Nucleotide disorders

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

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). 

Up to now, 101 different mutations have been identified (Fig. 11) (B29, H18). Most of the variant enzymes are produced by one or two missense mutations in the structural gene. G6PD Vancouver is caused by three nucleotide substitutions (M4). Although nucleotide deletions or nonsense mutations are common molecular abnormalities that may cause a variety of genetic disorders, they are rare in G6PD deficiency cases. Nucleotide deletions have been found in only five variants... 

Braun, P. E., Lee, J. and Gravel, M. 2, 3 -cyclic nucleotide 3 -phosphodiesterase Structure, biology and function. In R. A. Lazzarini (ed.), Myelin biology and disorders. San Diego, CA Elsevier Academic Press, 2004,499-522. 

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... 

Triplet repeat disorders are characterized by 3-base-pair nucleotide repeats that lie in either coding or noncoding regions and give rise to a multitude of different... 

The conclusion that the significance of the pentose phosphate shunt may be in keeping NADP in its reduced state and furnishing pentose phosphates for biosynthesis, rather than G-6-P utilization, is closely confirmed by the fact that individuals deficient in or lacking G-6-PDH activity suffer from a number of metabolic disorders due to lack of NADPH2 generation and nucleotide depletion. 

The properties of some GPCR variants are reviewed with respect to what can be learned from prototypical receptors, beginning with rhodopsin. The examples selected are summarized in Table 7.1 with respect to the common single-nucleotide polymorphisms (SNPs) that cause the disorders. 

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