Binding sites pyrimidine complexes

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

Platination of the N3 position in 1-substituted uracil and thymine derivatives requires proton abstraction and usually occurs only at high pH, but the Pt-N3 bond, once formed, is thermodynamically stable (log K 9.6) [7]. Platinum binding to N3 increases the basicity of 04, which becomes an additional binding site leading to di- and trinuclear complexes. A list of X-ray structurally characterized species is given by Lippert [7]. Pt complexes of uracil and thymine can form intensely colored adducts (e.g. platinum pyrimidine blues), which show anticar-cinogenic activity analogously to the monomeric species [7]. 

FIGURE 26-8 Common sequences in promoters recognized by eukaryotic RNA polymerase II. The TATA box is the major assembly point for the proteins of the preinitiation complexes of Pol II. The DNA is unwound at the initiator sequence (Inr), and the transcription start site is usually within or very near this sequence. In the Inr consensus sequence shown here, N represents any nucleotide Y, a pyrimidine nucleotide. Many additional sequences serve as binding sites for a wide variety of proteins that affect the activity of Pol II. These sequences are important in regulating Pol II promoters and vary greatly in type and... 

Tetranucleotides containing dG dC base pairs form stable duplexes at low temperature so that the self-complementary sequences dC-dC-dG-dG [contains dC(3 -5 )dG but no dG(3 -5 )dC binding sites] and dG-dG-dC-dC [contains dG(3 -5 )dC but no dC(3 -5 )dG binding sites] serve as excellent oligonucleotide duplexes for differentiating pyrimidine(3 -5 )purine specificity from purine(3 -5 )pyrimidine specificity associated with drug complexation (66, 67). ... 

The observation of partially resolved 31p resonances in the daunomycin poly(dA-dT) complex requires that the antibiotic exhibit a preferred specificity for either the pyrimidine(3 -5 ) purine or purine(3 -5 )pyrimidine binding sites. 

A comparative study of the tetrammine complex [Pt(NH3)4]+ has shown that for platinum, adenine is a better cr donor than ammonia but it has weak n capacity <93JCC45>. Mixed-ligand complexes of m-dichloroethionine-Pd(II) with purines and purine nucleosides have also been prepared. In the complexes of purines and their corresponding nucleosides, the ligand binding site is N-7 whereas in the case of pyrimidines and their nucleosides it is N-3 <90ICA129>. 

In general the pyrimidines show a much lower reactivity towards the metal ions. Apparently no reaction was observed with uracil while the stability constants of Cu-cytosine are even lower than the lgJCi and gK% values of Cu(NH3)62+ (79). The high stability of the purine metal complexes can be attributed to the binding site at the imidazole residue. There the imino proton competes with the metal ion. Fig. 1 presents a model of the 2 1 complex of Cu-(adenine)%. 

In contrary to all these results Bryan and Frieden (8) reported complex reactions of Cu2+ with the bases of undenatured DNA at 26°C (Table 4). They further assumed that only the purine nucleotide units bind to Cu2+ in a 1 1 complex. The predominant reactivity of the purine bases was also confirmed by other authors (19, 26, 39, 43). Another group (107) attributed the pyrimidine bases as the favored binding sites for Cu2+. 

Iron-nitrosyl complexes continue to attract attention. Complexes with mercaptopurines and mercaptopyrimidines have been examined by both NMR and ESR. (57) The mercapto group in mercaptopyrimidines is the preferred binding site for the Fe atom, provided that the pH value allows its ionization. At lower pH a pyrimidine nitrogen atom is the binding site. At biologically relevant pH values equilibrium between complexes of types I and III occurs [7]. In the... 

The use of paramagnetic ions to examine the binding sites and solution conformations of nucleosides and nucleotides is becoming very widespread. Studies that describe the complexing of a variety of nucleosides and nucleotides with paramagnetic ions involve the use of Mn(ii), (749-751) Cu(ii), (750, 752-754) and lanthanide ions. (755) Mn " ions appear to bind to multiple sites on purine and pyrimidine nucleosides (749) whereas the phosphate group is the primary binding site on monophosphate nucleotides. (750) relaxation studies indicate that Cu " ions bind to N-3 of 5 -cytidine monophosphate (5 -CMP). In contrast to cytidine [59], adenosine [60] appears to have... 

Application of Global Sequence Similarity to Find an Inhibitor of Acetolactate Synthase. Acetolactate synthase (ALS) Is the site of action of sulfonylurea, Imldazollnone, and trlazolo pyrimidine herbicides (10-14). Their mode of Inhibition and binding sites on ALS were ambiguous, because (1) these herbicides bear no obvious similarity In their chemical structures to those of ALS substrates (pyruvate and acetolactate), cofactors (thiamine pyrophosphate, FAD, and Mg ) and effectors (valine, Isoleuclne, and leucine) and (2) they Inhibit ALS In a mode too complex to be analyzed. 

Fig. 5 Superposition (in stereo) of 6-azaUMP, UMP and BMP bound to the active site of native M. thermoautotrophicum ODCase. Carbon atoms of the BMP and 6-azaUMP complexes are colored in grey and those of the UMP complex are in black. The green contour (accessible area calculated with 1.2 A probe radius using VOIDOO [29]) represents the cavity located next to the pyrimidine bases and proposed as a temporary binding site for the product CO2...

UMP, and BMP complexes. The remarkable difference, however, is the binding sites of both the purine and the pyrimidine bases. They are located outside the base-binding crevice, pointing towards the surface of the enzyme. They assume overlapping positions and display the same lower energy 3 endo-pucker and anti conformation favored in solution (Fig. 11a) and might indicate a substrate conformation found along the reaction coordinate. 

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