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Heavy metal mutagenicity: insights from bioinorganic model chemistry
www.elsevier.nl/locate/jinorgbio Journal of Inorganic Biochemistry 79 (2000) 261–265
Heavy metal mutagenicity: insights from bioinorganic model chemistry ¨ Jens Muller, Roland K.O. Sigel, Bernhard Lippert * ¨ Dortmund, 44221 Dortmund, Germany Fachbereich Chemie, Universitat Received 8 June 1999; received in revised form 26 August 1999; accepted 9 September 1999
Abstract The mutagenicity of metal species may be the result of a direct interaction with the target molecule DNA. Possible scenarios leading to nucleobase mispairing are discussed, and selected examples are presented. They include changes in nucleobase selectivity as a consequence of alterations in acid–base properties of nucleobase atoms and groups involved in complementary H bond formation, guanine deprotonation, and stabilization of rare nucleobase tautomers by metal ions. Oxidative nucleobase damage brought about by metal species will not be considered. q2000 Elsevier Science Inc. All rights reserved. Keywords: Heavy metal mutagenicity; Bioinorganic model chemistry
1. Introduction Mutagenesis is the result of spontaneous or induced base mispairing in DNA, hence a violation of proper Watson– Crick pairing undetected by the DNA repair machinery. The occurrence of rare nucleobase tautomers and/or a rotation of the nucleobase about the glycosidic bond to give syn rotamers (as opposed to the normal anti rotamers) has been implicated in mispairing scenarios [1–4]. The existence of non-Watson– Crick base pairs, hence base pair mismatches, in synthetic DNA is firmly established today, as demonstrated in many X-ray crystallographic [5,6] as well as NMR solution studies [7]. Without exception these mismatches include bases in their preferred tautomeric structures, occasionally with bases in a syn orientation, with bases being protonated, or with solvent (H2O) molecules included in the pair. There is only one example, intermolecular H bond formation between two DNA hairpins, which appears to contain a pair between two thymine residues, one of which adopts a rare enol tautomer structure [8]. Chemical modification of nucleobases, e.g. halogenation (5-bromouracil), alkylation (e.g. N(3) of purine bases or O(6) of guanine), or base cross-linking, to give these examples only, is known to be responsible for mutations. Oxidative damage of nucleobases or nucleotides, as brought about by reactive oxygen species or radicals in general, is commonly considered another major reason of mutagenesis [9,10]. * Corresponding author. Fax: q49-231-7553797; e-mail: lippert@ pop.uni-dortmund.de
Metal species can be involved in the generation of reactive oxygen species or, in a high oxidation state, directly oxidize nucleobases. NiII and CrO42y have been primarily studied in this context [11,12]. At present there is no unified picture on metal-induced mutagenicity, probably because different pathways exist which can lead to mutagenesis. Oxidative DNA damage [9,10], interference with metal ions essential for DNA replication or transcription [13], impairment of DNA repair processes [14], DNA cross-linking or DNA distortion [15] may all lead to mutagenesis. In any case, a decrease in fidelity of DNA synthesis (replication) in the presence of metal ions or metal coordination compounds is well established [16]. As far as the mutagenicity of the antitumor agent cis-Pt(NH3)2Cl2 (cisplatin) is concerned, it appears not to be related to any redox chemistry. Rather it has been suggested that it is the consequence of a replicative bypass of intrastrand 59-GpG and 59-ApG adducts [17], with an adenine misincorporated across the 59 base A [18] or G [19]. Our efforts to study basic aspects of metal–nucleobase interactions on a model-nucleobase level [20] has led us to pursue also the question of processes that might lead to mispairing of bases or, more generally, to a prevention of proper Watson–Crick pairing. In the following, selected examples will be presented and discussed. 2. Discussion Among the various scenarios that could lead to mismatch formation between nucleobases as a consequence of metal
0162-0134/00/$ - see front matter q2000 Elsevier Science Inc. All rights reserved. PII S 0 1 6 2 - 0 1 3 4 ( 9 9 ) 0 0 1 7 9 - 8
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coordination and could be studied on a model-nucleobase level, those affecting the nucleobase to be incorporated in the growing new strand or the template strand can be favorably modeled. These include (at least) i) blocking of H bonding sites, ii) cross-linking of nucleobases, iii) effect on acid–base properties of H bonding sites, iv) effect on tautomer equilibrium, v) metal-induced hydrolysis of exocyclic base groups, vi) hydrolysis of the glycosidic bond, vii) oxidative alterations of nucleobases, viii) saturation of C–C double bonds in pyrimidine bases. As pointed out above, most of these possibilities do not involve redox chemistry. In the following, only (iii) and (iv) will be discussed in more detail. Examples for (i) [21,22], (ii) [23,24], (vi) [25,26], (vii) [27–29] and (viii) [30] have been published or will be published (v). As far as metals applied in such studies are concerned, the use of kinetically inert, diamagnetic species appears to be advantageous (even though not always biologically relevant) in that reactions can easily be followed by NMR spectroscopy in solution and chances of isolating intermediates are generally better with kinetically inert species as opposed to labile ones. A point of differentiation has to be made: In most cases metal ions exhibit a charge effect which will pull electron density out of the heterocyclic ring, toward the metal. Exceptions to this rule are those metal entities having strong back-donation properties, and hence donate electron density from filled d orbitals into empty pU orbitals of the heterocycle, thereby overcompensating for the ordinary effect of a positively charged metal. RuII(NH3)5 is such an example [31,32], whereas the corresponding RuIII species behaves ‘normally’. In the following, only the ‘normal’ case will be considered. 2.1. Effects of metal coordination to acid–base properties of purine bases Base–base recognition and hence proper Watson–Crick pairing crucially depend on charge densities within the heterocyclic rings, pKa values of H donors as well as pKb values of H acceptors, and the tautomeric structures of the two bases [33]. From this it is evident that any chemical process affecting the complementarity of two bases, e.g. metal coordination, will have an influence on the H bonding behavior. PtII binding to N(7) of 9-methyladenine (9-MeA) reduces the basicity of the N(1) position by 1.5–2.5 log units [34,35], and hence makes this site a weaker H bonding acceptor in the Watson–Crick pair with thymine. From a limited number of data points it appears that there is a minor influence of the charge carried by the metal entity, e.g. [(NH3)3Pt]2q) [(NH3)Cl2Pt])[PtCl3]y. It is to be expected that the metal entity, while decreasing the basicity of N(1), simultaneously increases the acidity of the exocyclic amino group, even though this effect cannot be determined accurately due to the high pKa of this group. The question of how these two opposing effects influence the strength of the AT pair or whether
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the pairing specificity of A is affected, remains elusive. The problem will be solved once metal complexes of A are available that are sufficiently soluble in aprotic media such as CHCl3, etc., to permit the determination of association constants. MII binding to N(3) of A with MsPt or Pd dramatically decreases the basicity of N(1) by more than 5 log units [36]. Since it is unlikely that such a coordination mode would markedly increase the acidity of the exocyclic amino group at the 6-position, it is tentatively concluded that a metal entity bound to N(3) of A will strongly weaken pair formation with T. Of course, metal binding to N(1) of A [23,37] blocks any regular Watson–Crick pairing and therefore is not further discussed here. As far as Hoogsteen pairing is concerned, which involves N(7) and N(6), two opposing effects of the metal at N(1) are again operative, namely an increase of N(6)H2 acidity, and a concomitant decrease of N(7) basicity. Finally metal binding to N(6) of adenine, which can lead to a ‘metal-stabilized’ rare tautomer, will be discussed below. The guanine-N(7) position is a preferred metal binding site. Experimental findings allow a quantification of the acidifying effect of a metal (e.g. CuII, NiII, PtII, PdII) [38]. It amounts to an increase in pKa by 1.4–2.2 log units, with a maximum in the case of CuII. Auxiliary ligands bound to the metal have a modulating influence. As far as the two other groups involved in Watson–Crick pairing with C are concerned, O(6) and N(2)H2, it is to be expected that the former loses basicity and hence some of its H bonding acceptor properties, whereas the amino protons at N(2) become somewhat more acidic and hence will be better H donors. A quantification of the latter effects has not been achieved, however. Experiments on the strength of the Watson–Crick pair between N(7) platinated G and free C, carried out in Me2SO and studied by concentration-dependent 1H NMR spectroscopy, have been conducted in a number of cases [39]. As compared to the Watson–Crick pairing in the absence of a coordinated metal ion [40], there is a remarkable increase in the association constant of the Watson–Crick pair in the case of a PtII entity located at N(7) of guanine. For example, in DMSO Kass for this pair is 6.9"1.3 My1, whereas it increases to 13.0"2.0–16.3"4.0 My1 in the case of N(7) platinated guanines. This increase in Kass has been predicted on the basis of theoretical calculations (gas phase, 0 K) [41–43], yet has not previously been determined experimentally. As far as cisplatin binding to double-stranded DNA is concerned, this finding suggests that the experimentally observed destabilization of DNA is not the consequence of a loss in H bonding capacity but is rather due to other factors such as steric distortion and loss of base stacking. What is important with regard to the established mutagenicity of 1,2-intrastrand adducts in 59-GpG [19] and 59-ApG [18] sequences is that there is an apparent loss in selectivity, meaning that the increase in H bonding capacity of G upon platination also translates into a higher affinity for non-complementary bases
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such as adenine. For example, a GA mispair could be formed if the 59 base is G which could result in a transversion mutation with GC converted into TA (Scheme 1). 2.2. Guanine–guanine mispairing Neutral G and its N(1)-deprotonated form are self-complementary (Scheme 2). As a consequence, hemideprotonated guanine is able to form a base pair consisting of three H bonds. Such a base pair is expected to be primarily formed in a pH range that corresponds to the pKa of the deprotonation process. Whether it is of importance for guanine bases (pKa,9.5) is unknown. However, it definitely occurs with N(7)-methylguanine bases (pKa,7) [44,45] and, relevant to this discussion, for N(7) metalated (MsPtII) guanine entities (pKa,8) [46–50]. The pH argument for dimer formation should not be over-emphasized because experimentally it has been found that such GG pairs are also isolated at substantially lower pH values than 8. This situation is thus in a way reminiscent of hemiprotonated cytosine (‘i motif’ [51,52]), which likewise exists at physiological pH despite a pKa of about 4.5 for protonated C. Irrespective of the question of how easily a base incorporated in DNA undergoes deprotonation [53], it needs to be emphasized that realization of such a GG mispair in duplex DNA is possible, in principle. X-ray crystallography on GGC triplets in DNA triple helices has clearly established [54] that it is possible to have two Gs in an antiparallel strand direction (as required for B-DNA) with (i) a transoid orientation of the glycosidic bonds and (ii) an anti sugar orientation of both bases (Scheme 3(a); GG part shown only). If one of the bases were to be metalated and deprotonated, a simple rotation of the second G about the glycosidic bond (anti™syn) would be required to generate such a GG mispair (Scheme 3(b)).
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2.3. Metal binding and nucleobase tautomerism There are two principal ways of influencing nucleobase tautomerism by a metal entity: (i) The metal is bonded to a site not involved in Watson–Crick hydrogen bond formation, e.g. N(7) or N(3) of a purine base, yet affecting the tautomer equilibrium. We have attempted to prove such a scenario in the case of adenine by application of the ‘method of basicity measurements’ [34]. As we have pointed out, this method does not provide an unambiguous answer to the question, even though the assumption of the influence of the tautomer equilibrium makes sense from a chemical point of view. Moreover, the postulated mispair between a N(7) platinated rare adenine tautomer and a normal adenine tautomer (in syn orientation) would be in agreement with the observed AT™TA transversion caused by the d(ApG) adduct of cisplatin [18]. (ii) The metal replaces a proton involved in the proper tautomeric structure and ‘forces’ this proton to take another site. As a result a ‘metal-stabilized’ rare nucleobase tautomer is formed. In that case, the rare tautomer as its metal adduct can be isolated quantitatively! This principle can be applied to all four bases of DNA or RNA, and X-ray crystal structure analyses confirm this scenario (Scheme 4). For example, replacing the proton at the N(3) position of T or U by a metal entity and shifting the proton to O(4) gives the metalated form of the rare 2-oxo,4-hydroxo tautomer of these bases [55–57]. Similarly, metal binding to N(1) of G and proton shift to N(7) (or O(6)) [58] produces metalated
Scheme 3.
Scheme 1.
Scheme 2.
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Scheme 4.
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forms of (two different) rare tautomers of this base. In the case of C and A, protons of the exocylic amino groups need to be exchanged by metal entities and the substituted proton is shifted to N(3) (of CU) or N(1) (of AU), respectively, resulting in metalated forms of the iminooxo tautomer of cytosine and the imino tautomer of adenine. A complicating factor is that there is the possibility of rotation of the metal entity about the C–N bond of the exocyclic group. In the following, metal-stabilized adenine and cytosine rare tautomer forms are briefly discussed. Metal coordination to the exocyclic amino group of A, with replacement of one of the N–H protons, has been reported in a number of cases [59– 65]. Among them are those patterns of particular interest with regard to the mutagenicity aspect that leave the pyrimidine part of the base, specifically N(1), available for H bond formation and protonation. Three examples apply to this situation: a dinuclear MoII complex, with metal ions at N(7) and N(6) [63], a HgII complex [64], and to some extent also a PtII complex [65] even though the protonation site N(1) or N(7) is ambiguous. While in the first two cases the metal is anti with respect to the N(1) site and hence does not sterically interfere with H bonding at the pyrimidine entity, the (dien)PtII moiety in the third case is oriented syn, but solution NMR spectra indicate an equilibrium between syn and anti. The syn orientation of the metal entity inevitably prevents proper Watson–Crick pairing for steric reasons and the anti orientation does not permit it, provided the N(1) position is protonated, as is the case of the [MoII]2 and HgII compounds. As pointed out by Clarke [59] and Arpalahti and Klika [65], the pH and hence the protonation state of the A base have an effect on the orientation of the metal entity. Theoretical calculations [66] strongly suggest that N(6) metal binding inherently favors N(1) protonation, and hence the formation of a metal-stabilized rare tautomer. This suggests that mispairing scenarios of N(6) metalated adenine bases with either G (syn), leading eventually to a transversion mutation (AT™CG), or with C (anti), leading to a transition mutation (AT™GC), are viable possibilities [64]. The situation with N(4) metalated C is very similar to that of N(6) metalated A: Metal binding to this site causes a shift of the amino proton to N(3) and hence generates the rare imino tautomer of C. Depending on the pKa value of the proton at N(3), it may be lost. Examples of either case are known, e.g. for RuII [67], RuIII [59], HgII [68], PtIV [69] and PtII [70–72]. This list does not contain examples of multiple metal binding patterns, which include N(4) among other sites, e.g. N(3) [73], or N(4),N(3) chelation [62]. In the case of PtII binding to N(4) the mechanism of formation involves several PtIV species [69–72]. As far as potential mispairing patterns of the rare tautomer are concerned, it will depend on the orientation of the metal entity (syn or anti with respect to N(3)) and the protonation state of N(3), which mispairs are feasible [70]. Of the various mismatches between C and A, predicted or actually observed [74], and containing at least two H bonds, none would appear to be
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favored (or even possible) in the case of the N(4) metalated rare C tautomer [70]. 3. Summary Scenarios have been outlined as to how metal entities binding to nucleobases in DNA might result in the formation of mispairs which, if not repaired, could lead to point mutations. Only non-redox processes have been considered. Our present understanding of the mutagenic potential of cisplatin clearly supports the option that metal-related mutagenicity can arise from mispairing of metalated bases. However, we are aware that additional scenarios are feasible. For example, it has been suggested that an error-prone response to substitution-inert metal ions in bacterial DNA could also be the reason for mutagenicity [75]. Acknowledgements Financial support of this work from the DFG and FCI is gratefully acknowledged. R.K.O.S. wishes to thank the Swiss National Science Foundation and the Swiss Federal Office for Education and Science for a TMR-fellowship (No. 83 EU-046320) and J.M. thanks the Land Nordrhein-Westfalen for a fellowship. This work was also part of a COST-D8 collaboration with the group of H. Sigel, Basel, Switzerland. References [1] [2] [3] [4] [5] [6] [7]
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Article: 6277
Heavy metal mutagenicity: insights from bioinorganic model chemistry ¨ Jens Muller, Roland K.O. Sigel, Bernhard Lippert * ¨ Dortmund, 44221 Dortmund, Germany Fachbereich Chemie, Universitat Received 8 June 1999; received in revised form 26 August 1999; accepted 9 September 1999
Abstract The mutagenicity of metal species may be the result of a direct interaction with the target molecule DNA. Possible scenarios leading to nucleobase mispairing are discussed, and selected examples are presented. They include changes in nucleobase selectivity as a consequence of alterations in acid–base properties of nucleobase atoms and groups involved in complementary H bond formation, guanine deprotonation, and stabilization of rare nucleobase tautomers by metal ions. Oxidative nucleobase damage brought about by metal species will not be considered. q2000 Elsevier Science Inc. All rights reserved. Keywords: Heavy metal mutagenicity; Bioinorganic model chemistry
1. Introduction Mutagenesis is the result of spontaneous or induced base mispairing in DNA, hence a violation of proper Watson– Crick pairing undetected by the DNA repair machinery. The occurrence of rare nucleobase tautomers and/or a rotation of the nucleobase about the glycosidic bond to give syn rotamers (as opposed to the normal anti rotamers) has been implicated in mispairing scenarios [1–4]. The existence of non-Watson– Crick base pairs, hence base pair mismatches, in synthetic DNA is firmly established today, as demonstrated in many X-ray crystallographic [5,6] as well as NMR solution studies [7]. Without exception these mismatches include bases in their preferred tautomeric structures, occasionally with bases in a syn orientation, with bases being protonated, or with solvent (H2O) molecules included in the pair. There is only one example, intermolecular H bond formation between two DNA hairpins, which appears to contain a pair between two thymine residues, one of which adopts a rare enol tautomer structure [8]. Chemical modification of nucleobases, e.g. halogenation (5-bromouracil), alkylation (e.g. N(3) of purine bases or O(6) of guanine), or base cross-linking, to give these examples only, is known to be responsible for mutations. Oxidative damage of nucleobases or nucleotides, as brought about by reactive oxygen species or radicals in general, is commonly considered another major reason of mutagenesis [9,10]. * Corresponding author. Fax: q49-231-7553797; e-mail: lippert@ pop.uni-dortmund.de
Metal species can be involved in the generation of reactive oxygen species or, in a high oxidation state, directly oxidize nucleobases. NiII and CrO42y have been primarily studied in this context [11,12]. At present there is no unified picture on metal-induced mutagenicity, probably because different pathways exist which can lead to mutagenesis. Oxidative DNA damage [9,10], interference with metal ions essential for DNA replication or transcription [13], impairment of DNA repair processes [14], DNA cross-linking or DNA distortion [15] may all lead to mutagenesis. In any case, a decrease in fidelity of DNA synthesis (replication) in the presence of metal ions or metal coordination compounds is well established [16]. As far as the mutagenicity of the antitumor agent cis-Pt(NH3)2Cl2 (cisplatin) is concerned, it appears not to be related to any redox chemistry. Rather it has been suggested that it is the consequence of a replicative bypass of intrastrand 59-GpG and 59-ApG adducts [17], with an adenine misincorporated across the 59 base A [18] or G [19]. Our efforts to study basic aspects of metal–nucleobase interactions on a model-nucleobase level [20] has led us to pursue also the question of processes that might lead to mispairing of bases or, more generally, to a prevention of proper Watson–Crick pairing. In the following, selected examples will be presented and discussed. 2. Discussion Among the various scenarios that could lead to mismatch formation between nucleobases as a consequence of metal
0162-0134/00/$ - see front matter q2000 Elsevier Science Inc. All rights reserved. PII S 0 1 6 2 - 0 1 3 4 ( 9 9 ) 0 0 1 7 9 - 8
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coordination and could be studied on a model-nucleobase level, those affecting the nucleobase to be incorporated in the growing new strand or the template strand can be favorably modeled. These include (at least) i) blocking of H bonding sites, ii) cross-linking of nucleobases, iii) effect on acid–base properties of H bonding sites, iv) effect on tautomer equilibrium, v) metal-induced hydrolysis of exocyclic base groups, vi) hydrolysis of the glycosidic bond, vii) oxidative alterations of nucleobases, viii) saturation of C–C double bonds in pyrimidine bases. As pointed out above, most of these possibilities do not involve redox chemistry. In the following, only (iii) and (iv) will be discussed in more detail. Examples for (i) [21,22], (ii) [23,24], (vi) [25,26], (vii) [27–29] and (viii) [30] have been published or will be published (v). As far as metals applied in such studies are concerned, the use of kinetically inert, diamagnetic species appears to be advantageous (even though not always biologically relevant) in that reactions can easily be followed by NMR spectroscopy in solution and chances of isolating intermediates are generally better with kinetically inert species as opposed to labile ones. A point of differentiation has to be made: In most cases metal ions exhibit a charge effect which will pull electron density out of the heterocyclic ring, toward the metal. Exceptions to this rule are those metal entities having strong back-donation properties, and hence donate electron density from filled d orbitals into empty pU orbitals of the heterocycle, thereby overcompensating for the ordinary effect of a positively charged metal. RuII(NH3)5 is such an example [31,32], whereas the corresponding RuIII species behaves ‘normally’. In the following, only the ‘normal’ case will be considered. 2.1. Effects of metal coordination to acid–base properties of purine bases Base–base recognition and hence proper Watson–Crick pairing crucially depend on charge densities within the heterocyclic rings, pKa values of H donors as well as pKb values of H acceptors, and the tautomeric structures of the two bases [33]. From this it is evident that any chemical process affecting the complementarity of two bases, e.g. metal coordination, will have an influence on the H bonding behavior. PtII binding to N(7) of 9-methyladenine (9-MeA) reduces the basicity of the N(1) position by 1.5–2.5 log units [34,35], and hence makes this site a weaker H bonding acceptor in the Watson–Crick pair with thymine. From a limited number of data points it appears that there is a minor influence of the charge carried by the metal entity, e.g. [(NH3)3Pt]2q) [(NH3)Cl2Pt])[PtCl3]y. It is to be expected that the metal entity, while decreasing the basicity of N(1), simultaneously increases the acidity of the exocyclic amino group, even though this effect cannot be determined accurately due to the high pKa of this group. The question of how these two opposing effects influence the strength of the AT pair or whether
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the pairing specificity of A is affected, remains elusive. The problem will be solved once metal complexes of A are available that are sufficiently soluble in aprotic media such as CHCl3, etc., to permit the determination of association constants. MII binding to N(3) of A with MsPt or Pd dramatically decreases the basicity of N(1) by more than 5 log units [36]. Since it is unlikely that such a coordination mode would markedly increase the acidity of the exocyclic amino group at the 6-position, it is tentatively concluded that a metal entity bound to N(3) of A will strongly weaken pair formation with T. Of course, metal binding to N(1) of A [23,37] blocks any regular Watson–Crick pairing and therefore is not further discussed here. As far as Hoogsteen pairing is concerned, which involves N(7) and N(6), two opposing effects of the metal at N(1) are again operative, namely an increase of N(6)H2 acidity, and a concomitant decrease of N(7) basicity. Finally metal binding to N(6) of adenine, which can lead to a ‘metal-stabilized’ rare tautomer, will be discussed below. The guanine-N(7) position is a preferred metal binding site. Experimental findings allow a quantification of the acidifying effect of a metal (e.g. CuII, NiII, PtII, PdII) [38]. It amounts to an increase in pKa by 1.4–2.2 log units, with a maximum in the case of CuII. Auxiliary ligands bound to the metal have a modulating influence. As far as the two other groups involved in Watson–Crick pairing with C are concerned, O(6) and N(2)H2, it is to be expected that the former loses basicity and hence some of its H bonding acceptor properties, whereas the amino protons at N(2) become somewhat more acidic and hence will be better H donors. A quantification of the latter effects has not been achieved, however. Experiments on the strength of the Watson–Crick pair between N(7) platinated G and free C, carried out in Me2SO and studied by concentration-dependent 1H NMR spectroscopy, have been conducted in a number of cases [39]. As compared to the Watson–Crick pairing in the absence of a coordinated metal ion [40], there is a remarkable increase in the association constant of the Watson–Crick pair in the case of a PtII entity located at N(7) of guanine. For example, in DMSO Kass for this pair is 6.9"1.3 My1, whereas it increases to 13.0"2.0–16.3"4.0 My1 in the case of N(7) platinated guanines. This increase in Kass has been predicted on the basis of theoretical calculations (gas phase, 0 K) [41–43], yet has not previously been determined experimentally. As far as cisplatin binding to double-stranded DNA is concerned, this finding suggests that the experimentally observed destabilization of DNA is not the consequence of a loss in H bonding capacity but is rather due to other factors such as steric distortion and loss of base stacking. What is important with regard to the established mutagenicity of 1,2-intrastrand adducts in 59-GpG [19] and 59-ApG [18] sequences is that there is an apparent loss in selectivity, meaning that the increase in H bonding capacity of G upon platination also translates into a higher affinity for non-complementary bases
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such as adenine. For example, a GA mispair could be formed if the 59 base is G which could result in a transversion mutation with GC converted into TA (Scheme 1). 2.2. Guanine–guanine mispairing Neutral G and its N(1)-deprotonated form are self-complementary (Scheme 2). As a consequence, hemideprotonated guanine is able to form a base pair consisting of three H bonds. Such a base pair is expected to be primarily formed in a pH range that corresponds to the pKa of the deprotonation process. Whether it is of importance for guanine bases (pKa,9.5) is unknown. However, it definitely occurs with N(7)-methylguanine bases (pKa,7) [44,45] and, relevant to this discussion, for N(7) metalated (MsPtII) guanine entities (pKa,8) [46–50]. The pH argument for dimer formation should not be over-emphasized because experimentally it has been found that such GG pairs are also isolated at substantially lower pH values than 8. This situation is thus in a way reminiscent of hemiprotonated cytosine (‘i motif’ [51,52]), which likewise exists at physiological pH despite a pKa of about 4.5 for protonated C. Irrespective of the question of how easily a base incorporated in DNA undergoes deprotonation [53], it needs to be emphasized that realization of such a GG mispair in duplex DNA is possible, in principle. X-ray crystallography on GGC triplets in DNA triple helices has clearly established [54] that it is possible to have two Gs in an antiparallel strand direction (as required for B-DNA) with (i) a transoid orientation of the glycosidic bonds and (ii) an anti sugar orientation of both bases (Scheme 3(a); GG part shown only). If one of the bases were to be metalated and deprotonated, a simple rotation of the second G about the glycosidic bond (anti™syn) would be required to generate such a GG mispair (Scheme 3(b)).
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2.3. Metal binding and nucleobase tautomerism There are two principal ways of influencing nucleobase tautomerism by a metal entity: (i) The metal is bonded to a site not involved in Watson–Crick hydrogen bond formation, e.g. N(7) or N(3) of a purine base, yet affecting the tautomer equilibrium. We have attempted to prove such a scenario in the case of adenine by application of the ‘method of basicity measurements’ [34]. As we have pointed out, this method does not provide an unambiguous answer to the question, even though the assumption of the influence of the tautomer equilibrium makes sense from a chemical point of view. Moreover, the postulated mispair between a N(7) platinated rare adenine tautomer and a normal adenine tautomer (in syn orientation) would be in agreement with the observed AT™TA transversion caused by the d(ApG) adduct of cisplatin [18]. (ii) The metal replaces a proton involved in the proper tautomeric structure and ‘forces’ this proton to take another site. As a result a ‘metal-stabilized’ rare nucleobase tautomer is formed. In that case, the rare tautomer as its metal adduct can be isolated quantitatively! This principle can be applied to all four bases of DNA or RNA, and X-ray crystal structure analyses confirm this scenario (Scheme 4). For example, replacing the proton at the N(3) position of T or U by a metal entity and shifting the proton to O(4) gives the metalated form of the rare 2-oxo,4-hydroxo tautomer of these bases [55–57]. Similarly, metal binding to N(1) of G and proton shift to N(7) (or O(6)) [58] produces metalated
Scheme 3.
Scheme 1.
Scheme 2.
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Scheme 4.
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forms of (two different) rare tautomers of this base. In the case of C and A, protons of the exocylic amino groups need to be exchanged by metal entities and the substituted proton is shifted to N(3) (of CU) or N(1) (of AU), respectively, resulting in metalated forms of the iminooxo tautomer of cytosine and the imino tautomer of adenine. A complicating factor is that there is the possibility of rotation of the metal entity about the C–N bond of the exocyclic group. In the following, metal-stabilized adenine and cytosine rare tautomer forms are briefly discussed. Metal coordination to the exocyclic amino group of A, with replacement of one of the N–H protons, has been reported in a number of cases [59– 65]. Among them are those patterns of particular interest with regard to the mutagenicity aspect that leave the pyrimidine part of the base, specifically N(1), available for H bond formation and protonation. Three examples apply to this situation: a dinuclear MoII complex, with metal ions at N(7) and N(6) [63], a HgII complex [64], and to some extent also a PtII complex [65] even though the protonation site N(1) or N(7) is ambiguous. While in the first two cases the metal is anti with respect to the N(1) site and hence does not sterically interfere with H bonding at the pyrimidine entity, the (dien)PtII moiety in the third case is oriented syn, but solution NMR spectra indicate an equilibrium between syn and anti. The syn orientation of the metal entity inevitably prevents proper Watson–Crick pairing for steric reasons and the anti orientation does not permit it, provided the N(1) position is protonated, as is the case of the [MoII]2 and HgII compounds. As pointed out by Clarke [59] and Arpalahti and Klika [65], the pH and hence the protonation state of the A base have an effect on the orientation of the metal entity. Theoretical calculations [66] strongly suggest that N(6) metal binding inherently favors N(1) protonation, and hence the formation of a metal-stabilized rare tautomer. This suggests that mispairing scenarios of N(6) metalated adenine bases with either G (syn), leading eventually to a transversion mutation (AT™CG), or with C (anti), leading to a transition mutation (AT™GC), are viable possibilities [64]. The situation with N(4) metalated C is very similar to that of N(6) metalated A: Metal binding to this site causes a shift of the amino proton to N(3) and hence generates the rare imino tautomer of C. Depending on the pKa value of the proton at N(3), it may be lost. Examples of either case are known, e.g. for RuII [67], RuIII [59], HgII [68], PtIV [69] and PtII [70–72]. This list does not contain examples of multiple metal binding patterns, which include N(4) among other sites, e.g. N(3) [73], or N(4),N(3) chelation [62]. In the case of PtII binding to N(4) the mechanism of formation involves several PtIV species [69–72]. As far as potential mispairing patterns of the rare tautomer are concerned, it will depend on the orientation of the metal entity (syn or anti with respect to N(3)) and the protonation state of N(3), which mispairs are feasible [70]. Of the various mismatches between C and A, predicted or actually observed [74], and containing at least two H bonds, none would appear to be
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favored (or even possible) in the case of the N(4) metalated rare C tautomer [70]. 3. Summary Scenarios have been outlined as to how metal entities binding to nucleobases in DNA might result in the formation of mispairs which, if not repaired, could lead to point mutations. Only non-redox processes have been considered. Our present understanding of the mutagenic potential of cisplatin clearly supports the option that metal-related mutagenicity can arise from mispairing of metalated bases. However, we are aware that additional scenarios are feasible. For example, it has been suggested that an error-prone response to substitution-inert metal ions in bacterial DNA could also be the reason for mutagenicity [75]. Acknowledgements Financial support of this work from the DFG and FCI is gratefully acknowledged. R.K.O.S. wishes to thank the Swiss National Science Foundation and the Swiss Federal Office for Education and Science for a TMR-fellowship (No. 83 EU-046320) and J.M. thanks the Land Nordrhein-Westfalen for a fellowship. This work was also part of a COST-D8 collaboration with the group of H. Sigel, Basel, Switzerland. References [1] [2] [3] [4] [5] [6] [7]
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