Nucleotide acid anhydrides

Nucleotide acid anhydrides represent activated forms of their X component. The X may be transformed to another substance (Table III), may be transferred to an acceptor (Table IV), or X itself may bear a group which is activated, by virtue of its association with the anhydride compound, e.g., acetate in acetyl coenzyme A. All of these anhydrides can fimction naturally in catalytic amounts as coenzymes. 

Transfer of X Component OF Nucleotide Acid Anhydrides TO Acceptors... 

The enzymic reactions responsible for anhydride synthesis are reversible, and in some cases such as in DPN S3rnthesis, the equilibrium constant is close to unity (387). There are, however, several mechanisms by which formation of a nucleotide acid anhydride can be encouraged, and its destruction by the reverse reaction prevented. This may be illustrated in the synthesis of adenosine-5 -phosphosulfate (APS) which takes place by a reversible reaction that strongly favors its destruction [Eq. (77)] (334)... 

Nucleotides are formed when one or more phosphate groups is attached to the 5 carbon of a nucleoside (Figure 1-1-6). Nucleoside di- and triphosphates are high-energy compounds because of the hydrolytic energy associated with the acid anhydride bonds (Figure 1-1-7). 

Phosphoric acid molecules can form acid-anhydride bonds with each other. It is therefore possible for two nucleotides to be linked via the phosphate residues. This gives rise to dinucleotides with a phosphoric acid-anhydride structure. This group includes the coenzymes NAD(P) " and CoA, as well as the flavin derivative FAD (1 see p. 104). 

Since phosphate does not change its redox state in living cells (except in a few instances, see below), it is present in the cell only as free inorganic phosphate, as esters or as acid anhydrides, e.g., as constituent of nucleotides and their... 

The reaction is freely reversible and the enzyme catalyzing it has been called DPN pyrophos-phorylase. This transfer of one 5 -nucleotide to another produces a pyrophosphate bond between them. The reaction is the prototype of a large number of such nucleotidyl transfers to other phosphate compounds. These include transfers to various sugar phosphates to form the nucleoside diphosphate sugar coenzymes, to choline phosphate to form C3fiidine diphosphate choline, and to phosphatidic acid to form cytidine diphosphate diglyceride. This nucleotidyl transfer is the protot)q)e also for transfers of nucleotides to produce mixed acid anhydrides with fatty acids, amino acids, and sulfates. In each instance inorganic pyrophosphate is produced this is also true of the nucleotidyl transfers which produce RNA and DNA. 

ATP can transfer this potential energy to a variety of biochemically important compounds. For example, it has already been demonstrated that the energy for peptide bond formation (via intermediate acid-anhydride formation) may be acquired from the ATP molecule. Similarly, it will be shown shortly (see below) that cyclic nucleotides, which are also high energy, may be synthesized from an ATP (or GTP) precursor. 

Pantothenic acid, sometimes called vitamin B3, is a vitamin that makes up one part of a complex coenzyme called coenzyme A (CoA) (Figure 18.23). Pantothenic acid is also a constituent of acyl carrier proteins. Coenzyme A consists of 3, 5 -adenosine bisphosphate joined to 4-phosphopantetheine in a phosphoric anhydride linkage. Phosphopantetheine in turn consists of three parts /3-mercaptoethylamine linked to /3-alanine, which makes an amide bond with a branched-chain dihydroxy acid. As was the case for the nicotinamide and flavin coenzymes, the adenine nucleotide moiety of CoA acts as a recognition site, increasing the affinity and specificity of CoA binding to its enzymes. 

Succinylated derivatives of nucleic acids may be prepared by reaction of the anhydride with available —OH groups. The reaction forms relatively stable ester derivatives that create car-boxylates on the nucleotide for further conjugation or modification (Figure 1.83). This method has been used in nucleic acid synthesis (Matteucci and Caruthers, 1980) and to derivatize nucleotide analogs such as AZT (Tadayoni et al., 1993). 

Product distributions obtained on esterification of nucleosides and nucleotides under basic conditions throw further light on factors affecting selective reactivity. p-Toluenesulfonylation of adenosine 5 -monophosphate in aqueous alkali yielded exclusively (in 54-61% yield) the 2 -p-toluenesulfonate.107 Lack of reaction at HO-3 was attributed either to formation of a phosphoric p-toluenesulfonic anhydride, which sterically protected this hydroxyl group, or to the higher acidity of HO-2. It has been shown that the acidic site (with pKa 12.5) in adenosine is associated with the presence of both HO-2 and HO-3, as replacement of either of these by hydrogen, or of HO-2 by methoxyl, results in loss of this acidity.108 Inductive effects, or the sta-... 

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