Purine salvage synthesis

A similar reaction is catalyzed by adenylate kinase (see here also). The guanylate kinase-catalyzed reaction is part of de novo purine biosynthesis and can occur as part of purine salvage synthesis as well. 

Pentostatin (deoxycoformycin Fig. 4) is a purine isolated from cultures of Streptomyces antibioticus. Its mode of action involves inhibition of adenosine deaminase, which plays a key role in purine salvage pathways and DNA synthesis. As a consequence, deoxyadenosine triphosphate (dATP) is accumulated, which is highly toxic to lymphocytes. This is associated with augmented susceptibility to apoptosis, particularly in T cells. 

Purine Synthesis Purine Salvage Deoxynucleotides Purine Degradation... 

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. 

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent (see Chapter 57) that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydrogenase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo... 

Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP in many tissues, by a reaction similar to that of hypoxanthine-guanine phosphoribosyltransferase, but is quite distinct from the latter. It plays a minor role in purine salvage since adenine is not a significant product of purine nucleotide catabolism (see below). The function of this enzyme seems to be to scavenge small amounts of adenine that are produced during intestinal digestion of nucleic acids or in the metabolism of 5 -deoxy-5 -methylthioadenosine, a product of polyamine synthesis. 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Most of the free purines derived from the breakdown of DNA, RNA, and nucleotides in the diet are catabolized to xanthine and then to uric acid in the gut mucosa. The AMP and GMP biosynthesized in the body can also be bmken down to free purines, such as adenine, guanine, and hypoxanthine. These purines, in contrast to those derived frcim the diet, are largely reused for the synthesis of ATP and GTP- They are first converted back to AMP or GMP in a pathway of reutiliza-lion called the purine salvage pathway. For example, adenine phosphoribosyl-transferase (PRPP) catalyzes the conversion of adenine to AMP. Here, PRPP serves as the source of the phosphoribose group. Pyrophosphate is a product of the reaction. 

Figure 24-3 Metabolism of purines A, synthesis B, catabolism and C, salvage pathways.

Salvage pathways of purine nucleotide synthesis. The preformed purines can be converted to mononucleotides in a single step, using PRPP. 

Glycosomes are membrane-bound microbody like intracellular organelles, which contain all the enzymes necessary for glycolysis, glycerol metabolism and fixation of CO2. The glycosomes also possess some enzymes associated with pyrimidine synthesis, purine salvage and ether-lipid biosynthesis [1,2]. 

The synthesis of purine and pyrimidine nucleotides needed for the biosynthesis of nucleic acids, and in turn the processes of transcription and translation provide a number of suitable targets for therapeutic intervention. These have been subject of much interest for the discovery of new antiprotozoal drugs as well. Developments in two areas, viz. the purine salvage pathway and the pyrimidine biosynthesis have yielded useful drugs and are discussed. 

HGPRT Hypoxanthine-guanine phosphoribosyltransferase the enzyme that catalyzes the synthesis of inosine monophosphate (IMP) and guano-sine monophosphate (GMP) from hypoxanthine and guanine, respectively. It makes up part of the purine salvage pathway, a way of recycling purine bases back to the nucleotides. 

Purine salvage pathway The synthesis of purine nucleotides by the condensation of the purine bases with phosphoribosyl pyrophosphate. As the name suggests, it is a way in which purine bases can be recycled back to nucleotides. The purine salvage pathway consists of two enzymes, HGPRT and adenine phosphoribosyltransferase (APRT). 

In the purine salvage pathway, purine bases obtained from the normal turnover of cellular nucleic acids or (to a lesser extent) from the diet are reconverted into nucleotides. Because the de novo synthesis of nucleotides is metabolically expensive (i.e., relatively large amounts of phosphoryl bond energy are used), many cells have mechanisms to retrieve purine bases. Hypoxanthine-guaninephos-phoribosyltransferase (HGPRT) catalyzes nucleotide synthesis using PRPP and either hypoxanthine or guanine. The hydrolysis of pyrophosphate makes these reactions irreversible. 

The relative importance of the de novo and salvage pathways is unclear. However, the severe symptoms of hereditary HGPRT deficiency indicate that the purine salvage pathway is vitally important. In addition, investigations of purine nucleotide synthesis inhibitors for treating cancer indicate that both pathways must be inhibited for significant tumor growth suppression. 

See also De Novo Biosynthesis of Purine Nucleotides, De Novo Pyrimidine Nucleotide Metabolism, Nucleotide Salvage Synthesis... 

Purine salvage enzymes - The drugs allopurinol (see here) and formycin B inhibit the action of cellular purine salvage enzymes. Thus, these drugs can be used to treat individuals infected by the parasitic protozans, Plasmodium, and Leishmania because these parasites lack the capacity for de novo purine synthesis (i.e., they depend entirely upon cellular purine salvage enzymes and bases provided by the host)... 

See also The Importance of PRPP, De Novo Biosynthesis of Purine Nucleotides, Excessive Uric Acid in Purine Degradation, De Novo Pyrimidine Nucleotide Metabolism, Nucleotide Salvage Synthesis, Deoxyribonucleotide Biosynthesis, Biosynthesis of Thymine Deoxyribonucleotides, Salvage Routes to Deoxyribonucleotide Synthesis... 

HAT Selection - The compounds hypoxanthine, aminopterin (see here), and thymidine (H,A, and T, respectively) can be used to select for cells having functional salvage pathways. Aminopterin inhibits dihydrofolate reductase, which blocks de novo purine and thymidine synthesis. Only cells which can utilize thymidine (pyrimidine salvage) and hypoxanthine (purine salvage) can grow in this medium. 

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