Nucleotide-metal complexes, coordination

The second major type of stereochemical information that can be obtained about phosphotransferases and nucleotidyltransferases is the coordination structure of nucleotide-metal complexes as they are bound at the active sites of enzymes. Two of the simplest coordination complexes of MgATP are shown below to exemplify the stereochemical difference. These are two stereoisomers differing in screw sense in the coordination ring. 

Building towards models relevant for polymeric DNA and RNA, nucleotides contain a phosphate attached at the 5 or 3 position. The 5 -nucleotides are most commonly studied, for which the phosphate has a pAa 6 for the first protonation step. Unless otherwise noted, throughout this chapter nucleotide will refer to the 5 -phosphate linkage. In nucleotides, metal-phosphate coordination competes with metal-base interactions. Chelate complexes with both phosphate and base coordination can occur when sterically allowed. Thus, transition metal complexes with purine monophosphates tend to exhibit metal coordination to the base N7 position, with apparent hydrogen bonding of coordinated waters to the phosphate. By contrast, more ionic Mg" binds preferentially to the phosphate groups in nucleotide monophosphates. In di- and tri-phosphate complexes such as metal-ATP compounds, the proximity of multiple phosphates generally favors polyphosphate chelate complexes with metal ions. 

In contrast to the relatively simple structures incorporating one of the first three binding motifs, the polymeric complex [Cu3(5 -GMP)3(H20)8] has three distinct coordination environments about different Cu + ions. While this complex is unusually sophisticated, the polymeric nature of the material is common for many metal complexes with GMP or IMP, in which inner-sphere binding occurs to both the N-7 atom and phosphate oxygens of a single nucleotide residue, but does not involve the same metal ion. As described in Section 5.5, there are also unusual structures ( open complexes ) of Cu + species and GMP, which involve only inner-sphere metal binding to the phosphate group. 

Metal complexes of pyrimidine nucleotides have been studied much less intensively than those involving purines, undoubtedly reflecting the weaker coordination ability of the pyrimidine N-3 atom, relative to atoms N-7 and N-1 of purines. Nonetheless, the principal structures of such complexes have been determined. " Some of these are described below. 

Besides hydrophobic and coordinative interactions, hydrogen bonds and electrostatic interactions have been used to assemble luminescent metal complexes. In this context, Barigelletti and coworkers (45-47) reported on the luminescent properties of Ru(II) and Os(II) complexes containing bipyridines peripherally functionalized with nucleotide bases, cytosine, and guanine. 

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). 

Investigations on structural data of ternary enzyme-ATP-metal ion complexes have recently been published by COHN (1). A refinement of such structural data would be facilitated by a thorough investigation of the coordination chemistry of the respective binary nucleotide-metal ion complexes i. e, of the question How and to what extent do the different parts of the nucleotide ligands - N-heterocyclic and phosphate moieties - interact with a metal ion, if a binary complex is formed in aqueous solution ... 

For purine-nucleoside 5 -phosphates the formation of macrochelates was proposed nearly 60 years ago [131] and more than 50 years ago it was concluded that they actually exist [132-135], i.e., a metal ion coordinated to the phosphate residue of a purine nucleotide may also interact in the dominating anti conformation with N7 of the purine moiety. Nowadays formation of macrochelates in complexes formed by purine nucleotides with various metal ions including Cd " is well established [117,120,136-138]. Clearly, the formation of such a macrochelate must give rise to the intramolecular equilibrium (22) ... 

For Cd[(U2S - H)MP] exactly the same isomer distribution may be surmised [105] because for the chelate effect [164] only 0.11 0.15 log unit were derived [105]. Hence, within the error limits the chelate effect is zero, meaning that no chelate forms. However, based on the mentioned 0.11 log unit it could be that about 20% chelate, M[(U2S - H)MP] [, exist and that the remaining 80% of the open species are then present to ca. 79% with Cd " at the thiouracilate residue and about 1% bound at the phosphate group [105]. Of course, chelate formation of a metal ion coordinated at the (C2)S/(N3) site with the phosphate group (or vice versa) is only possible if the nucleotide is transformed into the syn confoimer (Figure 8). In any case, it is evident that replacement of (QO by (C)S in the nucleobase residue enhances the stability of the Cd " complexes considerably. 

Volume 1 Simple Complexes Volume 2 Mixed-Ligand Complexes Volume 3 High Molecular Complexes Volume 4 Metal Ions as Probes Volume 5 Reactivity of Coordination Compounds Volume 6 Biological Action of Metal Ions Volume 7 Iron in Model and Natural Compounds Volume 8 Nucleotides and Derivatives Their Ligating Ambivalency Volume 9 Amino Adds and Derivatives as Ambivalent Ligands Volume 10 Carcinogenicity and Metal Ions Volume 11 Metal Complexes as Anticancer Agents Volume 12 Properties of Copper Volume 13 Copper Proteins... 

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... 

A metal-nucleotide complex that exhibits low rates of ligand exchange as a result of substituting higher oxidation state metal ions with ionic radii nearly equal to the naturally bound metal ion. Such compounds can be prepared with chromium(III), cobalt(III), and rhodi-um(III) in place of magnesium or calcium ion. Because these exchange-inert complexes can be resolved into their various optically active isomers, they have proven to be powerful mechanistic probes, particularly for kinases, NTPases, and nucleotidyl transferases. In the case of Cr(III) coordination complexes with the two phosphates of ATP or ADP, the second phosphate becomes chiral, and the screw sense must be specified to describe the three-dimensional configuration of atoms. 

Coordination isomers of metal ion-nucleotide complexes. For most metal ions, for example Mg, the metal... 

Binding sites for Ca2+ and ATP have been explored by the use of metal probes and nucleotide analogues. The Mn2+ ion substitutes for Mg2+ but also binds at the Ca2+ sites. Such complications have led to the use of lanthanides134 as probes for the Ca2+ sites. Thus Gd3+ and Tb3+ compete with Ca2+ for the high affinity site. Luminescence studies with laser-excited Tb3+ at the Ca2+ sites show that two water molecules are present in the first coordination shell.151 Earlier work134 with Gd3+ shows that the Ca2+ sites are a maximum of 16.1 A apart, and that both sites involve a low level of hydration, consistent with a hydrophobic site. Gd3+ has also been used as an ESR probe, and, under certain conditions, evidence has been produced for two forms of an E-Gd34 complex, in accord with current mechanistic views. 

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