Purines/purine nucleotides disorders

Pyrimidine 5 -nucleotidase (P5N) is a unique enzyme that was recognized from studies of families with relatively common hemolytic disorders. The enzyme catalyzes the hydrolytic dephosphorylation of pyrimidine 5 -nucleotides but not purine nucleotides. The role of this enzyme is to eliminate RNA and DNA degradation products from the cytosol during erythroid maturation by conversion of nucleotide monophosphates to diffusible nucleosides. P5N is inhibited by lead, and its activity is considered to be a good indicator of lead exposure (PI). 

Deficiency of the muscle-specific myoadenylate deaminase (MADA) is a frequent cause of exercise-related myopathy and is thought to be the most common cause of metabolic myopathy. MADA catalyzes the deamination of AMP to IMP in skeletal muscle and is critical in the purine nucleotide cycle. It is estimated that about 1-2% of all muscle biopsies submitted to medical centers for pathologic examination are deficient in AMP deaminase enzyme activity. MADA is 10 times higher in skeletal muscle than in any other tissue. Increase in plasma ammonia (relative to lactate) after ischemic exercise of the forearm may be low in this disorder, which is a useful clinical diagnostic test in patients with exercise-induced myalgia... 

A serious genetic disorder is associated with the salvage pathways, the Lesch-Nyhan syndrome. It is believed that it is caused by a failure to control the de novo purine biosynthetic pathway. In the Lesch-Nyhan syndrome, the enzyme HGPRTase is severely depressed. Because the de novo pathway is controlled largely via feedback effects of purine nucleotides, the pathway is derepressed and excessive quantities of purine nucleotides and their degradation product, uric acid, are accumulated. This results is neurologic effects, self-mutilation, and mental retardation. 

In muscle, a unique nucleotide reutilization pathway, known as the purine nucleotide cycle, uses three enzymes myoadenylate deaminase, adenylosuccinate synthetase, and adenylosuccinate lyase. In this cycle, AMP is converted to IMP with formation of NH3, and IMP is then reconverted to AMP. Myoadenylate deaminase deficiency produces a relatively benign disorder of muscle... 

Myoadenylate deaminase (or AMP deaminase) deficiency is a relatively benign muscle disorder characterized by fatigue and exercise-induced muscle aches. This disorder is presumably inherited as an autosomal recessive trait. The relationship between the exercise-induced skeletal muscle dysfunction and AMP deaminase deficiency is explained by an interruption of the purine nucleotide cycle. 

The answer is a. (Murray, pp 812—828. Scriver, pp 2537-2570. Sack, pp 97—158. Wilson, pp 287-320.) The child has Lesch-Nyhan syndrome (308000), an X-linked recessive disorder that is caused by HGPRT enzyme deficiency. HGPRT is responsible for the salvage ol purines from nucleotide degradation, and its deficiency elevates levels ol PRPP, purine synthesis, and uric acid. PRPP is also elevated in glycogen storage diseases due to increased amounts of carbohydrate precursors. 

One genetic disorder which should be singled out is Lesch-Nyhan syndrome, an X-linked disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransfera.se. an enzyme which is involved in salvaging purine ba.ses for resynthesis to purine nucleotides. The... 

I. H. Fox, Metabolic basis for disorders of purine nucleotide degradation Metabolism. 30 616 (1981). 

Free purines can be salvaged and rebuilt into nucleotides. Genetic deficiencies in certain salvage enzymes cause serious disorders such as Lesch-Nyhan syndrome and ADA deficiency. 

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