Nucleosides complexes with metal ions

The method of circular dichroism has been applied in investigations that have determined the reactions between Pt(II) compound and nucleosides, nucleotides, and DNA. Many antimicrobial preparations are excellent ligands. The activity of some of the antimicrobial preparations has been based on their complexing with metal ions. For example, increased effectiveness of tetracycline has been observed after its coordination with Ca. The complex is more lipophilic and very oil-soluble, which explains its transportation through the cell membrane. The opposite situation occurs when the ion-metal is toxic and the coordinated antibiotic serves as carrier through the membrane. 

Fiskin, A. M., and M. Beer. 1965. Determination of Base Sequence in Nucleic Acids with the Electron Microscope. IV. Nucleoside Complexes with Certain Metal Ions. Biochem. 4,1287. 

Hartman, K. A., Jr. The infrared spectra of some complexes of metal ions with nucleosides and nucleotides. Biochim. Biophys. Acta 138, 192 (1967). 

Nucleic acids are known to be responsible for the storage and transcription of genetic information in living cells and are involved in protein synthesis. Nucleic acids are polymers of nucleoside phosphates and hence negatively charged in neutral solutions. Nucleic acids interact strongly with metal ions. Such an interaction with metal ions helps to maintain the conformational stability of nucleic acids and their function. The formation of a complex... 

Table XIX contains stability constants for complexes of Ca2+ and of several other M2+ ions with a selection of phosphonate and nucleotide ligands (681,687-695). There is considerably more published information, especially on ATP (and, to a lesser extent, ADP and AMP) complexes at various pHs, ionic strengths, and temperatures (229,696,697), and on phosphonates (688) and bisphosphonates (688,698). The metal-ion binding properties of cytidine have been considered in detail in relation to stability constant determinations for its Ca2+ complex and complexes of seven other M2+ cations (232), and for ternary M21 -cytidine-amino acid and -oxalate complexes (699). Stability constant data for Ca2+ complexes of the nucleosides cytidine and uridine, the nucleoside bases adenine, cytosine, uracil, and thymine, and the 5 -monophosphates of adenosine, cytidine, thymidine, and uridine, have been listed along with values for analogous complexes of a wide range of other metal ions (700). Unfortunately comparisons are sometimes precluded by significant differences in experimental conditions.

Quantitative estimation of the stability constants for metal ion complexation with 1-substituted tetrazoles has been performed <2005CEJ6246>. It was demonstrated that tetrazole nucleoside 277 shows a low tendency to form stable complexes with ions Ag(l) and Hg(ll) comparing with imidazoles and 1,2,4-triazoles. Only Ag+ is able to form a 1 1 complex with compound 277 (log0.86), and no coordination of Hg2+ to 277 can be detected. 

For many metal ions, the initial electrostatic interaction can be followed by stronger and more specific binding with nucleic acids via the formation of outer- and inner-sphere complexes. The formation of such complexes may be strongly accelerated (in comparison to binding to nucleosides and nucleotides) because of the polyelecfrolyte effect. 

Kinetic studies of NMP kinases, as well as many other enzymes having ATP or other nucleoside triphosphates as a substrate, reveal that these enzymes are essentially inactive in the absence of divalent metal ions such as magnesium (Mg2+) or manganese (Mn2+), but acquire activity on the addition of these ions. In contrast with the enzymes discussed so far, the metal is not a component of the active site. Rather, nucleotides such as ATP bind these ions, and it is the metal ion-nucleotide complex that is the true substrate for the enzymes. The dissociation constant for the ATP-Mg2+ complex is approximately 0.1 mM, and thus, given that intracellular Mg + concentrations are typically in the millimolar range, essentially all nucleoside triphosphates are present as NTP-Mg + complexes. 

The coordination properties of the nucleobases have been reviewed by Houlton (40) and by Lippert (2). In a recent review, Lippert discussed the influence of the metal coordination on the piSTa of the nucleobases (41), which correlates with their coordination properties. While the coordination properties of nucleobases, nucleosides, and nucleotides have been extensively studied and reviewed, the number of articles dedicated to the coordination properties of nucleic acids is signihcantly smaller. DeRose et al. (42) recently published a systematic review of the site-specific interactions between both main group and transition metal ions with a broad range of nucleic acids from 10 bp DNA duplexes to 300 00 nucleotide RNA molecules as well as with some nucleobases, nucleosides, and nucleotides. They focused on results obtained primarily from X-ray crystallographic studies. Egli also presented information on the metal ion coordination to DNA in reviews dedicated to X-ray studies of nucleic acids (43, 44). Sletten and Fr0ystein (45) reviewed NMR studies of the interaction between nucleic acids and several late transition metal ions and Zn. Binding of metal complexes to DNA by n interactions has been reviewed by Dupureur and Barton (46). 

A second method for studying the coordination structures of active Mg-nucleotide complexes is to use the P-chiral nucleoside thiotriphosphates and various divalent metal ions as substrates. The divalent metal ions form coordination exchange-labile complexes with ATPaS and ATPjSS, but the various metal ions preferentially form coordination bonds with either S or O. In general, the coor-... 

The first and clearest example of the use of nucleoside phosphorothioates to determine coordination geometry at an active site was the work of Jaffe and Cohn on hexokinase (22). They found that (7 p)-ATP)3S is a far better substrate with Mg(II) as the activating cation than with Cd(Il) however, (5p)-ATP/3S is a far better substrate with Cd(ll) than with Mg(ll) as the metal ion. That is, the favored complex depended on both the metal ion and the configuration at P of ATP/8S, and a change in metal ion from Mg(II) to Cd(II) led to a change in selectivity for the configuration at P. The structures of the preferred substrates were thereby deduced as those shown below. The other isomers, Mg(Sp)-ATP/3S and Cd(7 p)-ATP)8S, were less active or practically inactive. By the simplest interpretation of the data, both active complexes were the A-screw sense isomers shown here, in which Mg is coordinated to oxygen in one and Cd is coordinated to sulfur in the other. 

In some kinases, such as nucleoside diphosphate kinase, " an intermediate step is the phosphoryl transfer to a group belonging to the enzyme, as happens in ATPase and as was discussed in detail for alkaline phosphatase (Section V.B). In other kinases the phosphoryl transfer occurs directly from the donor to the acceptor in a ternary complex of the enzyme with the two substrates.Often metal ions like magnesium or manganese are needed. These ions interact with the terminal oxygen of the ATP molecule, thus facilitating the nucleophilic attack by the acceptor. The metal ion is often associated with the enzyme. For mechanistic schemes, see the proposed mechanism of action of alkaline phosphatase, especially when a phosphoryl enzyme intermediate is involved. 

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