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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
Neurologic dysfunction in this disease has been attributed to deficiency of the products of the PNP reaction see (Figure 70.3) hypoxanthine and guanine. These are, of course, the subjects of the hypoxanthine guanine phosphoribosyltransferase (HPRT) reaction. In this sense, there are some similarities to the neurology of Lesch-Nyhan disease, but some notable differences include the abnormalities in behavior in HPRT deficiency.
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.
Purine, pyrimidine and porphyria disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
This disorder belongs to a group of conditions known as purine metabolic disorders. It is a rare and devastating genetic disorder associated with an almost complete absence of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which metabolises hypoxanthine and guanine to uric acid, the nucleotides IMP and GMP. The disorder is characterised by increased levels of uric acid in the blood and urine and by the absence of the enzyme HPRT.
The latest automated docking technologies for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
In other interesting work, Scafuri et al [61] applied a reverse docking protocol to generate a list of human proteins potentially bound by apple phenolic compounds with colorectal cancer chemo-preventive effects. They found that the proteins guanosine triphosphatase, guanosine 5′-monophosphate oxidoreductase, and hypoxanthine-guanine phosphoribosyltransferase might be the key targets for these compounds. In other work, Maccari et al [62] used a target fishing procedure based on shape similarity, reverse docking, and consensus score to investigate the mode of action of macrocyclic amidinoureas previously identified as antifungal agents. They found that chitinase represents at least one of the main targets of the studied macrocyclic amidinoureas. In other work, Lee and Kim [63] developed the fully automated web tool CRDS (Consensus Reverse Docking System) for target fishing. This tool predicts potential interaction sites for a given drug. In a search, the web server provides the list of top 50 predicted interaction sites, docking conformations, 10 most significant pathways, and the distribution of consensus scores based on the combination of three different scoring functions.
Diagnosis and management of tumor lysis syndrome.
Published in Journal of Community Hospital Internal Medicine Perspectives, 2020
Isha Puri, Deep Sharma, Krishna S. Gunturu, Andaleeb A. Ahmed
A: Allopurinol is the agent of choice in intermediate-risk patients. The usual dose of allopurinol is 100 mg/m2 every 8 h (maximum 800 mg per day) in adults and 50 to 100 mg/m2 every 8 h (maximum 300 mg/m2 per day) or 10 mg/kg per day in divided doses every 8 h in children [6,7]. Dose of allopurinol must be reduced in the setting of acute kidney injury or concomitant administration of azathioprine or mercaptopurine. Intravenous allopurinol must be given in patients who cannot tolerate oral route (dose: 200 to 400 mg/m2 per day, in one to three divided doses (maximum dose 600 mg per day). Xanthine nephropathy and nephrolithiasis is a rare complication of allopurinol therapy especially in patients with deficiencies in the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT)[10].
Late diagnosis of Lesch–Nyhan disease complicated with end-stage renal disease and tophi burst: a case report
Published in Renal Failure, 2020
Cahyani Gita Ambarsari, Daffodilone Cahyadi, Lenny Sari, Oryza Satria, Felly Sahli, Thyrza Laudamy Darmadi, Agustina Kadaristiana
Lesch–Nyhan disease (LND, OMIM #300322) is the most severe manifestation of hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme deficiency, which is characterized by overproduction of uric acid, neurological disorders, and behavioral problems [1,2]. LND is a rare X-linked recessive genetic disorder (Xq26.2–q26.3) that commonly affects males [3]. In LND, mutations to the HPRT1 gene result in diminished activity of HPRT, an enzyme that plays a central role in the generation of purine nucleotides in the purine salvage pathway, resulting in increased uric acid levels [1]. Although first recognized in 1964, LND is commonly misdiagnosed, as patients with LND are assumed to have early-onset cerebral palsy during the course of the disease [2,4]. Late diagnosis of LND may result in severe morbidity, as with the present case. Here, we report a male who was diagnosed with LND at the age of 15 years in Indonesia. LND cases have never been reported in Indonesia. This case is probably the second report of LND with chronic renal failure. Notably, this case report provides detailed information about the clinical manifestations of LND, such as spontaneous tophi bursts.