Purine-Pyrimidine Metabolism

Pyrimidines and purines are the building blocks of DNA and RNA. In addition, they have a role in the formation of coenzymes and active intermediates in carbohydrate and phospholipid metabolism. 

Controversy exists concerning the cause and effect relationships between deficiencies of the enzymes adenylate kinase (AK EC 2.7.4.3) and adenosine triphosphatase (ATPase EC 3.6.1.3) and hemolytic disease. Since the consensus seems to be that there is no association, these enzymes will not be discussed here. 

Pyrimidine-5 -nucleotidases are a group of enzymes dephos-phorylating pyrimidine nucleotides to the corresponding nucleosides. The pyrimidine bases diffuse out of the erythrocyte and the phosphates are retained. Pyrimidine phosphates are present on ribosomes of erythroblasts and reticulocytes, but there are normally no pyrimidines in mature RBCs. Two cytoplasmic forms of the enzyme were identified in the erythrocyte, P5 N-1 and P5 N-2. These enzymes are encoded by different genes and have different molecular properties and substrate specificities. Since there are no known disorders associated with deficiency of P5 N-2, this enzyme will not be further discussed here. 

P5 N-1 deficiency (OMIM 266120) is a relatively common cause of nonspherocytic hemolytic anemia, and, because of the relatively mild phenotypic expression, many cases might be undetected as The disease is inher- 

After the recent identification of the gene, there have been a number of reports describing the mutations that cause P5 N-1 deficiency. To date, 23 patients have been characterized at the molecular level, identifying 14 different mutations. Four are missense, three cause aberrant splicing, two introduce a premature stop codon, and five result m a frameshift. No relationship between tlie genotype and phenotype could be estabhshed. 

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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. 

Unlike purines, pyrimidine metabolism, with the exception of the amitochon-drial protists Giardia lamblia, Trichomonas vaginalis and Tritrichomonas foetus, is... 

Fig. 3.2 Classification of "metabolism ESTs. Tentative unique genes (TUGs) from each species that clustered into the metabolism category (see Fig. 3.1J were further subdivided. Here, carbohydrate incorporates all glycoside hydrolases, lipid includes lipases, B-oxidation and steroid metabolizing enzymes, protein includes predominantly proteases and their precursors, and amino acid includes all enzymes involved in the interconversion of amino acids. Esterase includes those esterase-like enzymes with unknown substrates, and other contains those TUGs that do not sort into other categories. These include predominantly oxidoreductases and purine/pyrimidine metabolizing enzymes.

SECTION 30 AMINE, AMIDE, LACTAM, PURINE, PYRIMIDINE METABOLISM... 

Purines—Metabolism—Congresses. I.Bruyn, Chris H. M. M. De. II. Simmonds, H. Anne. III. Muller, Mathias M. IV. Series. [DNLM 1. Purine-Pyrimidine Metabolism, Inborn Errors—Congresses. 2. Purines—Metabolism— Congresses. W3 IN918RP 4th 1982p / WD 205.5.P8 1605 1982p]... 

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

AO is also effective in metabolizing a wide range of nitrogen-containing heterocycles such as purines, pyrimidines, pteridines, quinolines, and diazanaphthalenes (95). For example, phthalazine is rapidly converted to 1-phthalazinone by AO and the prodrug, 5-ethynyl-2-(l//)-pyrimidone, is oxidized to the dihydropyrimidine dehydrogenase mechanism-based inhibitor, 5-ethynyluracil, by AO (Fig. 4.40) (96). 

Sterol biosynthesis Bile acid biosynthesis C2rSteroid hormone metabolism Androgen and estrogen metabolism Nucleotide Metabolism Purine metabolism Pyrimidine metabolism Nucleotide sugar metabolism Amino sugar metabolism Amino Acid Metabolism Glutamate metabolism Alanine and aspartate metabolism Glycine, serine, and threonine metabolism... 

For the regulation of metabolic pathways metabolites are often used which are a product of that pathway. The basic strategy for the regulation is exemplified in the mechanisms employed in the biosynthetic and degradation pathways of amino acids, purines, pyrimidines, as well as in glycolysis. In most cases a metabolite (or similar molecule) of the pathway is utilized as the effector for the activation or inhibition of enzymes in that pathway. 

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. 

Febuxostat is a potent and selective inhibitor of xanthine oxidase, and thereby reduces the formation of xanthine and uric acid. No other enzymes involved in purine or pyrimidine metabolism are inhibited. In clinical trials, febuxostat at a daily dose of 80 mg or 120 mg was more effective than allopurinol at a standard 300 mg daily dose in lowering serum urate levels. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia—overproduction or underexcretion. 

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. 

Berens, R.L., Krug, E.C. and Marr, J.J. (1995) Purine and pyrimidine metabolism. In Marr, J. and Muller, M. (eds) Biochemistry and Molecular Biology of Parasites. Academic Press, New York, pp. 89-117. 

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