Nucleotide coenzymes synthesis

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. 

Synthesis of nucleotides and nucleosides, nucleotide coenzymes, polynucleotides, and histidine... 

A. The cell maintains an important pool of purine nucleotides for synthesis of coenzymes and precursors for DNA and RNA and to support reactions that are coupled to ATP hydrolysis. 

An alternative pathway for synthesis of quinoli-nate from aspartate and a triose phosphate exists in bacteria and in plants and provides the major route of nicotinic acid synthesis in nature. In E. coli the reaction is catalyzed by two enzymes, one an FAD-containing L-aspartate oxidase which oxidizes aspartate to a-iminoaspartate.228 The latter condenses with dihydroxyacetone-P to form quinolinate (Eq. 25-13).229 There are at least two other pathways for synthesis of quinolinic acid as well as five or more salvage pathways for resynthesis of degraded pyridine nucleotide coenzymes.224/230/231... 

For recent reviews of the chemistry of the nucleic acids and related topics see B. Lythgoe, Chemistry of Nucleosides and Nucleotides, Ann. Repts. on Progress Chem. (Chem. Soc. London), 41, 200 (1945) R. S. Tipson, The Chemistry of the Nucleic Acids, Advances in Carbohydrate Chemistry, 1, 193 (1945) A. R. Todd, Synthesis in the Study of Nucleotides, J. Chem. Soc., 647 (1946) B. Lythgoe, Chemistry of Adenine Nucleotide Coenzymes, Ann. Repts. on Progress Chem. (Chem. See. London), 42, 175 (1946) B. Lythgoe and A. R. Todd, Structure and Synthesis of Nucleotides, Symposia Soc. Expll. Biol. I. Nucleic Acid, 1947, 15 A. R. Todd, Synthase de Nucleotides, Bull. soc. chim. France, 1948,933 B. Lythgoe, Some Aspects of Pyrimidine and Purine Chemistry," Quart. Revs., 3, 181 (1949). 

It is not strictly correct to regard niacin as a vitamin. Its metabolic role is as the precursor of the nicotinamide moiety of the nicotinamide nucleotide coenzymes, nicotinamide adenine dinucleotide (NAD) and NADP, and this can also be synthesized in vivo from the essential amino acid tryptophan. At least in developed countries, average intakes of protein provide more than enough tryptophan to meet requirements for NAD synthesis without any need for preformed niacin. It is only when tryptophan metabolism is disturbed, or intake of the amino acid is inadequate, that niacin becomes a dietary essential. 

Apart from the relatively small amounts that are required for synthesis of the neurotransmitter serotonin (5-hydroxytryptamine), and for net new protein synthesis, essentially the whole of the dietary intake of tryptophan is metabolized by way of the oxidative pathway shown in Figures 8.4 and 9.4, which provides both a mechanism for total catabolism by way of acetyl coenzyme A and a pathway for synthesis of the nicotinamide nucleotide coenzymes (Section 8.3). 

Nucleoside S -phosphoramidates have proved to be useful intermediates in the synthesis of nucleoside 5 -pyrophosphates and nucleotide coenzymes. Nucleoside phosphoramidates may also be prepared by treatment of a nucleoside 5 -phosphate with ammonia in the presence of N, IV -dioyclohexylcarbodiimide [R. W. Chambers and J. G. Moffatt, J. Am. Chem. Soc., 80, 3752 (1958)]. 

Established in Manchester, Todd continued research on vitamin E and the constituents of Cannabis. He had many wartime commitments, including research on chemical defence and antimalarials, and was a member of the British team on penicillin. He was, however, able to begin the work whose ultimate objective was the synthesis of the nucleotide coenzymes, several of which are closely related to the B vitamins, and potentially leading to a study of the nucleic acids. Attention was directed initially to each of the components, the heterocyclic bases, the nucleosides, and the chemistry of phosphoric esters. This broad strategic plan,3 begun in Manchester, was continued and expanded when Todd was appointed to the Chair of Organic Chemistry in Cambridge in 1944. 

First DNA polymerase discovered, which copied DNA strands Nobel Prize for work on nucleotides and nucleotide coenzymes Calvin cycle of photosynthesis published First diphosphane metal complex reported Used DNA polymerase for laboratory synthesis of DNA from nucleotides... 

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 kinase step enables cells to utilize nucleosides from their milieu for the incorporation into nucleotide coenzymes and polynucleotides, and has the obvious value that synthesis de novo is spared. The kinase reaction, operating in sequence with the readily reversible uridine phosphorylase reaction, also provides a route by which uracil may enter into the pyrimidine nucleotide pool. 

As shown in Figure 11.13, the nicotinamide nucleotide coenzymes can be synthesized from either of the niacin vitamers, and from quinolinic acid, an intermediate in the metabolism of tryptophan. In the liver, the oxidation of tryptophan results in a considerably greater synthesis of NAD than is required, and this is catabolized to release nicotinic acid and nicotinamide, which are taken up and used by other tissues for synthesis of the coenzymes. 

A considerable advance in elaborating the pathway of pyridine coenzyme synthesis resulted from the contributions of Preiss and Handler (118, 1B6-1B8). Before discussing the experiments of these investigators, it may be of value to review some of the earlier work on the metabolism of nicotinic acid and nicotinamide in erythrocytes. It has been known for some time that nicotinic acid taken orally results in a significant increase in the pyridine nucleotide content of human red blood cells (1B9, ISO). When equal concentrations of nicotinamide were given under identical conditions, there was no effect on the erythrocyte DPN level. Isolated erythrocytes have also been found to show a rise in DPN when incubated with nicotinic acid and not with nicotinamide. However, incubation with nicotinamide leads to a marked accumulation of nicotinamide mononucleotide (ISl). In this connection, it is of importance to point out that the level of the DPN pyrophosphorylase is extremely low in the red blood cell (ISB). 

The fact is, however, that synthesis began, not as a pursuit of oligonucleotides perse, but as a development or offshoot of phosphorylation studies aimed more at polyphosphates, the nucleotide coenzymes, and other cofactors—a formidable project (3,4). It is this beginning that may provide some historical understanding of the way that oligonucleotide or polyphosphodiester synthesis developed. 

Of the two pyridine nucleotide coenzymes, NAD is present mainly as the oxidized form in the tissues, whereas NADP is principally present in the reduced form, NADPH2. There are important homeostatic regulation mechanisms which ensure and maintain an appropriate ratio of these coenzymes in then-respective oxidized or reduced forms in healthy tissues. Once converted to coenzymes within the cells, the niacin therein is effectively trapped, and can only diffuse out again after degradation to smaller molecules. This implies, of course, that the synthesis of the essential coenzyme nucleotides must occur within each tissue and cell type, each of which must possess the enzymatic apparatus for their synthesis from the precursor niacin. Loss of nicotinamide and nicotinic acid into the urine is minimized (except when the intake exceeds requirements) by means of an efficient reabsorption from the glomerular filtrate. 

Imidazolium adenosine-5 phosphate allowed to react with 2-4 moles of N,N -carbonyldiimidazole in anhydrous dimethylformamide imidazolium adeno-sine-5 imidazol-l-ylphosphonate. Y almost 100%. Reactions, incl. a novel facile synthesis of nucleotide coenzymes, s. L. Goldman, J. W. Marsico, and G. W. Anderson, Am. Soc. 82, 2969 (1960). 

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