Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman

García‐Pavía, Pablo; Torres, Rosa J.; Rivero, Manuel Fajardo; Ahmed, Maqbool; García-Puig, Juan; Becker, Michael A.

doi:10.1002/art.11058

Cited by 30 publications

(17 citation statements)

References 51 publications

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“…These variant forms of PRPP synthase have increased activity primarily because of their reciprocal effects on allosteric regulation by ADP and P i , namely, reduced inhibition by the former and increased stimulation by the latter (72,123). Studies of these PRPP synthase mutant variants have proven valuable in the elucidation of the allosteric regulation of the enzyme, and we shall return to a further description of them in the section "Regulation of PRPP Synthase Activity.…”

Section: Class I Prpp Synthasesmentioning

confidence: 99%

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

169

187

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SUMMARY Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP → PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds. PRPP is utilized in the biosynthesis of purine and pyrimidine nucleotides, the amino acids histidine and tryptophan, the cofactors NAD and tetrahydromethanopterin, arabinosyl monophosphodecaprenol, and certain aminoglycoside antibiotics. The participation of PRPP in each of these metabolic pathways is reviewed. Central to the metabolism of PRPP is PRPP synthase, which has been studied from all kingdoms of life by classical mechanistic procedures. The results of these analyses are unified with recent progress in molecular enzymology and the elucidation of the three-dimensional structures of PRPP synthases from eubacteria, archaea, and humans. The structures and mechanisms of catalysis of the five diphosphoryltransferases are compared, as are those of selected enzymes of diphosphoryl transfer, phosphoryl transfer, and nucleotidyl transfer reactions. PRPP is used as a substrate by a large number phosphoribosyltransferases. The protein structures and reaction mechanisms of these phosphoribosyltransferases vary and demonstrate the versatility of PRPP as an intermediate in cellular physiology. PRPP synthases appear to have originated from a phosphoribosyltransferase during evolution, as demonstrated by phylogenetic analysis. PRPP, furthermore, is an effector molecule of purine and pyrimidine nucleotide biosynthesis, either by binding to PurR or PyrR regulatory proteins or as an allosteric activator of carbamoylphosphate synthetase. Genetic analyses have disclosed a number of mutants altered in the PRPP synthase-specifying genes in humans as well as bacterial species.

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Section: Class I Prpp Synthasesmentioning

confidence: 99%

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

169

187

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“…Mutations in PRPS1 cause a wide variety of disorders that include: (i) PRS-I superactivity (MIM 300661), which results in purine overproduction causing hyperuricemia and hyperuricosuria with infantile or early childhood onset of gout, and with neurodevelopmental abnormalities, which may include intellectual disability, ataxia, hypotonia, delayed motor development, arreflexia, and/or sensorineural deafness (4)(5)(6)(7)(8); (ii) Nonsyndromic sensorineural hearing impairment (DFNX1, formerly DFN2, MIM 304500) of prelingual or postlingual onset (9-13); (iii) Charcot-Marie-Tooth disease-5 (CMTX5, also known as Rosenberg-Chutorian syndrome, MIM311070), which may include ataxia, hypotonia, loss of deep tendon reflexes, early-onset hearing impairment, and optic neuropathy (13-15); (iv) Arts syndrome (MIM 301835), which comprises the clinical signs of CMTX5 plus intellectual disability, delayed motor development, and increased susceptibility to infections of the upper respiratory tract, which can lead to an early death (16); and (v) A recently described very severe condition that associates prenatal growth restriction, dysmorphic facial features, short stature, intellectual disability, spastic…”

mentioning

confidence: 99%

Mutations in PRPS1 causing syndromic or nonsyndromic hearing impairment: intrafamilial phenotypic variation complicates genetic counseling

et al. 2015

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“…29) Overactivity of PRPS leads to generating a great of PRPP and subsequently excessive producing uric acid, in association with hyperuricemia and gout. 30) PRPPAT is the rate-limiting enzyme in the biosynthesis of uric acid. The elevated activity and/or concentration of PRPPAT and the increase in the affinity of PRPPAT binding to PRPP reduce the sensitive of feedback inhibition on purine nucleoside, resulting in overproduction of uric acid.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of 3,5,2′,4′-Tetrahydroxychalcone on Production of Uric Acid in Hypoxanthine-Induced Hyperuricemic Mice

Niu

Zhou

Lin

et al. 2018

Biological & Pharmaceutical Bulletin

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The mechanism of 3,5,2′,4′-tetrahydroxychalcone on lowing urate level is still unknown. Here we investigated the effects of 3,5,2′,4′-tetrahydroxychalcone on urate levels, xanthine oxidase/xanthine dehydrogenase (XOD/XDH) activities in hypoxanthine-induced hyperuricemic mice, as well as the effects of 3,5,2′,4′-tetrahydroxychalcone on the mRNA expression levels and content of phosphoribosyl pyrophosphate synthetase (PRPS), phosphoribosyl pyrophosphate amidotransferase (PRPPAT) and hypoxanthine-guanine phosphoribosyl transferase (HGPRT). Our results demonstrated that 3,5,2′,4′-tetrahydroxychalcone (1.0, 2.0, and 4.0 mg/kg) reduced the uric acid levels in serum of the hyperuricemic mice in dose-and time-dependent manners. The activities of XOD/XDH in serum and liver were also significantly inhibited by 3,5,2′,4′-tetrahydroxychalcone; In addition, 3,5,2′,4′-tetrahydroxychalcone decreased the mRNA expression of HGPRT in brain and content of PRPS and PRPPAT in liver. These findings demonstrated that 3,5,2′,4′-tetrahydroxychalcone suppresses uric acid production by affecting the critical enzymes, XOD/XDH, PRPS, PRPPAT and HGPRT in purine nucleotide metabolism.Key words 3,5,2′,4′-tetrahydroxychalcone; purine metabolism enzyme; hyperuricemia Gout and hyperuricemia are metabolic disorders associated with abnormal amounts of uric acid in the body. The overproduction of uric acid is one of the major factors in most patients with gout. Maintaining uric acid level <6 mg/dL is important for prevention of gout. Many enzymes participated in purine metabolic pathway, such as xanthine oxidase/xanthine dehydrogenase (XOD/XDH), hypoxanthine-guanine phosphoribosyl transferase (HGPRT), phosphoribosyl pyrophosphate synthetase (PRPS), and phosphoribosyl pyrophosphate aminotransferase (PRPPAT).1) The dysfunction of these enzymes increases the production of uric acid, resulting in hyperuricemia.2) Particularly, the XOD has been recognized as one of the promising targets for the treatment of hyperuricemia. Allopurinol, a potent XOD inhibitor with a purine backbone, has been used clinically for more than 50 years.3,4) However, allopurinol induces serious side effects such as renal failure, impaired hepatic function and allergic reactions, 5) limiting its clinical application. Recently, a new non-purine XOD inhibitor, Febuxostat, has been approved for management of gout in the European Union and USA. 6) But a few side effects of febuxostat have been reported, 7) such as liver function abnormalities, nausea, arthralgias, and rash. Therefore, novel alternatives to allopurinol with potent XOD inhibitory activity and less side effects are in great demand.3,5,2′,4′-Tetrahydroxychalcone is one of chalcones (Fig. 1). It has been reported to possess various pharmacological activities, such as antitumor, 8) free radical scavenging, 9) antibiosis, 10) antiulcer 11) and spasmolysis. 12) Currently, there are few reports about their inhibitory effects against the XOD activity. In a previous study, we reported that 3,5,2′,4′-tetrahydroxychalcone had an i...

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Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman

Cited by 30 publications

References 51 publications

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Mutations in PRPS1 causing syndromic or nonsyndromic hearing impairment: intrafamilial phenotypic variation complicates genetic counseling

Inhibition of 3,5,2′,4′-Tetrahydroxychalcone on Production of Uric Acid in Hypoxanthine-Induced Hyperuricemic Mice

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