Pyrimidines disorders

Simmonds HA (1996) Purine and pyrimidine disorders. In Blau N, Duran M, Blaskovics ME (eds) Physician s Guide to the Laboratory Diagnosis of Metabolic Diseases. Chapman Hall Medical, London, pp 341-357... 

Shnmonds HA. Purine and pyrimidine disorders. In Holton JB, ed. The Inherited Metabolic Diseases. Philadelphia Churchill Livingstone, 1994 297-350. 

Table E.4. Purine/pyrimidine disorders associated with abnormal metabolite levels (from [7]) ...

In an emergency clinicians can consult the appropriate reference guide to laboratories diagnosing purine and pyrimidine disorders locally. 

It is impossible to provide an adequate coverage of disorders with the wide clinical spectrum of presentation exemplified by the purine and pyrimidine disorders listed here in a book aiming at providing a summary to assist clinicians in the rapid diagnosis of all genetic metabolic disorders. The reader is referred to specific and comprehensive reviews (referenced in [1], which include references to earlier work in the particular disorder of interest). 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

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). 

Ethyl l-(arylimino)-l//-pyrido[l,2-c]pyrimidine-3-carboxylates exhibited anti-inflammatory activities in the carrageenan mouse paw edema model <2001JME1011>. 2-Arylimino-2,3,6,7-tetrahydro- <2000W020/058308> and 2-aryloxy-6,7-dihydro-477-pyrimido[6,l- ]isoquinolin-4-ones <2000W020/0558309> were patented as PDE inhibitors and as useful agents for treatment of respiratory disorders, respectively. 

Antimetabolites. This class of drugs includes purine, pyrimidine, and folic acid analogs that have been successfully used to treat various carcinomas, autoimmune diseases, and dermatological disorders such as psoriasis. Because of their structural similarities to normal components of DNA and RNA synthesis, they are capable of competing with the normal macromolecules and alkylating biological nucleophiles. 

Problems caused by an imbalance of the concentrations of deoxynncleotides In experiments with replicating cells in cnltnre, if the cnltnre medium contains an imbalance in the concentrations of the four deoxynucleotides, especially an imbalance between the pyrimidine deoxynncleotides, the mntation rate increases markedly. Dehcien-cies or low activities of at least three enzymes can resnlt in an imbalance of the nncleotides and do, in fact, give rise to disorders (Box 20.2). 

Other examples of pyrimidine-based pharmaceuticals include busipirone 1130, used to treat anxiety disorders, piribedil 1131 used for Parkinson s disease, epirizole 1132, a nonsteroidal antinflammatory (NSAID), pyrimethamine 1133, an antimalarial, minoxidil 1134, which is used for treating alopecia (male baldness), primidone 1135, which is used as an antiepileptic agent, and pyrantel pamoate 1136, which is used as an antiparasitic. 

Sumi S, Kidouchi K, Ohba S et al. Automated screening system for purine and pyrimidine metabolism disorders using high performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1995 672 233-239. 

Screening for Disorders of Purine and Pyrimidine Metabolism Using HPLC-Electrospray Tandem Mass Spectrometry... 

Concentrations of metabolites outside the reference ranges may constitute a typical pattern indicating the presence of an inborn error of purine or pyrimidine metabolism. However, altered excretions of purine and pyrimidines may also be a secondary phenomenon due to the presence of other metabolic disorders, such as a deficiency of the urea cycle [15]. Increased concentration of a single metabolite or combinations of metabolites may also result from bacterial contamination, sample conditions, medication, or dietary compounds [6]. 

Ito T, van Kuilenburg ABP, Bootsma AH, Haasnoot AJ, van Cruchten AG, Wada Y, van Gen-nip AH (2000) Rapid screening of high-risk patients for disorders of purine and pyrimidine metabolism using HPLC-electrospray tandem mass spectrometry of liquid urine or urine-soaked filter paper strips. Clin Chem 46 445-452... 

This four-volume set has good chapters on disorders of amino acid, porphyrin, and heme metabolism. See also the chapters on inborn errors of purine and pyrimidine metabolism. 

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