NMR Determination of the Conformation of a Trimethylene Interstrand Cross-Link in an Oligodeoxynucleotide Duplex Containing a 5‘-d(GpC) Motif

Dooley, Patricia A.; Zhang, Mingzhou; Korbel, Gregory A.; Nechev, Lubomir V.; Harris, Constance M.; Stone, Michael P.; Harris, Thomas M.

doi:10.1021/ja0207798

Cited by 37 publications

(66 citation statements)

References 42 publications

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“…The are not many studies (10,(12)(13)(14) on the toxicology of MDA. Draper et al showed that its administration in a range of 0.1-10 µg/g/day to mice produces dose-dependent neoplastic changes in the liver (14).…”

Section: Resultsmentioning

confidence: 99%

Malondialdehyde Contents in Infant Milk Formulas

Cesa

2004

J. Agric. Food Chem.

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Malondialdehyde (MDA) levels in infant milk formulas have been monitored by using an aqueous acid extraction method combined with the thiobarbituric acid method (TBA-test). Vegetable oils, with a remarkable content of polyunsaturated fatty acids (PUFA) are used to enrich the infant milk formulas. As PUFA are more susceptible to autoxidation, it becomes of great interest to have information about the safety and preservation of these products. We monitored MDA content in twenty of the most popular infant milk formulas and in some commercial cow milk samples and compared the obtained data. Levels of MDA ranged between 200 and 1200 ppb: all values but one were higher, up to five times, than those found in cow milk samples. To evaluate the accuracy of the data obtained from the TBA-test, some samples were also analyzed with an HPLC derivative method: preliminary results show a good agreement between the two analytical techniques.

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Section: Resultsmentioning

confidence: 99%

Malondialdehyde Contents in Infant Milk Formulas

Cesa

2004

J. Agric. Food Chem.

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“…(33). The changes in the aromatic region chemical shifts upon Fe 2+ binding in this study were approximately 0.1–0.25 p.p.m.…”

Section: Discussionmentioning

confidence: 99%

Preferential binding and structural distortion by Fe2+ at RGGG-containing DNA sequences correlates with enhanced oxidative cleavage at such sequences

Rai

Wemmer

Linn

2005

Nucleic Acids Research

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Certain DNA sequences are known to be unusually sensitive to nicking via the Fe2+-mediated Fenton reaction. Most notable are a purine nucleotide followed by three or more G residues, RGGG, and purine nucleotides flanking a TG combination, RTGR. Our laboratory previously demonstrated that nicking in the RGGG sequences occurs preferentially 5′ to a G residue with the nicking probability decreasing from the 5′ to 3′end of these sequences. Using 1H NMR to characterize Fe2+ binding within the duplex CGAGTTAGGGTAGC/GCTACCCTAACTCG and 7-deazaguanine-containing (Z) variants of it, we show that Fe2+ binds preferentially at the GGG sequence, most strongly towards its 5′ end. Substitutions of individual guanines with Z indicate that the high affinity Fe2+ binding at AGGG involves two adjacent guanine N7 moieties. Binding is accompanied by large changes in specific imino, aromatic and methyl proton chemical shifts, indicating that a locally distorted structure forms at the binding site that affects the conformation of the two base pairs 3′ to the GGG sequence. The binding of Fe2+ to RGGG contrasts with that previously observed for the RTGR sequence, which binds Fe2+ with negligible structural rearrangements.

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“…62 When the N 2 -dG:N 2 -dG trimethylene linkage (37), a surrogate for the non-observed cross-link in the 5′-GpC-3′ sequence, was constructed in d(TCCXCGGA) 2 , its structure was distorted, and its T m was reduced. 59,63 Interstrand Cross-linking of (6R) and (6S) Crotonaldehyde 1,N 2 -PdG AdductsRing-opening of the diastereomeric 1,N 2 -dG adducts 11 and 12 was incomplete at pH 7 when placed opposite dG in duplex DNA. The incomplete ring-opening was attributed to the positioning of the CH 3 groups to avoid steric clash with N3 of guanine, which becomes significant in the N 2 -(1-methyl-3-oxopropyl)-dG aldehydes (3,4).…”

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Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

et al. 2008

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ConspectusSignificant levels of the 1,N 2 -γ-hydroxypropano-dG adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxy-2E-nonenal (HNE) have been identified in human DNA, arising from both exogenous and endogenous exposure. They yield interstrand DNA cross-links between guanines in the neighboring C•G and G•C base pairs located in 5′-CpG-3′ sequences, as a result of opening of the 1,N 2 -γ-hydroxypropano-dG adducts to form reactive aldehydes that are positioned within the minor groove of duplex DNA. Using a combination of chemical, spectroscopic, and computational methods, we have elucidated the chemistry of cross-link formation in duplex DNA. NMR spectroscopy revealed that, at equilibrium, the acrolein and crotonaldehyde cross-links consist primarily of interstrand carbinolamine linkages between the exocyclic amines of the two guanines located in the neighboring C•G and G•C base pairs located in 5′-CpG-3′ sequences, that maintain the Watson-Crick hydrogen bonding of the cross-linked base pairs. The ability of crotonaldehyde and HNE to form interstrand cross-links depends upon their common relative stereochemistry at the C6 position of the 1,N 2 -γ-hydroxypropano-dG adduct. The stereochemistry at this center modulates the orientation of the reactive aldehyde within the minor groove of the doublestranded DNA, either facilitating or hindering the cross-linking reactions; it also affects the stabilities of the resulting diastereoisomeric cross-links. The presence of these cross-links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease. Reduced derivatives of these cross-links are useful tools for studying their biological processing. IntroductionThe α,β-unsaturated aldehydes (enals) acrolein, crotonaldehyde, and 4-hydroxynonenal (4-HNE) (Scheme 1) are endogenous byproducts of lipid peroxidation, arising as a consequence of oxidative stress. [1][2][3][4] Acrolein and crotonaldehyde exposures also occur from exogenous sources, e.g., cigarette smoke 5 and automobile exhaust. 6 Enals react with DNA nucleobases to give exocyclic adducts; they also react with proteins. 7 Addition of enals to dG involves Michael addition of the N 2 -amine to give N 2 -(3-oxopropyl)-dG adducts (1, 3-8), followed by * Michael P. Stone telephone, 615-322-2589; fax, 615-322-7591; michael.p The lipid peroxidation product 4-HNE afforded related dGadducts (13-16). 14 Identification of acrolein adducts of other nucleosides followed. 15,16 The principal acrolein adduct is γ-OH-PdG (9), 10,12 although the regioisomeric 6-hydroxypyrimido[1,2-a]purin-10(3H)-one (α-OH-PdG, 10) has also been observed. 12,17 The γ-OH-PdG adduct (9) exists as a mixture of C8-OH epimers. With crotonaldehyde, addition at N 2 -dG creates a stereocenter at C6. Of four possible products, the two with the trans relative configurations at C6 and C8 (11,12) are observed. 12,18 These are also formed through the reaction of dG with two equivalents of acetaldehyde. 5,19,20 The cor...

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NMR Determination of the Conformation of a Trimethylene Interstrand Cross-Link in an Oligodeoxynucleotide Duplex Containing a 5‘-d(GpC) Motif

Cited by 37 publications

References 42 publications

Malondialdehyde Contents in Infant Milk Formulas

Malondialdehyde Contents in Infant Milk Formulas

Preferential binding and structural distortion by Fe2+ at RGGG-containing DNA sequences correlates with enhanced oxidative cleavage at such sequences

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

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