Nucleotide function

Nucleotides are synthesized from many simple precursors and the pentose, phosphoribosyl pyrophosphate. Nucleotides function as energy carriers and regulatory molecules and as precursors to coenzymes and nucleic acids. 

Base-off nucleotide function not coordinated to a cobalt center in a complete corrin... 

Vitamin B12 (1) was discovered some 55 years ago as the (extrinsic) antipemicious anemia factor, important for human and animal metabolism The cobalt complex (1) was structurally characterized by X-ray analysis in the laboratory of D.C. Hodgkin. In these studies, the unique buildup of the tetrapyrrolic corrin ligand and the intramolecularly coordinating pseudo-nucleotide function of the vitamin were discovered. ... 

The coenzyme B12 molecule consists of several unique stractural units the corrin ligand, the intramolecularly coordinating nucleotide function, the corrin-bound Co -ion, and the organometallically bound 5 -deoxyadenosyl ligand (Figure 3). The cyanide derivative, vitamin B12 (1), is an isolation artifact that appears not to have a physiological role itself ... 

So far, for the highly oxygen-sensitive Co -forms of cobalt-corrinoids (such as Co -cobalamin, (6)), information from X-ray analysis on their three-dimensional structure is not available. However, in these strongly nucleophihc, highly reduced cobalt complexes, the diamagnetic Co -center (a d metal ion, isoelectronic with a Ni"-ion) presumably is ligated by the corrin ligand only, in a tetracoordinated, nearly square-planar fashion. As a consequence, the Co -forms of complete corrins would have to be base-off, that is, the nucleotide function would not be attached to the central cobalt ion. 

Two major mechanisms have to be taken into consideration for the alkylation of Co -corrins. The classical mechanism of a bimolecular nucleophilic substitution reaction at carbon (the Co -corrin acts as a nucleophile) leads to /3-aUcylated Co -corrins with high diastereoselectivity. Secondly, an electron transfer-induced radical process (where the Co -corrin acts as a one-electron reducing agent) may also lead to cobalt alkylation. The observed formation of incomplete a-aUcylated Co -corrins under kinetically controlled conditions has been proposed to occur via this path. The high nucleophilic reactivity of Co -corrins and their diastereoselective nucleophilic reaction on the ( upper ) /3-face are not increased by the nucleotide function on the ( lower ) a-face rather they appear to be an inherent reactivity of the corrin-bound tetracoordinate Co -center. Among the organometallic B12 derivatives prepared to date, neopentylcobalamin, benzylcobalamin, and... 

Nucleotides functionalized by carboranyl clusters as a new entity for DNA oligonucleotide modification 03EJO4489. 

Subsequent to the original quest for vitamin B12 (1), driven by medicinal purposes mainly, further investigations on the natural corrinoids laid bare the central roles of the Bi2-coenzymes in the metabolism of microorganisms, in particular. These primitive organisms uniquely possess the capacity to build up the complex B12 structure in nature, in which they may vary the constitution of the nucleotide function in a species-specific way (Figure 2). The cobalt-corrins, in turn, have been proposed to be structural and functional remnants of early (primitive) forms of life, where presumably, central metabolic processes could rely considerably on organometallic chemistry at cobalt and nickel centers. ... 

The remarkable nucleotide loop , which contains an unusual a-configured nucleotide function, forms a nearly strain-free 19-membered ring to allow for coordination of the nucleotide base to the lower side of the corrin-bound metal center (base-on forms). Protonation at the nitrogen atom of the nucleotide base (in some cases, mere solvolysis) leads to the base-off form (Figure 4). 

Fig. 1.1 In a gene, the DNA nucleotides function as letters spelling out which amino acids are to be incorporated into the protein...

Vitamin Bo (1, CNCbl), and other Bo-derivatives, where the cyanide ligand of 1 is replaced by a different upper /3-ligand are 5, 6 -dimethylbenzi-midazolyl-cobamides and are the most commonly discussed Bo-derivatives. Only base-on cobalamins, where the nucleotide functionality coordinates in an intramolecular mode, have been analyzed by x-ray crystallography [27, 28]. In this present chapter a systematic atomic numbering is used for vitamin... 

In solution the intramolecular coordination of the nucleotide function to the lower a-axial coordination site of the corrin-bound cobalt center of complete corrins occurs with Httle build-up of strain [149]. This allows the (coordinating) nucleotide to steer the reactivity, as well as the face-selectivity, of certain organometalUc reactions involving the corrin-boimd cobalt center [75]. Experiments by Eschenmoser demonstrated that cobal-amins can self-constitute in solution from the Bi2-nucleotide portion and incomplete cobyrinic acid derivatives to show a remarkable kinetic and thermodynamic preference for the specific formation of the B 12-structure, and to a pre-enzymatic origin of the basic structural elements of the complete corrins [149]. 

The large number of purine and pyrimidine nucleotides found in nature su ests that these compounds will also have a large number of functions in cells, and might participate in many areas of metabolism. Similarly, the quantitative predominance of ATP among all of these compounds would seem to suggest a special importance for this nucleotide in intermediary metabolism. Both conclusions appear to be justified, and they will be illustrated in more det in this chapter. Because a detailed consideration of nucleotide function would cover almost the whole field of biochemistry, this survey will be brief and will stress types of reactions, and will generalize broadly. 

Three vitamins are composed in part of heterocyclic rings derived from purine bases or nucleotides. In the plants and microorganisms which make these compounds, therefore, these reactions may be considered either as a nucleotide function or as a new area of nucleotide metabolism. 

Bi2 derivatives, several unique structural units are assembled around the cobalt(III) center the corrin ligand, the intramolecularly coordinating dimethylbenzimidazole-nucleotide function, and (in 2) an organometallic 5 -deoxy-5 -adenosyl ligand (15-17) (see Figs. 1 and 2). 

Therefore, nucleotide receptors have been built trying to simultaneously satisfy several of these characteristics complementary charged functions, hydrogen-bonding capacity to any of the nucleotide functions, and stacking interactions... 

This discussion will be limited to aerobic hydroxylation reactions. As already mentioned, it is a reaction which appears to be restricted to the metabolism of rather inert molecules. The reason for this is not apparent, but it may be because the reaction is energetically expensive for the cell. If, in the hydration type of hydroxylation reaction, a pyridine nucleotide functions as the hydrogen acceptor, the subsequent reoxidation of the DPNH or TPNH over the flavin-cytochrome hydrogen transport system could be coupled to the synthesis of 3 moles of ATP per mole of DPNH oxidized. In the aerobic type of hydroxylation reaction, utilizing TPNH as the electron donor, the oxidation of the TPNH is apparently not coupled to high-energy phosphate-bond synthesis and the cell therefore loses the equivalent of three ATP s. 

It should be emphasized that the net reaction (18) is not an indication that pyridine nucleotides function as cofactors in the hydroxylation reaction, but only that DPNH can reduce back substrate molecules which have participated as electron donors in the hydroxylation of other substrate molecules. 

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