Nucleoside 5 -diphosphate coenzymes

The subsequent cleavage of the thio-ester succinylCoA into succinate and coenzyme A by succinic acid-CoA ligase (succinyl CoA synthetase, succinic thiokinase) is strongly exergonic and is used to synthesize a phosphoric acid anhydride bond ( substrate level phosphorylation , see p. 124). However, it is not ATP that is produced here as is otherwise usually the case, but instead guanosine triphosphate (CTP). However, GTP can be converted into ATP by a nucleoside diphosphate kinase (not shown). 

The synthesis of purine nucleotides (1) starts from IMP. The base it contains, hypoxanthine, is converted in two steps each into adenine or guanine. The nucleoside monophosphates AMP and CMP that are formed are then phos-phorylated by nucleoside phosphate kinases to yield the diphosphates ADP and GDP, and these are finally phosphorylated into the triphosphates ATP and CTP. The nucleoside triphosphates serve as components for RNA, or function as coenzymes (see p. 106). Conversion of the ribonucleotides into deoxyribo-nucleotides occurs at the level of the diphosphates and is catalyzed by nucleoside diphosphate reductase (B). 

The -amino groups of lysyl residues serve as attachment sites of a number of coenzymes in proteins (e.g. biotin in pyruvate carboxylase, pyridoxal phosphate in phosphorylase, lipoic acid in lipoate acetyl-transferase) and form covalent intermediates in several enzymic reactions (e.g. transaldolase, aldolase, etc.). Discussion of all of these naturally-occuring derivatives of lysine will not be attempted in this treatise, but the investigator using chemical modification of proteins should be aware of their possible presence and effect on the results of his experiments. It should be noted that e-N-phospholysine has been reported in nucleoside diphosphate kinase (Walinder 1968). 

Figure 17,13 Reaction mechanism of succinyl CoA synthetase. The reaction proceeds through a phosphorylated enzyme intermediate. (1) Orthophosphate displaces coenzyme A, which generates another energy-rich compound, succinyl phosphate. (2) A histidine residue removes the phosphoryl group with the concomitant generation of succinate and phosphohistidine. (3) The phosphohistidine residue then swings over to a bound nucleoside diphosphate, and (4) the phosphoryl group is transferred to form the nucleoside triphosphate.

Harwood, H.J. Brandt, K.G. Rodwell, V.W. Allosteric activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by nucleoside diphosphates. J. Biol. Chem., 259, 2810-2815 (1984)... 

Figure 10.2 shows that ATP is formed by the phosphoglycerate kinase and pyruvate kinase glycolytic reactions and in the Krebs cycle by succinyl coenzyme A (CoA) synthetase in co-operation with nucleoside diphosphate kinase (Fig. 10.3). NB These reactions do...

Cytidine phosphates cytidine S -monophosphate (CMP, cytidylic acid, M, 323.2), cytidine 5 -diphos-phate (CDP, M, 403.19) and cytidine 5 -triphosphate (CTP, M, 483.16). For structure, see e. g. Pyrimidine biosynthesis. CTP is a precursor of RNA synthesis, while deoxy-CTP is a precursor of DNA synthesis. CDP may be regarded as the coenzyme of phospholipid biosynthesis (see Membrane lipids) (activated choline is CDP-choline). Glycerol and the sugar alcohol, ribitol, are also activated by bonding to CDP (see Nucleoside diphosphate sugars). Reduction of ribose... 

Nucleotide coenzyme a coenzyme containing a nucleotide structure. N.c. are Pyridine nucleotide coenzymes (see), and the nucleoside diphosphate moieties of Nucleoside diphosphate sugars (see) and Coenzyme A (see). The Flavin nucleotides (see) are also N.c. Strictly speaking FMN is not a nucleotide but the term nucleotide can be generally applied to any base-sugar-phosphate group. 

With the advent of an adequate nucleotide technology and the development of widespread interest in nucleotide metabolism, many free nucleotides have been found in cells however, no comprehensive survey has appeared since the 1958 report of Henderson and LePage (17), which lists over 100 nucleotides, and the list has probably more than doubled since. A large number of free nucleoside diphosphate conjugates have been isolated from cells and characterized many such compounds serve as coenzymes in group-transfer reactions, for example, CDP-X and UDP-X derivatives participate, respectively, in phospholipid and polysaccharide synthesis (see Chapter 3). As well, many new nucleotides have been recognized as metabolites of nucleoside antibiotics and of synthetic purine and pyrimidine analogues. 

In the synthesis of homopolysaccharides the monosaccharide units are activated by the formation of nucleoside diphosphate derivatives from which they are transferred to a nonactivated growing polymer. The following nucleotide coenzymes are used in the synthe of the most common polymers. 

The breakdown of succinyl coenzyme A may also be linked to the phosphorylation of GDP and IDP to yield GTP and ITP in the presence of inorganic phosphate. The enzyme catalyzing that reaction has been named the phosphorylating enzyme, and has been prepared in a crude form from heart muscle. This preparation also contains another enzyme, nucleoside diphosphate kinase, which catalyzes the transfer of phosphorus from GTP or ITP to ADP to yield ATP. The phosphorylation of ADP coupled to the oxidation of a-ketoglutarate is the only substrate level phosphorylation in the Krebs cycle, and, as can be expected, it is not inhibited by dinitrophenol. When O-labeled phosphate is used in the reaction, the label appears... 

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. 

Among noteworthy recent achievements may also be mentioned the total synthesis of steroidal sapogenins and certain steroidal alkaloids , of griseofulvin independently by two groups , of chlorophyll and of coenzyme A, a complex nucleoside diphosphate... 

Nucleosides are also encountered in the structures of adenosine triphosphate (ATP) and coenzyme A (HSCoA). ATP provides nature with its currency unit for energy. Hydrolysis of ATP to adenosine diphosphate (ADP) liberates energy, which can be coupled to energy-requiring processes in biochemistry, and synthesis of ATP from ADP can be coupled to energy-releasing processes (see Box 7.25). 

CAS 58-96-8. C9I I l3N2()6. The nucleoside of uracil. It is a constituent of ribonucleic acid and some coenzymes (such as uridine diphosphate glucose). 

Nucleoside 2 (or 3 ),5 -diphosphates have been isolated by degradation of certain coenzymes, as well as from hydrolyzates of nucleic acids. Adenosine 3, 5 -diphosphate (see p. 320) has been isolated by enzymic hydrolysis of coenzyme A and from active sulfate (adenosine 3 -phosphate 5 -phosphosulfate). Adenosine 2, 5 -diphosphate was shown to be present in the adenylic acid moiety of the coenzyme adenine-nicotinamide dinucleotide phosphate which, by treatment with a 5 -nucleotidase from potatoes, is converted into adenosine 2 -phosphate. Adenosine 3, 5 -di-phosphate is reported to play a role as a cofactor in the bioluminescence of Renilla reniformis (pansy) Ribonucleic acid carrying a terminal 5 -phos-phate group yields ribonucleoside 3, 5 -diphosphates on digestion with phosphoesterases. ... 

The reductase of Lactobacillus leichmamii has also been extensively studied. It differs from the E. coli enzyme in that it requires cobalamin as a coenzyme and uses nucleoside triphosphates, rather than diphosphates, as substrates [7,139]. The enzyme also shows allosteric properties which are governed by nucleoside triphosphates as effectors. The interpretation of these effects and analysis of kinetic data are complicated by the fact that the modifiers are also substrates and products, and that their effects are profoundly influenced by ionic strength and concentrations. 

Bibose-l-phosphate is quite labile in acid, in contrast to stable ribose-5-phosphate. With extracts of some organisms, it had been noted that the product of nucleoside cleavage in the presence of inorganic phosphate was an acid-stable compound, eventually identified as ribose-5-phosphate. This pointed to the existence of a phpsphoribomutase, analogous to phos-phoglucomutase, and the active coenzyme, ribose-1,5-diphosphate, catar lyzing the reaction shown in Fig. 20. 

Roseman, S., Distler, J. J., Moffatt, J. G., and Khorana, H. G., 1961a, Nucleoside polyphosphates. XI. An improved general method for the synthesis of nucleotide coenzymes. Synthesis of uridine-5, cytidine-5, and guanosine-5 diphosphate derivatives, 7. Am. Chem. Soc. 83 659-663. 

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