Nucleotide salvage pathways

Many cells, however, are resistant to antifolates because they contain enzymes that can synthesize the necessary nucleotides from purine bases and thymidine (Figure 6-39, bottom). Two key enzymes In these nucleotide salvage pathways are thymidine kinase (TK) and hypoxanthine-guanine phosphoribosyl transferase (HGPRT). Cells that produce these enzymes can grow on HAT medium, which supplies a... 

Deamination of purine and pyrimidine bases (Figures 6(b) and 6(c)) is an important reaction in nucleotide salvage pathways and RNA editing. In nucleosides, two of the most characterized reactions involve the conversion of adenosine and cytidine to form inosine and uridine (with the elimination of one molecule of... 

The ability of cells to uptake thymidine and phosphorylate it is exploited in the so-called HAT selection medium (see here), which selects for cells that have functional nucleotide salvage pathways. 

In principle, all therapeutic oligonucleotides that enter cells will eventually be metabolized to individual monomeric forms and be subject to endogenous nucleotide salvage pathways and join endogenous nucleotide pools within any given cell. The actual extent and rate at which this occurs will rely... 

On the other hand, as seen in this chapter and in earlier chapters, the formation of phosphates of adenine (e.g., AMP, ADP, and ATP), guanidine (e.g., GTP), cytosine (e.g.,cytidine monophosphate [CMP]), uracil (e.g., uridine monophosphate [UMP]), and dTMP have all involved the carbohydrate scaffold as a building block for the formation of the finished heterocyclic base (purine or pyrimidine). It is also important to realize that, as part of nucleotide salvage pathways, it has been found that a family of enzymes collectively known as phosphorylases serves to catalyze reactions between free bases and phosphate esters of carbohydrates (and related compounds). For example, as shown in Scheme 14.13, the generalized enzyme, purine nucleoside phosphorylase (EC 2.4.2.1), catalyzes the conversion of a purine with... 

Inosine monophosphate dehydrogenase (EVDPDH) is a key enzyme of purine nucleotide biosynthesis. Purine synthesis in lymphocytes exclusively depends on the de novo synthesis, whereas other cells can generate purines via the so-called salvage pathway. Therefore, IMPDH inhibitors preferentially suppress DNA synthesis in activated lymphocytes. 

Guanine Phosphoribosyl Transferase. Guanine phosphoribosyl transferase (GPRT) is one of the enzymes of the purine salvage pathway, which is needed by protozoa because they lack the ability to synthesize purine nucleotides. 

In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis. In patients with Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation, Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. These patients also all have hyperuricemia because purines cannot be salvaged. 

The nucleosides are converted back to nucleosides is reactions known as salvage pathways (Chapter 20). RNA supplements in the diet are also hydrolysed to form nucleosides, which can be taken up by cells in the body to form nucleotides. Although proliferating cells can synthesise nucleotides de novo, provision of nucleosides bypasses a considerable amount of biochemistry. This is important, for example, in lymph nodes for proliferating immune cells in the bone marrow and also for stem cells in the crypts of the villi (Chapter 20). 

The de novo synthesis of inosinic acid The salvage pathways Purine nucleotide interconversions Other enzymes... 

De novo synthesis of purines and pyrimidines yields the monophosphates IMP and UMP, respectively (see p. 188). All other nucleotides and deoxynucleotides are synthesized from these two precursors. An overview of the pathways involved is presented here further details are given on p. 417. Nucleotide synthesis by recycling of bases (the salvage pathway) is discussed on p. 186. 

A. Salvage pathways allow synthesis of nucleotides from free purines or pyrimidines that arise from nucleic acid degradation or dietary sources, which is more economical for the cell than de novo synthesis. 

When nucleoside analogs, such as cytosine arabinoside (AraC), azidothymidine (zidovudine orAZT), and dideoxyinosine (ddi), are converted into the corresponding nucleotides by salvage pathways, they can be Incorporated into nascent DNA strands by DNA polymerases. 

Two types of pathways lead to nucleotides the de novo pathways and the salvage pathways. De novo synthesis of nucleotides begins with their metabolic precursors amino acids, ribose 5-phosphate, C02, and NH3. Salvage pathways recycle the free bases and nucleosides released from nucleic acid breakdown. Both types of... 

Free purine and pyrimidine bases are constantly released in cells during the metabolic degradation of nucleotides. Free purines are in large part salvaged and reused to make nucleotides, in a pathway much simpler than the de novo synthesis of purine nucleotides described earlier. One of the primary salvage pathways consists of a single reaction catalyzed by adenosine phosphoribosyltransferase, in which free adenine reacts with PRPP to yield the corresponding adenine nucleotide ... 

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... 

The Purine Nucleotide Cycle and Salvage Pathways for Purines... 

Thymidvlate Is Formed from dUMP Formation of Nucleotides from Bases and Nucleosides (Salvage Pathways)... 

Like purine nucleotides, pyrimidine nucleotides can be synthesized either de novo or by the salvage pathways from nucleobases or nucleosides. However, salvage is less efficient because, except in the case of utilization of uracil by bacteria, and to some extent by mammalian cells, pyrimidine nucleobases are not converted to nucleotides directly but only via nucleosides. 

Nucleotides are the building blocks for nucleic acids they are also involved in a wide variety of metabolic processes. They serve as the carriers of high-energy phosphate and as the precursors of several coenzymes and regulatory small molecules. Nucleotides can be synthesized de novo from small-molecule precursors or, through salvage pathways, from the partial breakdown products of nucleic acids. The highlights of our discussion in this chapter are as follows. 

Mycophenolate mofetil is a functionally selective cytotoxic agent for B and T lymphocytes, where it blocks the production of guanosine nucleotides required for DNA synthesis. For purine biosynthesis, B and T lymphocytes rely on de novo synthesis rather than on the salvage pathway. Lymphocytes have little or no salvage pathway as opposed to other blood marrow elements and parenchymal cells that... 

Purine and pyrimidine nucleotides are essential components of many biochemical molecules, from DNA and RNA to ATP and NAD. In recent years, the pyrimidine and especially the purine metabolism of parasitic helminths have been investigated extensively, mainly because they are different from the pathways in the mammalian host such that they have potential as targets for chemotherapeutic attack. For a review of purine and pyrimidine pathways in parasitic helminths and protozoa, see Berens et al. (1995). Although parasitic helminths do not synthesize purines de novo, but obtain them from the host, they do possess elaborate purine salvage pathways for a more economical management of this resource. Pyrimidines, on the other hand, are synthesized de novo by all parasitic flat-worms studied so far and, as with mammalian... 

Salvage pathways of nucleotide sugars represent biochemical short-cuts by which the cellular metabolism circumvents complex pathways for secondary nucleotide sugars. These de novo syntheses involve kinases phosphorylating the... 

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