Synthesis of nucleic acids

Fohc acid is a precursor of several important enzyme cofactors required for the synthesis of nucleic acids (qv) and the metaboHsm of certain amino acids. Fohc acid deficiency results in an inabiUty to produce deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and certain proteins (qv). Megaloblastic anemia is a common symptom of folate deficiency owing to rapid red blood cell turnover and the high metaboHc requirement of hematopoietic tissue. One of the clinical signs of acute folate deficiency includes a red and painhil tongue. Vitamin B 2 folate share a common metaboHc pathway, the methionine synthase reaction. Therefore a differential diagnosis is required to measure foHc acid deficiency because both foHc acid and vitamin B 2 deficiency cause... 

Transcription Template DNA-directed synthesis of nucleic acids typically DNA-directed synthesis of RNA. 

The dilemma described above, that cytosine-rich matrices lead to (complementary) sequences which are low in cytosine and are themselves ineffective matrices, makes the synthesis of nucleic acids in the absence of enzymes almost impossible. Thus, other models and model experiments must be looked for. 

Delayed action cytotoxins that inhibit the synthesis of nucleic acids. They are obtained from various molds/fungi (Aspergillus flavus, Aspergillus parasiticus). They are colorless to pale-yellow crystalline materials melting above 450°F. The "B" toxins fluoresce blue in the presence of UV light while the "G" toxins fluoresce green. They are only slightly soluble in water, but are soluble in methanol, acetone, and chloroform. Aqueous solutions are "probably stable" and "probably tolerant" to chlorine at purification concentrations. 

Showdomycin inhibits synthesis of nucleic acid. Thiols, such as cysteine and glutathione (among other compounds), reverse this inhibition, and it is considered that the interaction of the maleimide moiety with sulfhydryl groups within the cell or in the membrane may be responsible for the selective inhibition of enzymes by show-... 

The chemistry, metabolism, and clinical importance of folic acid have been the subject of many excellent reviews (A7, Gil, H14, H20, Rl). Folic acid deficiency leads to a macrocytic anemia and leucopenia. These symptoms are due to inadequate synthesis of nucleic acid. The synthesis of purine bases and of thymine, required for nucleic acid synthesis, is impaired in folic acid deficiency. Detection of folic acid activity in biologic fluids and tissues is of the utmost importance it distinguishes between the various anemias, e.g., those due to vitamin Bi2 or folic acid deficiency. Because morphology of the abnormal red cell does not help in diagnosing vitamin deficiency, one must rely on assay methods for differential diagnosis. Treatment of pernicious anemia with folic acid has led to subacute combined degeneration of the spinal cord despite... 

In a recent report, the divergent solid-phase synthesis of nucleic acid dendrimers was also reported and the purity assessed using PAGE [24], however, the details are not included here due to space constraints. 

This pathway is variously known as the pentose phosphate, hexose monophosphate or phosphogluconate pathway, cycle or shunt. Although the pentose phosphate pathway achieves oxidation of glucose, this is not its function, as indicated by the distribution of the pathway in different tissues. Only one of the carbons is released as CO2, the key products are NADPH and ribose 5-phosphate, both of which are important for nucleotide phosphate formation and hence for synthesis of nucleic acids (Chapter 20). The... 

Figure 17.38 A simple diagram illustrating the two roles of glutamine (i) generation of ATP, via glutaminolysis, (ii) formation of purine and pyrimidine nucleotides, for the synthesis of nucleic acids in proliferating cells (Chapter 20). ( represents the carbon atoms of glutamine, one of which is released as CO2 and the others are converted to aspartate, via part of the Krebs cycle (Chapter 9). (N) represents the amide nitrogen of glutamine.

Deoxyribonucleic acid (DNA) serves as a template for the synthesis of nucleic acids. Ribonucleic acid (RNA) executes protein synthesis and thus permits cell growth. Synthesis of new DNA is a prerequisite for cell division. Substances that inhibit reading of genetic information at the DNA template damage the regulatory center of cell metabolism. The substances listed below are useful as antibacterial drugs because they do not affect human cells. 

Nature is also selective in the geometry involved in nucleic acid synthesis. This specificity involves both the base order and the particular sugar employed. For DNA the employed sugar is (3-2-deoxy-D-ribose, deoxyribose (below left). Deoxyribose has three chiral centers but only one of them is employed in the synthesis of nucleic acids. Ribose, the sugar employed in the synthesis of RNA, has four geometric sites (below right). 

So, by competing with natural pyrines and pyrimidines in metabolic schemes, they interfere with the synthesis of nucleic acids, thus being included in place of ordinary metabolites. This leads to the formation of cellular products, which cannot function normally. Thus, cellular processes of division and multiplication are disrupted. 

Vinblastine and vincristine are alkaloids isolated from plants of the periwinkle family (Vinca rosea). These compounds cause cells to stop at metaphase and inhibit assembly of microtubules, and likewise, failure of mitotic spindle formations. They inhibit synthesis of nucleic acids and proteins. 

Chloroquine is the drug of choice for preventing and treating acute forms of malaria caused by P. vivax, P. malariae, P ovale, as well as sensitive forms of P. falciparum. The mechanism of its action is not completely clear, although there are several hypotheses explaining its antimalarial activity. Chloroquine and its analogs inhibit synthesis of nucleic acids of the parasite by affecting the matrix function of DNA. This happens by preliminary... 

Like chloroquine, quinine binds with plasmodium DNA, thus interfering in the synthesis of nucleic acids and preventing its replication and transcription. Quinine also suppresses a large portion of the enzymatic system and therefore it is characterized as a general protoplasmid toxin. This fact agrees well with the action of quinine on membranes, its local anesthetizing and its cardiodepressive effects. 

Table 11.5. Synthesis of nucleic acids and protein expression in vesicles... 

Despite all of the activity in pyrimidine-based synthesis, only one study has emerged of solid-phase versions of these reactions <2003TL1267, 20030BC1909>. This chemistry was based upon condensation of dicarbonyl compounds with resin-bound pyrimidine-5,6-diamines through a 2-alkylthio link and oxidative cleavage as described in Section 10.18.7.2. The value of alkylthio substituents in the synthesis of complex substituted pterins has also been demonstrated in the synthesis of nucleic acid conjugates <2004OBC3588> (see Section 10.18.12.4). 

The active triazine metabolite, inhibits plasmodial dihydrofolate reductase and thus disrupts the synthesis of nucleic acids in the parasite. 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

All cells must be able to make pyrimidine and purine bases to be used in synthesis of nucleic acids and coenzymes. The pathway for synthesis of pyrimidine begins with aspartic acid and that for purines with glycine. In many organisms the pathway of purine formation is further enhanced because uric acid or a... 

The origin of life probably occurred in three phases (fig. 1.23) (1) The earliest phase was a period of chemical evolution during which the compounds needed for the nu-cleation of life must have been formed. These compounds include the most important class of biological macromolecules, the nucleic acids. In this phase of evolution, the synthesis of nucleic acids was noninstructed. (2) As soon as some nucleic acids were present, physical forces between them must have led to an instructed synthesis, in which the already formed molecules served as templates for the synthesis of new polymers. It seems likely that feedback loops selected out certain nucleic acids for preferential synthesis. At some point during this period of instructed synthesis more nucleic acids and possibly protein macromolecules were formed. The products of this phase of mo-... 

These enzymes catalyze the replication and transcription of DNA, and have a specific requirement for Mg2+ or Mn2+." Both enzymes have been thought to require Zn2+ in addition,334,335 in accord with the well-known effect of zinc deficiency on Euglena gracilis, which results in defects in synthesis of nucleic acids and proteins, and in cell division. However, it appears now that the DNA polymerase is not a zinc enzyme.336... 

The PPC allows the generation of NADPH reduction equivalents required for cell anabolism, and ribose 5-phosphate molecules for the synthesis of nucleic acids. Alternatively, ribose 5-phosphate can also be generated or transformed into fructose 6-phosphate or glyceraldehyde 3-phosphate, providing metabolic flexibility to the cell, in order to balance the fluxes through these pathways. The flux through the PPC is related to the nucleic acid requirements for DNA duplication or RNA transcription, and could probably be controlled by the cell cycle (Wagner, 1997). 

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