Purine biosynthesis salvage reactions

A few other less studied biochemical approaches such as purine and pyrimidine metabolism protein biosynthesis and lipid metabohsm in helminths also provide targets for antiparasitic drug design [83]. Like protozoal parasites, some helminths such as S. mansoni (adult and larval forms) lack de novo purine biosynthesis and, therefore, depend entirely on the salvage mechanism for their purine requirements. Similarly amino acid metabolism and biosynthesis of proteins has also been not worked out in many parasites [83a]. Although the helminths meet their requirements of amino acids by absorbing freely from the host, they may also synthesize some amino acids. For example. Fasciola hepatica, schistosomes and other trematodes produce proline by a reaction sequence given in Chart 8. Similarly H. diminuta can... 

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. 

Hyperuricemia in Lotta Topa ne s case arose as a consequence of over-j production of uric acid. Treatment with allopurinol not only inhibits xan-thine oxidase, lowering the formation of uric acid with an increase in the excretion of hypoxanthine and xanthine, but also decreases the overall synthesis of purine nucleotides. Hypoxanthine and xanthine produced by purine degradation are salvaged (i.e., converted to nucleotides) by a process that requires the consumption of PRPP. PRPP is a substrate for the glutamine phosphoribosyl amidotransferase reaction that initiates purine biosynthesis. Because the normal cellular levels of PRPP and glutamine are below the of the enzyme, changes in the level of either substrate can accelerate or reduce the rate of the reaction. Therefore, decreased levels of PRPP cause decreased synthesis of purine nucleotides. 

Which of the following reactants and products are involved in the salvage reactions of purine biosynthesis ... 

Ribose phosphates phosphorylated derivatives of ribose. Ribose is phosphorylated in position 5 by the action of ribokinase (EC 2.7.1.15) and ATP ribose 5-phosphate is also produced in the Pentose phosphate cycle (see), and in the Calvin c cle (see) of photosynthesis. Phosphoribomutase cat yses the interconversion of ribose 5-phospbate and ribose 1-phosphate, and the cosubstrate of this reaction is ribose l,5-f>isphosphate. 5-Phosphoribosyl 1-pyrophos-phate donates a ribose 5-phosphate moiety in the de novo biosynthesis of purine and pyrimidine nucleotides (see Purine biosynthesis. Pyrimidine biosynthesis), in the Salvage pathway (see) of purine and pyrimidine utilization, in the biosynthesis of L-Histi-dine (see) and L-Tryptophan (see) and in the conversion of nicotinic acid into nicotinic acid ribotide (see Pyridine nucleotide cycle). Ribose 1-phosphate can also take part in nucleotide synthesis (see Salvage pathway). 

Liver, the major site of purine nucleotide biosynthesis, provides purines and purine nucleosides for salvage and utilization by tissues incapable of their biosynthesis. For example, human brain has a low level of PRPP amidotransferase (reaction 2, Figure 34-2) and hence depends in part on exogenous purines. Erythrocytes and polymorphonuclear leukocytes cannot synthesize 5-phosphoribosylamine (strucmre III, Figure 34-2)... 

Answer D. IMP is a feedback inhibitor of PRPP amidophosphoribosyl transferase, the first reaction in the biosynthesis of purines. IMP is formed by the HPRT reaction in the salvage of hypoxanthine. 

The salvage pathway does not involve the formation of new heterocyclic bases but permits variation according to demand of the state of the base (B), i.e. whether at the nucleoside (N), or nucleoside mono- (NMP), di- (NDP) or tri- (NTP) phosphate level. The major enzymes and routes available (Scheme 158) all operate with either ribose or 2-deoxyribose derivatives except for the phosphoribosyl transferases. Several enzymes involved in the biosynthesis of purine nucleotides or in interconversion reactions, e.g. adenosine deaminase, have been assayed using a method which is based on the formation of hydrogen peroxide with xanthine oxidase as a coupling enzyme (81CPB426). 

The pathways for the biosynthesis of nucleotides fall into two classes de novo pathways and salvage pathways (Figure 25.1). In de novo (from scratch) pathways, the nucleotide bases are assembled from simpler compounds. The framework for a pyrimidine base is assembled first and then attached to ribose. In contrast, the framework for a purine base is synthesized piece by piece directly onto a ribose-based structure. These pathways comprise a small number of elementary reactions that are repeated with variation to generate different nucleotides, as might be expected for pathways that appeared very early in evolution. In salvage pathways, preformed bases are recovered and reconnected to a ribose unit. 

The reaction of carbamoyl phosphate with aspartate to produce W-carbamo-ylaspartate is the committed step in pyrimidine biosynthesis. The compounds involved in reactions up to this point in the pathway can play other roles in metabolism after this point, A -carbamoylaspartate can be used only to produce pyrimidines—thus the term committed step. This reaction is catalyzed by aspartate transcarbamoylase, which we discussed in detail in Ghapter 7 as a prime example of an allosteric enzyme subject to feedback regulation. The next step, the conversion of A-carbamoylaspartate to dihydroorotate, takes place in a reaction that involves an intramolecular dehydration (loss of water) as well as cyclization. This reaction is catalyzed by dihydroorotase. Dihydroorotate is converted to orotate by dihydroorotate dehydrogenase, with the concomitant conversion of NAD to NADH. A pyrimidine nucleotide is now formed by the reaction of orotate with PRPP to give orotidine-5 -monophosphate (OMP), which is a reaction similar to the one that takes place in purine salvage (Section 23.8). Orotate phosphoribosyltransferase catalyzes this reaction. Finally, orotidine-5 -phosphate decarboxylase catalyzes the conversion of OMP to UMP... 

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