Metal-nucleotide interactions

Table 3. Equilibrium constants of metal nucleotide interactions /i = 0, pH approx. 8.0 [Mean values from refs. (64, 88) ...

Au and Au° have been used to model interactions between gold and DNA, and a crystal structure for a metal-nucleotide interaction has been reported. In trichloro(l-methylcytosinato) gold(III), three Cl and the N3 atom of 1-methylcytosine are coordinated to the Au ion producing a nearly square-planar geometry. Due to steric hindrance, the cytosine ring is placed almost perpendicular to the AuCls plane. 

A special issue of Biochimie devoted to a symposium on co-ordination chemistry and cancer therapy held in 1978 and a review article on mechanisms of antitumour activity summarize the present state of knowledge in this field of research. A few recent articles dealing with mechanistic aspects on metal-nucleotide interaction will be mentioned below (see refs. 66—69, 79, 80, 98). 

Davis have used the c.d. of the cobalt(ii)-activated enzyme to investigate the local environment of the metal at the active site of the rabbit muscle enzyme. It appears that the metal-nucleotide interaction remains essentially the same throughout the enzyme turnover as that found in the free complex. E.s.r. evidence has been provided for a similar non-bridging role for the metal in reactions of ATP phospho-ribosyltransferase from E. coli. 

Sites and thermodynamic quantities associated with proton and metal ion interaction with ribonucleic acid, deoxyribonucleic acid and their constituent bases, nucleosides and nucleotides. R. M. Izatt, J. J. Christensen and J. H. Rytting, Chem. Rev., 1971, 71, 439-481 (229). 

Fig. 2.7. Characteristic rate constants (s 1) for substitution of inner-sphere H20 of various aqua ions. Note The substitution rates of water in complexes ML(H20)m will also depend on the symmetry of the complex (adapted from Frey, C.M. and Stuehr, J. (1974). Kinetics of metal ion interactions with nucleotides and base free phosphates in H. Sigel (ed.), Metal ions in biological systems (Vol. 1). Marcel Dekker, New York, p. 69).

Exchange-inert complexes of Co(III) with nucleotides that have proven to be extremely useful as chirality probes because the different coordination isomers are stable and can be prepared and separated In addition, these nucleotides can be used as dead-end inhibitors of enzyme-catalyzed reactions and, since Co(III) is diamagnetic, a number of spectroscopic protocols can be utilized. See Exchange-Inert Complexes Chromium-Nucleotide Complexes Metal Ion-Nucleotide Interactions... 

The most important point is that this procedure provides a reliable and effective way for dealing with metal ion interactions with nucleotides. By maintaining the free magnesium ion at a single fixed concentration, the experimenter avoids any chance of uncontrolled variation in the [MgATp2-]/[ATP -j ratio. 

There are two cation-binding sites per subunit, classified nL and n2. The n, site is a structural site, which may involve the reorientation of a glutamate carboxyl group. Metals bind first at this site. The n2 site is the catalytic site and may bind metal or metal-nucleotide. Co111 and Cr111 can be incorporated into the nj metal-binding sites in un-adenylylated glutamine synthetase from E. co/i.318 Both derivatives were inactive, but were able to bind Mn2+ at the n2 site. Comparison of the quaternary enzyme-Crin-Mnn-ADP (which shows spin-spin interaction between the two metal centres) with enzyme-Com-Mnn-ADP leads to an estimate of the distance between n, and n2 sites of 7 2 A. 

Molecular mechanics and dynamics studies of metal-nucleotide and metal-DNA interactions to date have been limited almost exclusively to modeling the interactions involving platinum-based anticancer drugs. As with metal-amino-acid complexes, there have been surprisingly few molecular mechanics studies of simple metal-nucleotide complexes that provide a means of deriving reliable force field parameters. A study of bis(purine)diamine-platinum(II) complexes successfully reproduced the structures of such complexes and demonstrated how steric factors influenced the barriers to rotation about the Pt(II)-N(purine) coordinate bonds and interconversion of the head-to-head (HTH) to head-to-tail (HTT) isomers (Fig. 12.4)[2011. In the process, force field parameters for the Pt(II)/nucleotide interactions were developed. A promising new approach involving the use of ab-initio calculations to calculate force constants has been applied to the interaction between Pt(II) and adenine[202]. 

This method is especially suitable for studies with polymer nucleotide-metal ion interaction. When dissolved nucleic acids are exposed with and without metal ions to an increase of temperature structural changes, some reversible, some irreversible can be observed (27, 24, 27, 30, 39, 54—56, 75, 100, 108). The two parameters Tm (or midpoint of the transition) and a (the width of the transition) allow conclusions about conformational alterations. The application of this procedure for quantitative studies of metal complexing still needs to be elucidated. 

Relaxation experiments with the temperature jump method (18) give valuable information about the kinetics of nucleotidepolyphosphate and metal ion interaction in solution (20). Differences of kinetic dissociation or association constants of such metal complexes are helping to reveal some biochemical specificities of certain metal ions in metal-nucleotide complexes. 

There was no change in the metal ion-phosphate interaction when the heterocyclic ring was substituted and the ribose residue replaced by deoxysugar (77, 76). According to the magnitude of the stability constants of the Mn2+, Co2+, Ni2+ and Zn2+ metal nucleotide complexes (Table 3) it can be concluded that the electronic structure of the metal ion seems to have little effect to the extent of binding. Rather, the... 

The diastereomers of Mg-ATP in Fig. 2 exemplify in a limited way the stereochemical problem in metal nucleotides. The two isomers shown are in rapid exchange equilibrium, however, so it is not possible to separate them and study their individual interactions with enzymes. The problem is further complicated by the fact that these diastereomers represent the stereochemical possibilities in only one of the coordination isomers. Others are possible, including the a-, / - and y-monodentate isomers and a,/ ,y-tridentate isomers, most of which exist as two or more diastereoi-somers. All of the coordination isomers and their diastereoisomers of Mg-ATP are in rapid exchange equilibrium. 

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