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Purine nucleoside phosphorylase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
A patient with deficiency of purine nucleoside phosphorylase (PNP) (Figure 70.1) was reported in 1975 by Giblett and colleagues [1]. The girl was a five-year-old with severe deficiency of T-lymphocyte-mediated immunity. She had had a long series of infections and was found to have marked lymphopenia. Skin tests for delayed hypersensitivity were negative, and her lymphocytes failed to respond to phytohemagglutinin. On the other hand, B-lymphocyte-medicated immunity was normal, as indicated by normal levels of IgA and IgM, an elevated level of IgG and normal antibody responses to immunization. There was a small number of other patients reported [2–6], in each of whom there was selective severe T-cell deficiency. It is now clear that some patients with PNP deficiency may have abnormal B-cell function as well [7, 8]. In these patients, levels of immunoglobulins are reduced.
Primary Immunodeficiencies
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Alain Fischer, Durandy Anne, Claude Griscelli
Similarly, another purine metabolism disorder, purine nucleoside Phosphorylase (PNP) deficiency, provokes a progressive T-cell deficiency.2’ In addition, neurological abnormalities are often observed. PNP deficiency provokes the accumulation of deoxyguanosine triphosphate, which inhibits ribonucleotide reductase in T-lymphocytes. Rare diseases involving pyrimidine synthesis (oroticuria) folate metabolism (methionine synthase deficiency) or carboxylases (biotin-dependent multicarboxylase deficiency) can also lead on some occasions to T- and B-cell deficiencies.
Synergistic Combinations of Hyperthermia and Inhibitors of Nucleic Acids and Protein Synthesis
Published in Leopold J. Anghileri, Jacques Robert, Hyperthermia In Cancer Treatment, 2019
Inosine and its analogues undergo phosphorolysis by the enzyme purine nucleoside Phosphorylase. The liberated bases may then be converted to the corresponding nucleotide by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Similarly, 2′-deoxyinosine and related analogues may react with purine nucleoside Phosphorylase, the product of which (a purine base or analogue) is then converted to the corresponding ribonucleoside 5′-monophosphate. 6-Mercaptopurine (6-MP, see Figure 4) is an excellent substrate for HGPRT, resulting in the formation of 6-thioinosine-5-phosphate (T-IMP) which accumulates within the cell. This may then lead to the inhibition of several vital metabolic processes, e.g., the conversion of inosinate (IMP) to adenylosuccinate (AMPS) and then to adenosine-5′-phosphate (AMP) as well as the oxidation of IMP to xanthylate (XMP) by inosinate dehydrogenase. In addition, T-IMP may result in “pseudo-feedback inhibition” of the first committed step in the de novo pathway of purine biosynthesis. In view of these various effects, it can be appreciated that the accumulation of T-IMP (and analogues of various purine nucleotides) can cause severe metabolic disruptions and may lead to cell death.
Mechanism of biotin carboxylase inhibition by ethyl 4-[[2-chloro-5-(phenylcarbamoyl)phenyl]sulphonylamino]benzoate
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Matthew K. Craft, Grover L. Waldrop
For inhibition studies that varied ATP or biotin, initial velocities were measured as previously reported30. In brief, pyruvate kinase and lactic dehydrogenase were used to couple ADP production to NADH oxidation, which can be measured spectrophotometrically at 340 nm. For inhibition studies varying ADP, activity was determined by following the production of inorganic phosphate (Pi) using the EnzChek® Phosphate Assay Kit (Molecular Probes) according to the manufacturer’s protocol. In brief, purine nucleoside phosphorylase converts 2-amino-6-mercapto-7-methylpurine riboside to ribose 1-phosphate and 2-amino-6-mercapto-7-methylpurine in the presence of Pi. This reaction is monitored at 360 nM32. Kinetic data were collected on a Cary60 UV-Vis spectrophotometer (Agilent Technologies)
Purine metabolites can indicate diabetes progression
Published in Archives of Physiology and Biochemistry, 2022
Yogaraje Gowda C. Varadaiah, Senthilkumar Sivanesan, Shivananda B. Nayak, Kashinath R. Thirumalarao
Purines are fundamental parts of nucleotides and nucleic acids, playing numerous important roles in human physiology, disturbing tissue function, cell integrity and oxidation. Purine metabolism comprises of synthesis and degradation of purine nucleotides and regulates the level of the adenylate and guanylate pool (Dudzinska et al. 2010). In this way, it is responsible for the complete concentrations of intracellular ATP and GTP. In purine catabolism, their monophosphate forms are transformed to inosine and guanosine; purine nucleoside phosphorylase changes them to hypoxanthine and guanine, respectively (Figure 1). Xanthine oxidase (XO) and guanine deaminase are the enzymes that convert them to xanthine which is oxidized by XO to uric acid (Maiuolo et al. 2016). Serum uric acid, an end product of purine metabolism, has been shown to be associated with an increased risk of hypertension, cardiovascular disease, and chronic kidney disease. Hyperuricemia raises the risk of peripheral arterial disease, insulin resistance, and components of the metabolic syndrome (Ekpenyong and Akpan 2014). In diabetes, hyperuricemia has been associated with both micro and macrovascular complications. It is well known that purine metabolic pathway may be strongly linked with the development of diabetic microvascular complications (Xia et al. 2014).
The First Purine Nucleoside Phosphorylase Deficiency Patient Resembling IgA Deficiency and a Review of the Literature
Published in Immunological Investigations, 2019
Saba Fekrvand, Reza Yazdani, Hassan Abolhassani, Javad Ghaffari, Asghar Aghamohammadi
Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive form of primary immunodeficiency disorders characterized by T-cell immunodeficiency (cellular immunity) and variable abnormalities of humoral (B-cell) immunity (Al-Herz et al., 2014). Patients with PNP deficiency present with recurrent infections, neurologic impairment (including ataxia, developmental delay, failure to thrive, mental retardation and spasticity), malignancies, and autoimmunity (especially autoimmune hemolytic anemia) (Markert, 1991; Tabarki et al., 2003; Watson et al., 1981). PNP is one of the enzymes involved in the purine salvage pathway which reversibly converts inosine to hypoxanthine and guanosine to guanine (Markert, 1991). PNP deficient-patients have increased amounts of deoxyguanosine and deoxyinosine in plasma and urine (Grunebaum et al., 2013). Intracellular accumulation of deoxyguanosine triphosphate has a toxic effect on thymocytes of the affected patients, resulting in dysfunctional development and function of cellular immunity (Cohen et al., 1978). PNP deficiency is often fatal in the first two years of life (Fleischman et al., 1998) and hematopoietic stem cell transplantation (HSCT) is the only curative treatment for these patients (Classen et al., 2001). Herein, we report the third Iranian case with PNP deficiency with a tentative diagnosis of IgA deficiency without neurologic manifestations and a review of the literature of the previously reported patients.