Stability constants of metal ion complexes formed with N3-deprotonated uridine in aqueous solution

Proc. Natl. Acad. Sci. U.S.A.

2005

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The acidity constants for (N3)H of the uridine-type ligands (U) 5-fluorouridine, 5-chloro-2-deoxyuridine, uridine, and thymidine (2-deoxy-5-methyluridine) and the stability constants of the M(U-H) ؉ complexes for M 2؉ chelate formation ͉ equilibrium constants ͉ metal ion complexes ͉ nucleic acids ͉ nucleobase properties T he importance of metal ion-nucleic acid interactions in the metabolic machinery is well recognized and applied, e.g., in medicinal chemistry (1). Crystal-structure analyses of nucleic acids (2), especially RNAs (3), show that metal ions coordinate to the phosphate-diester bridges as well as to nucleobase residues, and they are important for folding and catalysis of ribozymes (3-5).The N7 sites of purine residues are exposed in the major groove of DNA (2) and accessible for metal ion binding (6). Maybe this is one reason why their metal ion-coordinating properties are relatively well studied (6-11) in contrast to those of pyrimidine-nucleobase residues (8-10). In fact, the stabilities and solution structures of cytidine (Cyd) complexes of biologically relevant metal ions were quantified only recently (12). Knowledge on uridine complexes is scarce: The carbonyl oxygens (C2)O and (C4)O of uracil residues in low (2, 13) and high (2, 3, 14, 15) molecular weight derivatives may interact in the solid state with metal ions, but in aqueous (aq) solution monodentate carbonyl-oxygen ligands bind only if correctly positioned by primary sites (16).In a recent study (17) with Mg 2ϩ

mentioning

confidence: 71%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 91%

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Metal ion-binding properties of (N3)-deprotonated uridine, thymidine, and related pyrimidine nucleosides in aqueous solution

Knobloch

Linert

Proc. Natl. Acad. Sci. U.S.A.

2005

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“…The other two pyrimidine nucleobases, i.e., the uracil and thymine residues (Figure 1), bind strongly to metal ions only after deprotonation of their (N3)H site [87]. This means that carbonyl groups interact significantly with metal ions only if a suitable primary binding site is available (Section 3.3).…”

Section: Cadmium(ii) Complexes Of Pyrimidine Derivativesmentioning

confidence: 99%

Complex Formation of Cadmium with Sugar Residues, Nucleobases, Phosphates, Nucleotides, and Nucleic Acids

Skilandat

Cadmium: From Toxicity to Essentiality

et al. 2012

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Cadmium(II), commonly classified as a relatively soft metal ion, prefers indeed aromaticnitrogen sites (e.g., N7 of purines) over oxygen sites (like sugar-hydroxyl groups). However, matters are not that simple, though it is true that the affinity of Cd(2+) towards ribose-hydroxyl groups is very small; yet, a correct orientation brought about by a suitable primary binding site and a reduced solvent polarity, as it is expected to occur in a folded nucleic acid, may facilitate metal ion-hydroxyl group binding very effectively. Cd(2+) prefers the guanine(N7) over the adenine(N7), mainly because of the steric hindrance of the (C6)NH(2) group in the adenine residue. This Cd(2+)-(N7) interaction in a guanine moiety leads to a significant acidification of the (N1)H meaning that the deprotonation reaction occurs now in the physiological pH range. N3 of the cytosine residue, together with the neighboring (C2)O, is also a remarkable Cd(2+) binding site, though replacement of (C2)O by (C2)S enhances the affinity towards Cd(2+) dramatically, giving in addition rise to the deprotonation of the (C4)NH(2) group. The phosphodiester bridge is only a weak binding site but the affinity increases further from the mono-to the di-and the triphosphate. The same also holds for the corresponding nucleotides. Complex stability of the pyrimidine-nucleotides is solely determined by the coordination tendency of the phosphate group(s), whereas in the case of purine-nucleotides macrochelate formation takes place by the interaction of the phosphate-coordinated Cd(2+) with N7. The extents of the formation degrees of these chelates are summarized and the effect of a non-bridging sulfur atom in a thiophosphate group (versus a normal phosphate group) is considered. Mixed ligand complexes containing a nucleotide and a further mono-or bidentate ligand are covered and it is concluded that in these species N7 is released from the coordination sphere of Cd(2+). In the case that the other ligand contains an aromatic residue (e.g., 2,2'-bipyridine or the indole ring of tryptophanate) intramolecular stack formation takes place. With buffers like Tris or Bistris mixed ligand complexes are formed. Cd(2+) coordination to dinucleotides and to dinucleoside monophosphates provides some insights regarding the interaction between Cd(2+) and nucleic acids. Cd(2+) binding to oligonucleotides follows the principles of coordination to its units. The available crystal studies reveal that N7 of purines is the prominent binding site followed by phosphate oxygens and other heteroatoms in nucleic acids. Due to its high thiophilicity, Cd(2+) is regularly used in so-called thiorescue experiments, which lead to the identification of a direct involvement of divalent metal ions in ribozyme catalysis.

Complex Formation of Divalent Metal Ions with Uridine 5′‐O‐Thiomonophosphate or Methyl Thiophosphate: Comparison of Complex Stabilities with Those of the Parent Phosphate Ligands

2003

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The stability constants of the 1:1 complexes formed in aqueous solution between Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Zn2+, or Cd2+ (M2+) and methyl thiophosphate (MeOPS(2-)) or uridine 5'-O-thiomonophosphate (UMPS(2-)) (PS(2-)=MeOPS(2-) or UMPS(2-)) have been determined (potentiometric pH titrations; 25 degrees C; I = 0.1 M, NaNO(3)). Comparison of these results for M(PS) complexes with those known for the parent M(PO) phosphate species, where PO(2-)=CH(3)OPO(2-)(3) or UMP(2-) (uridine 5'-monophosphate), shows that the alkaline earth metal ions, as well as Mn2+, Co2+, and Ni2+ have a higher affinity for phosphate groups than for their thio analogues. However, based on the linear log K(M)(M(R-PO3)) versus pK(H)(H(R-PO3)) relationships (R-PO(2-)(3) simple phosphate monoester or phosphonate ligands with a non-interacting residue R) it becomes clear that the indicated observation is only the result of the lower basicity of the thiophosphate residue. In contrast, the thio complexes of Zn2+ and Cd2+ are more stable than their parent phosphate ones, and this despite the lower basicity of the PS(2-) ligands. This stability increase is identical for M(MeOPS) and M(UMPS) species and amounts to about 0.6 and 2.4 log units for Zn(PS) and Cd(PS), respectively. Since no other binding site is available in MeOPS(2-), this enhanced stability has to be attributed to the S atom. Indeed, from the mentioned stability differences it follows that Cd2+ in Cd(PS) is coordinated by more than 99% to the thiophosphate S atom; the same value holds for Pb(PS), which was studied earlier. The formation degree of the Sbonded isomer amounts to 76+/-6 % for Zn(PS) and is close to zero for the corresponding Mg2+, Ca2+, and Mn2+ species. It is further shown that Zn(MeOPS)(aq)(2+) releases a proton from a coordinated water molecule with pK(a) approximately 6.9; i.e., this deprotonation occurs at a lower pH value than that for the same reaction in Zn(aq)(2+). Since Mg2+, Ca2+, Mn2+, and Cd2+ have a relatively low tendency for hydroxo complex formation, it was possible, for these M2+, to also quantify the stability of the binuclear complexes, M(2)(UMPS-H)+, where one M2+ is thiophosphate-coordinated and the other is coordinated at (N3)(-) of the uracil residue. The impact of the results presented herein regarding M2+/nucleic acid interactions, including those of ribozymes (rescue experiments), is briefly discussed.