Pyrimidine metabolic disorders

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. 

C9H16N3O14P3 483.158 Prod, by Leishmania and Streptomyces griseus found in erythrocytes and lymphocytes. Enzyme inhibitor. Implicated in purine and pyrimidine metabolism disorders. Contracts arteries. Cryst. powder (as Na salt). 

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. 

A number of these enzymes are expressed in other tissues as well but cause a notable deficiency predominantly in red blood cells because of the life span of the erythrocyte after the loss of protein synthesis. Once an enzyme is degraded or otherwise becomes nonfunctional, it cannot be replaced by new or other compensating proteins because of the lack of nucleus, mitochondria, ribosomes, and other cell organelles in mature red cells. Disorders have been described in the EMP, HMP, Rapoport-Luebering cycle, the glutathione pathway (Figure 21-9), purine-pyrimidine metabolism and methemoglobin reduction. 

Certain metabolites of the pyrimidine pathway are excreted in excess of the normal in inherited metabolic disorders of the urea cycle. They include orotic acid, uridine, and uracil. Of these substances, only uracil is a normal constituent of urine, the other two either being absent or present in very small amount. They are readily detected qualitatively as dark bands at the appropriate Rf values when a paper chromatogram of the urine is examined under ultraviolet light. They may be estimated by an ion exchange method similar to that for urinary pseudouridine (R13). 

Table 41.4. Gene Disorders in Purine and Pyrimidine Metabolism...

Although it is still not clear which potential mechanism best explains the arrested development of immune cells, it is clear that elevated levels of adenosine and deoxyadenosine are toxic. The biochemical disorders of purine and pyrimidine metabolism discussed in this chapter are summarized in Table 41.4. 

Webster DR, Becroft DMO, Van Gennip AH, Van Kuilenberg ABR Hereditary orotic aciduria and other disorders of pyrimidine metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, vol II, 8th Ed. New York McGraw-Hill, 2001 2663-2702. 

Isotachophoresis has already been successfully applied to the analysis of urine of persons exposed to styrene, toluene, and xylene, for the contents of mandelic, phenylglyoxylic, hippuric and methylhippuric acids . For the clinical disgnostic of inborne metabolic disorders of purines and pyrimidines, it has been elaborated permitting the identification of different inborne disorders of the metabolism of these bases by the contents of characteristic metabolites excreted in urine (adenine, uric acid, xanthin, deoxyinosin, deoxyguanosin etc.). 

B6 Beardmore, T. D. and Kelley, W. N. Ultraviolet-absorbing compounds in urine from patients with hereditary disorders of purine and pyrimidine metabolism. Clin. Chem., 17, 795 (1971)... 

A.H. van Gennip, D.Y. van Noordenburg-HirLstra, P.K. de Bree and S.K. Wadman, Two-dimensional thin-layer chromatography for the screening of disorders of purine and pyrimidine metabolism, Clin. Chim. Acta, 86 7-20 (1978). 

Another extension of the scope is represented by studies on the molecular genetics of the genes controlling different purine metabolic pathways. Por the first time papers from the recombinant DNA field are included. It was hoped that this meeting would also see more contributions from the lesser known field of pyrimidine metabolism and the equally important contributions on the overall control at the cellular level, together with new developments in the field of the known inherited disorders of purine metabolism, will stimulate further work in these interesting areas. 

Valentine, W.N., Paglia, DJ3., 1980. Erythroeyte disorders of purine and pyrimidine metabolism. Hemoglobin 4, 669—681. 

Inherited disorders of purine and pyrimidine metabolism exhibit a wide variety of clinical symptoms, including anemia, immunodeficiency, kidney stones, seizures, mental retardation, autism and growth retardation. Refer to Chap. 23 and ref. 7 for further details. 

The broad spectrum of clinical presentation highlights the importance of particular steps in purine and pyrimidine metabolism to different cells and tissues and should have assisted in the development of appropriate treatment. Unfortunately, only three of the nineteen disorders described can be treated successfully hereditary orotic aciduria with life-long uridine, 2,8-di-hydroxyadenine lithiasis with allopurinol. ADA deficiency is treatable by bone marrow transplantation (BHT), or enzyme replacement with polyethylene glycol (PEG)-ADA, but the cost is prohibitive. Er/throcyte-encapsu-lated ADA is effective and less expensive. Oral ribose is reportedly beneficial in myoadenylate deaminase deficiency [1, 4] and also in adenylosucci-nase deficiency [1, 5]. PNP deficiency is also treatable by BMI. 

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). 

Adam T, Fairbanks LD, Cevcic J, Bartack P. Capillary elettrophoresis for detection of inherited disorders of purine and pyrimidine metabolism. Clin Chem 1999 45 2086-2093... 

Ito, T., van Kuilenburg, A.B.B., Bootsma, A.H., Haasnoot, A.J., van Crutchen, A., Wada, Y. and van Gennip, A.H., 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 (2000). 

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. 

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. 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

Orotidine 5 -phosphate decarboxylase (ODCase, E. C. 4.1.1.23) catalyzes the decarboxylation of orotidine 5 -phosphate (OMP) to form uridine 5 -phos-phate in the sixth and final step of pyrimidine biosynthesis (Fig. 1) [1]. The discovery of ODCase in 1954 followed the identification, three years earlier, of orotic acid as the metabolic precursor of nucleic acids [2, 3]. ODCase is a distinct, monofunctional polypeptide in bacteria and fungi, whereas in mammals it combines with orotate phosphoribosyltransferase (OPRTase) to form the bifunctional enzyme UMP synthase. Human deficiencies in either OPRTase or ODCase activity result in an autosomal recessive disorder called hereditary orotic aciduria [4]. The disease is characterized by depleted levels of pyrimidine nucleotides in the blood and by the appearance of crystalline... 

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