Disorders of purine and pyrimidine metabolism

UCSD School of Medicine, Department of Pediatrics, 0830, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.63). 09/2005; 86(1-2):25-33. DOI: 10.1016/j.ymgme.2005.07.027
Source: PubMed


The disorders of purine and pyrimidine metabolism are unusual in their variety of clinical presentations and in the mechanisms by which these presentations result from the fundamental mutations. In the most common of the hyperuricemic metabolic disorders, deficiency of hypoxanthine phosphoribosyl transferase, the fundamental deficiency in the activity of an enzyme of purine salvage leads to enormous overactivity of de novo pathway of purine synthesis and purine overproduction. In the other hyperuricemic disorder, that of phosphoribosylpyrophosphate synthetase, mutation leads not to deficient activity, but superactivity of the enzyme in an early stage of the synthetic pathway leading to overproduction. A number of disorders of purine metabolism lead to immunodeficiency; these include adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. Marked susceptibility to infection is also seen in disorders of pyrimidine metabolism, classically in orotic aciduria, but also in pyrimidine nucleotide depletion syndrome. Orotic aciduria is a disorder of pyrimidine nucleotide synthesis, UMP synthetase deficiency, in which a single gene mutation can cause deficiency of two enzyme activities, orotic phosphoribosyltransferase and orotidine monophosphate decarboxylase which reside in a single protein. Pyrimidine degradation defects, dihydropyrimidine dehydrogenase and dihydropyrimidinase deficiencies leading to developmental delay are detected by analysis of the urine for pyrimidines and dihydropyrimidines. The recent discovery of aminoimidazolecarboxamideriboside deficiency points up the utility of simple colorimetric tests in bringing to light disorders of metabolism. Adenylosuccinatelyase deficiency and molybdenum cofactor deficiency illustrate the same point.

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    • "Despite the adaptations to diving and the physiological adjustments during diving, when oxygen reserves are depleted, blood and tissues become hypoxic and ATP hydrolysis results in the accumulation of xanthine and uric acid, purine metabolites which can not be recycled (Janssen, 1993; Elsner, 1999). An alternative mechanism for maintenance of the purine nucleotide pool is the salvage pathway, which conserves energy and uses preformed bases from degradation of nucleic acids and from the diet (Alexiou and Leese, 1992; Carver, 1999; Moriwaki et al., 1999; Nyhan, 2005; Zhang et al., 2008). Nucleotides such as inosine 5 ′ -monophosphate (IMP), guanosine 5 ′ -monophosphate (GMP), and adenosine 5 ′ -monophosphate (AMP) can be regenerated by this pathway (Carver, 1999; Zhang et al., 2008). "
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    ABSTRACT: Aquatic and semiaquatic mammals have the capacity of breath hold (apnea) diving. Northern elephant seals (Mirounga angustirostris) have the ability to perform deep and long duration dives; during a routine dive, adults can hold their breath for 25min. Neotropical river otters (Lontra longicaudis annectens) can hold their breath for about 30 s. Such periods of apnea may result in reduced oxygen concentration (hypoxia) and reduced blood supply (ischemia) to tissues. Production of adenosine 5′-triphosphate (ATP) requires oxygen, and most mammalian species, like the domestic pig (Sus scrofa), are not adapted to tolerate hypoxia and ischemia, conditions that result in ATP degradation. The objective of this study was to explore the differences in purine synthesis and recycling in erythrocytes and plasma of three mammalian species adapted to different environments: aquatic (northern elephant seal) (n = 11), semiaquatic (neotropical river otter) (n = 4), and terrestrial (domestic pig) (n = 11). Enzymatic activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) was determined by spectrophotometry, and activity of inosine 5′-monophosphate dehydrogenase (IMPDH) and the concentration of hypoxanthine (HX), inosine 5′-monophosphate (IMP), adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP), ATP, guanosine 5′-diphosphate (GDP), guanosine 5′-triphosphate (GTP), and xanthosine 5′-monophosphate (XMP) were determined by high-performance liquid chromatography (HPLC).TheactivitiesofHGPRTandIMPDHandtheconcentrationofHX,IMP,AMP,ADP, ATP, GTP, and XMP in erythrocytes of domestic pigs were higher than in erythrocytes of northern elephant seals and river otters. These results suggest that under basal conditions (no diving, sleep apnea or exercise), aquatic, and semiaquatic mammals have less purine mobilization than their terrestrial counterparts.
    Frontiers in Physiology 07/2015; 6. DOI:10.3389/fphys.2015.00212 · 3.53 Impact Factor
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    • "There also are intercellular signaling pathways involving adenine or guanine metabolites , and G-proteins that require cAMP or cGMP. The importance of purines for normal brain function is highlighted by several rare inherited disorders of purine metabolism [7] [8] [9] [10]. For example , defects in purine recycling mediated by the enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt) cause the severe neurobehavioral problems of Lesch–Nyhan disease (LND). "
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    ABSTRACT: The importance of specific pathways of purine metabolism for normal brain function is highlighted by several inherited disorders, such as Lesch-Nyhan disease (LND). In this disorder, deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt), causes severe neurological and behavioral abnormalities. Despite many years of research, the mechanisms linking the defect in purine recycling to the neurobehavioral abnormalities remain unclear. In the current studies, an unbiased approach to the identification of potential mechanisms was undertaken by examining changes in protein expression in a model of HGprt deficiency based on the dopaminergic rat PC6-3 line, before and after differentiation with nerve growth factor (NGF). Protein expression profiles of 5 mutant sublines carrying different mutations affecting HGprt enzyme activity were compared to the HGprt-competent parent line using the method of stable isotopic labeling by amino acids in cell culture (SILAC) followed by denaturing gel electrophoresis with liquid chromatography and tandem mass spectrometry (LC-MS/MS) of tryptic digests, and subsequent identification of affected biochemical pathways using the Database for Annotation, Visualization and Integrated Discovery (DAVID) functional annotation chart analysis. The results demonstrate that HGprt deficiency causes broad changes in protein expression that depend on whether the cells are differentiated or not. Several of the pathways identified reflect predictable consequences of defective purine recycling. Other pathways were not anticipated, disclosing previously unknown connections with purine metabolism and novel insights into the pathogenesis of LND. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Genetics and Metabolism 03/2015; 114(4). DOI:10.1016/j.ymgme.2015.02.007 · 2.63 Impact Factor
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    • "Pyrimidine metabolism, along with purine pathway, fulfill a variety of functions in the metabolism of the cell, of which the most important are, regulation of energy conservation and transport, formation of coenzymes and active intermediation in phospholipid and carbohydrate metabolism (GENNIP, 1999). Nyhan postulated that the catabolic pathways for pyrimidine have caused specific enzymatic deficiencies in a number of patients, most of them with mental retardation, seizures, or both (Nyhan, 2005). Degradation disorders of pyrimidine can be presented as anemia, neurological deficits, or devastating multisystem mitochondrial disorder (Anne Simmonds and Gennip, 2003). "
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    ABSTRACT: About 1% of scorpion stings in Iran have been reported in cities and more than 5% in rural areas. The genus Hemiscorpous lepturus belongs to the family Hemiscorpiidae that is endemic in the south-western province of Khoozestan and other parts of western Iran. Although this species is responsible for only 10% of the reported stings, it is also responsible for 95% of mortalities. The heavy cytotoxic and neurotoxic venomous effects of scorpion sting may cause serious disorders such as erythema, purpuric changes, bulla, necrosis and ulcer, either alone or in combination. The toxic effects of Hemiscorpius lepturus venom cause vast changes in both primary and secondary metabolites of the victim, which finally lead to death if not treated early enough. Metabolomics is the systematic study of chemical fingerprints resulting from cytotoxic and pathogenic reactions of cells. We studied the toxic mechanism of Hemiscorpius lepturus venom on metabolome profiling of the victims along with biochemical pathways, organs and physiological detectable effects of this venom by the help of (1)H NMR. Our results showed that pyrimidine, histidine and tyrosine metabolisms, and steroid hormone biosynthesis were the most affected pathways. The major action of the crude venom is on the pancreas, and also on the nerve cells, spleen and mitochondria, causing acute seizures, which resemble the early markers of myocardial injury and seizure disorders. Copyright © 2014. Published by Elsevier Ltd.
    Toxicon 12/2014; 94. DOI:10.1016/j.toxicon.2014.12.003 · 2.49 Impact Factor
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