Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mutant hypoxanthine-phosphoribosyltransferase (EC 2.4.2.8.) from a patient with gout is examined. The activity of the erythrocyte enzyme is about 5% of normal in this case. Immunoprecipitation studies using antiserum against highly purified human hypoxanthine-phosphoribosyltransferase reveal that the patient's erythrocytes contain a normal amount of cross-reacting material. The mutant enzyme has an altered net charge as shown by preparative isoelectric focusing (pI values of 5.75 and 4.55). The influence of chemical modification on enzymic activity was studied using a number of different reagents directed against sulfhydryl-, amino-, and guanidino-groups. Compared with normal hypoxanthine-phosphoribosyltransferase the mutant enzyme shows a generally lowered susceptibility to active site-directed inhibition. It is concluded that the patient's enzyme is the product of a structural mutation.
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PMID:Partial deficiency of hypoxanthine-phosphoribosyltransferase:evidence for a structural mutation in a patient with gout. 11 May 99

In the majority of patients with gout and excessive uric acid production, underlying enzyme abnormalities have not been identified. In the present study, measurement of both the rate of generation and concentration of phosphoribosylpyrophosphate (PP-ribose-P) and the concentration of ribose-5-phosphate in cultured cells were undertaken to establish a classification of purine overproducers to direct study of additional enzyme defects. Fibroblasts were cultured from 24 individuals assigned to 4 groups: group 1, 5 normal controls; group 2, 5 patients with gout and normal dialy urinary uric acid excretion (gouty controls); group 3, 7 patients with well-defined enzyme abnormalities and excessive urinary acid excretion (4 with hypoxanthine-guanine phosphoribosyltransferase deficiency and 3 with excessive PP-ribose-P synthetase activity); and group 4, 7 patients with gout and excessive uric acid excretion but without grossly abnormal activities of the above enzymes in erythrocyte lysates. In all 14 fibroblast strains from patients showing excessive production of uric acid (groups 3 and 4), rates of purine synthesis de novo and PP-ribose-P concentrations exceeded values for cells from control groups. Cells from group 3 patients with hypoxanthine-guanine phosphoribosyltransferase deficiency showed normal PP-ribose-P generation, while those with excessive PP-ribose-P synthetase activity demonstrated increased generation of this regulatory substrate. All strains from group 3 patients had normal ribose-5-phosphate concentrations. Five cell strains from group 4 patients showed one of the two patterns of abnormalities in these measurements seen in strains from group 3 patients: two resembled hypoxanthine-guanine phosphoribosyltransferase-deficient cells, and three resembled cells with excessive PP-ribose-P synthetase activity. Analyses of erythrocyte enzyme preparations from two of these patients in group 4 have led to identification of a kinetic variant of each enzyme as predicted from the foregoing patterns. Two additional group 4 cell lines that showed increased ribose-5-phosphate concentrations in addition to increased PP-ribose-P concentrations and generation were classified in a separate subgroup, since in the individuals excessive purine synthesis appeared to result from increases ribose-5-phosphate concentration, leading to increased availability of PP-ribose-P. No abnormality in either hypoxanthine-guanine phosphoribosyltransferase or PP-ribose-P synthetase has been found in erythrocyte preparations from one patient so classified.
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PMID:Patterns of phosphoribosylpyrophosphate and ribose-5-phosphate concentration and generation in fibroblasts from patients with gout and purine overproduction. 17 78

The purine phosphoribosyltransferases have emerged as important enzymes in the metabolic economy of the developing human. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT, EC 2.4.2.8) catalyses the conversion of hypoxanthine and guinine into their respective nucleotides. Inherited variation in HGPRT first became evident through clinical observations with the definition of the Lesch-Nyhan syndrome. In this disorder, HGPRT activity in erythrocytes is almost zero, although the fact that sensitive electrophoretic analysis reveals a tiny amount of activity suggests that a protein of altered structure is present. Furthermore, this variant enzyme has been activated by manipulation in the presence of small amounts of normal enzyme. Nevertheless, no cross-reacting material could be detected in lysates of red cells or fibroblasts of patients with the syndrome when tested with antiserum prepared in rabbits to normal erythrocyte HGPRT. We have tested for the presence of cross-reacting material in 18 patients, and all were negative. More HGPRT variants are coming to light. Most of the patients have renal stone disease or gout but no other feature of the Lesch-Nyhan syndrome. In one family four affected males displayed about 5% of normal activity, and the enzyme migrated electrophoretically more rapidly than normal. Cross-reacting material could not be demonstrated in erythrocyte lysates, although it was clear that a variant protein was present. A boy with renal stone disease has been found to have about 1% of normal erythrocyte activity of HGPRT. Cross-reacting material was found in his erythrocytes. The data indicate that mutations which produce diminished enzyme activity in this protein with a distinct subunit structure may or may not so alter the tertiary state of the protein that immunoreactive sites are no longer available to antibody prepared against the normal enzyme. So far whenever a variant normal HGPRT has been found there has been an identifiable clinical illness. The different forms of illness provide for correlation of molecular structure and function in man.
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PMID:Genetic heterogeneity at the locus for hypoxanthine-guanine phosphoribosyltransferase. 30 34

Unknown concentrations of orotic acid can be measured by competition with a known amount of [carboxyl-14C]orotic acid for reaction with a limiting amount of phosphoribosylpyrophosphate in the presence of orotate phosphoribosyltransferase and orotidine monophosphate decarboxylase. The dilution of the specific radioactivity in the product 14CO2 is a sensitive and accurate measure of the amount of orotic acid present in the sample. Orotidine can also be determined after hydrolytic cleavage to orotic acid. The method was used to measure orotic acid and orotidine in urine samples from newborns, healthy controls and patients with gout or deficiency of hypoxanthine-guanine phosphoribosyltransferase receiving allopurinol. Urinary excretion of orotic acid and orotidine in newborns was similar whether the infants were breast-fed or received milk powder. The excretion of orotidine was increased in all patients receiving allopurinol. After allopurinol administration orotic acid excretion was increased in gouty patients but close to normal values in patients with deficiency of hypoxanthine-guanine phosphoribosyltransferase. The results are discussed in relation to the mechanism by which allopurinol inhibits pyrimidine metabolism.
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PMID:The urinary excretion of orotic acid and orotidine, measured by an isotope dilution assay. 36 97

A family is reported where four males have developed hyperuricemia, renal damage and, except for the youngest person affected, gout at an early age. The disease appears to be inherited as an X-linked recessive metabolic error. Clinically the patients have developed classical, tophaceous gout before the age of 25 and have suffered repeated attacks of renal colic. Renal tubular damage with decreased ability to concentrate and acidify urine was seen in a family member of only 16 years of age. Progressive renal failure seems to develop slowly. None in the family has shown neurologic symptoms, and two of the four affected men are apparently of at least average intelligence, two slightly below average. One female carrier has repeatedly passed uric acid stones. Studies of the red blood cell lysate have shown a normal activity of enzyme hypoxanthine phosphoribosyltransferase, and an increased level of adenine phosphoribosyltransferase. Skin fibroblasts from affected family members grew normally in the presence of 8-azaguanine. Administration of azathioprine to the patients did not decrease their serum uric acid levels. This is the first family described with this type of disorder of the purine metabolism.
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PMID:Recessive X-linked hyperuricemia with gout and renal damage, normal activity of hypoxanthine phosphoribosyltransferase and resistance to azaguanine. 42 44

In several patients with different degrees of HPRT deficiencies, residual activities have been determined in both lysed and intact erythrocytes. No close correlation could be found between the degree of HPRT deficiency and the severity of the clinical expression. Unless HPRT activity in both intact and lysed erythrocytes was below detection level, the residual activity in intact red blood cells was higher than in lysates. Tissue-specific heterogeneity was illustrated with a patient suffering from X-linked gout. Lysates from erythrocytes, leukocytes, and cultured fibroblasts showed 1%, 8%, and 100% of normal HPRT activity, respectively. Characterization of the erythrocyte and fibroblast HPRT from this patient showed no kinetic abnormalities. However, there was a decreased heat stability. It is concluded that for a better understanding of the pathophysiology in HPRT deficiency studies on nucleated cells from the different tissues are needed.
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PMID:Molecular and tissue-specific heterogeneity in HPRT deficiency. 57 18

Some physicochemical properties of HGPRTase were studied in hemolysates and fibroblasts of a gout patient with partial deficiency of this enzyme. In comparison to normal HGPRTase the mutant enzyme from erythrocytes was found to have an elevated apparent Km-value for hypoxanthine and guanine and a lower Km-value for PRPP. The patient's enzyme from erythrocytes is more stable at +4 degrees C and +80 degrees C, the enzyme from fibroblasts more labile than that of controls. The inhibition of the mutant enzyme by some purine nucleosides and -nucleotides differed from that found in controls. No evidence was shown for an inhibitor of the patient's HGPRTase from erythrocytes. Ultracentrifugation of hemolysate in a saccharose gradient revealed no difference in the sedimentation coefficient.
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PMID:[Properties of hypoxanthineguanine-phosphoribosyltransferase (HGPRTase) in a gout patient with partial deficiency of this enzyme (author's transl)]. 76 46

A patient is reported with X-linked hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency. He had gout but no neurological symptoms. The patient had negligible HGPRT activity as determined by thin layer chromatography and liquid scintillation counting. Autoradiography of fibroblast cultures revealed no uptake of -3H-hypoxanthine. His mother and two sisters were shown to be heterozygotes.
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PMID:X-linked hypoxanthine-guanine phosphoribosyltransferase deficiency without neurological disorders. a report of a family. 113 86

Molecular characterization of in vivo mutation at the human hypoxanthine phosphoribosyltransferase (hprt) locus has revealed a broad spectrum of mutation, both with regard to germ-line mutation in Lesch-Nyhan and gout patients, and somatic mutation in 6-thioguanine resistant T-lymphocytes from healthy individuals. The pattern of missense mutation shows a non-random distribution with a preferential location to codons for amino acids which are identical in human and the two parasites Schistosoma mansoni and Plasmodium falciparum. Although these 'evolutionary conserved' amino acids account for only 32% of the amino acids in the human hprt protein, they are involved in 76% of the missense mutations at the hprt locus in human T-lymphocytes, 67% in Lesch-Nyhan patients (with severe hprt-deficiency), but only 43% in gout patients (with partial hprt deficiency). This observation supports the notion that evolutionary conserved amino acids constitute functionally important sites in the hprt enzyme, and missense mutations affecting these amino acids will often lead to complete loss of enzyme activity. Substitutions of 'non-conserved' amino acids cause less severe hprt-deficiency (as seen in the gout patients), or may even escape clinical diagnosis. These considerations are important for the understanding of structure-activity relationships in the hprt protein, possible differences between hprt mutational spectra in germ-line and somatic cells, and the mutational spectra induced by specific exogeneous mutagens.
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PMID:Missense mutations and evolutionary conserved amino acids at the human hypoxanthine phosphoribosyl-transferase locus. 130 34

Hypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8) is a purine salvage enzyme that catalyses the conversion of hypoxanthine and guanine to their respective mononucleotides. Partial deficiency of this enzyme can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes the Lesch-Nyhan syndrome which is characterised by hyperuricaemia, mental retardation, choreoathetosis and compulsive self-mutilation. The HPRT-encoding gene is located on the X chromosome in the region q26-q27 and consists of nine exons and eight introns totalling 57 kb. This gene is transcribed to produce an mRNA of 1.6 kb, which contains a protein encoding region of 654 nucleotides. With the advent of increasingly refined techniques of molecular biology, it has been possible to study the HPRT gene of individuals with a deficiency in HPRT activity to determine the genetic basis of the enzyme deficiency. Many different mutations throughout the coding region have been described, but in the absence of precise information on the three-dimensional structure of the HPRT protein, it remains difficult to determine any consistent correlation between the structure and function of the enzyme.
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PMID:A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. 148 31


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