DNA duplexes: opposite orientations in the stereoisomer pairs computed for the nucleosides are observed by high-resolution NMR in the similarly modified DNA double helices, and are likely to play important roles in their interactions with enzymes involved in DNA transactions, and hence their biological activities. Figure 1) (8,9). DNA can react with these metabolites to form covalently modified duplexes containing these bulky substituents (10). The stereoisomeric 1R (+) and 1S (−)-trans-anti-B[c]Ph-N 6 -dA adducts ( Figure 1) are among these. Thermal melting studies revealed that these R and S adducted DNA duplexes have the same stabilities as the unmodified one (11). In addition, it has been found that they are not repaired by the nucleotide excision repair machinery (2) which removes bulky DNA adducts (12); thus these unrepaired adducts have the chance to encounter the DNA replication machinery. Mutations caused by the unfaithful replication of DNA adducts can contribute to cancer initiation via alteration in function of proto-oncogenes and tumor suppressor genes (13-15). Site specific mutagenesis studies show that the 1R (+) and 1S (−)-trans-anti-B[c]Ph-N 6 -dA adducts have different mutagenic specificities due to the different configurations of the chiral carbon at the linkage point (3). HHS Public AccessHigh resolution NMR solution ...

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supporting

confidence: 92%

Section: Energy Computationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Conformational searches elucidate effects of stereochemistry on structures of deoxyadenosine covalently bound to tumorigenic metabolites of benzo[C] phenanthrene

Wu¹

2004

Front Biosci

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“…For 14, the absolute configuration of the pyridyl-substituted carbon was determined by reaction of chiral nornicotine with protected 2-fluoroinosine 23. While few previous studies of nitrosamine-DNA adducts have elaborated absolute stereochemistry (16,25,26), this has been an area of extensive research in the study of DNA adducts of polycyclic aromatic hydrocarbons (27)(28)(29). The results of those studies clearly demonstrate that the absolute stereochemistry of DNA adducts is critical in determining their mutagenic and carcinogenic effects.…”

Section: Discussionmentioning

confidence: 99%

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

Upadhyaya

McIntee

Villalta

et al. 2006

Chem. Res. Toxicol.

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N′-Nitrosonornicotine (NNN) is believed to play an important role as a cause of cancer in people who use tobacco products and is considered to be a human carcinogen. NNN requires metabolism to form DNA adducts, which are absolutely critical to its carcinogenic properties. Previous studies have identified cytochrome P450-catalyzed 2′-and 5′-hydroxylation of NNN as potential DNA adduct forming metabolic pathways. 5′-Hydroxylation is the more prevalent of these in monkeys and humans, and is known to generate mutagenic intermediates, but the DNA adducts formed by this pathway have never been characterized. In this study, we used 5′-acetoxyNNN as a stable precursor to 5′-hydroxyNNN, and investigated its esterase-catalyzed reactions with deoxyguanosine (dGuo) and DNA. Adducts resulting from carbocation and oxonium ion intermediates, produced by the spontaneous decomposition of 5′-hydroxyNNN, were identified. The carbocation pathway resulted in the formation of 2-[2-hydroxy-5-(3-pyridyl)pyrrolidin-1-yl]deoxyinosine (12) which was characterized by comparison to an independently synthesized standard. Treatment of 12 with NaBH 3 CN produced two diastereomers of 2-[2-(3-pyridyl)pyrrolidin-1-yl]deoxyinosine (14), and their absolute configurations at the 2-position were determined by comparison to synthetic standards. The oxonium ion pathway produced diastereomers of N 2 [5-(3-pyridyl)tetrahydrofuran-2-yl]dGuo (16), identified by comparison to synthetic standards. The absolute configuration at the 5-position was determined by establishing the stereochemistry of the enantiomers of 5-(3-pyridyl)-2-hydroxytetrahydrofuran at the 5-position, and allowing these to react individually with dGuo. Treatment of 16 with NaBH 3 CN produced N 2 [4-hydroxy-4-(3-pyridyl)but-1-yl]dGuo (18) which was also synthesized independently. Using liquid chromatography-electrospray ionization-tandem mass spectrometry with selected reaction monitoring, adducts 12 and 16 were identified as products of the reactions of 5′-acetoxyNNN with dGuo. Similarly, adducts 14 and 18 were identified as products of the reaction of 5′-acetoxyNNN with DNA followed by NaBH 3 CN treatment and enzymatic hydrolysis. These results provide the first structural characterization of DNA adducts that can be formed by 5′-hydroxylation of NNN.

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Elucidating Structure–Function Relationships in Bulky DNA Lesions: From Solution Structures to Polymerases

Broyde

Wang

Patel

et al. 2010

The Chemical Biology of DNA Damage

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Principles Governing Conformations in Stereoisomeric Adducts of Bay Region Benzo[a]pyrene Diol Epoxides to Adenine in DNA: Steric and Hydrophobic Effects Are Dominant

Cited by 24 publications

References 47 publications

Conformational searches elucidate effects of stereochemistry on structures of deoxyadenosine covalently bound to tumorigenic metabolites of benzo[C] phenanthrene

Conformational searches elucidate effects of stereochemistry on structures of deoxyadenosine covalently bound to tumorigenic metabolites of benzo[C] phenanthrene

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

Elucidating Structure–Function Relationships in Bulky DNA Lesions: From Solution Structures to Polymerases

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