Disease relevance of APRT

• Distribution of mutant alleles encoding APRT deficiency among the Japanese was similar to that seen in cystic fibrosis genes among Caucasians and Tay-Sachs genes among the Ashkenazi Jews [1].
• In humans, APRT deficiency results in serious kidney illness such as nephrolithiasis, interstitial nephritis, and chronic renal failure as a result of 2,8-dihydroxyadenine (DHA) precipitation in the renal interstitium [2].
• 2,8-Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT [3].
• All the errors were due to the PCR process and not to subcloning, as shown by sequence analysis of 5 APRT-positive clones isolated from a phage genomic library [4].
• In patients with small cell bronchogenic carcinoma, enzyme levels were also determined in granulocytes, where increased APRT activity was found [5].

Psychiatry related information on APRT

• Hypoxanthine guanine phosphoribosyltransferase (HGPRT) and adenosine phosphoribosyltransferase (APRT) were examined from 11 individuals with Gilles de la Tourette syndrome, 10 of their first- or second-degree relatives, and 3 normal controls [6].
• Although the doubly-deficient mice excrete adenine and its highly insoluble derivative, 2,8-dihydroxyadenine, which are also associated with human APRT deficiency, additional abnormalities or any self-injurious behavior were not detected [7].
• (a) NADH has an apparent competitive behavior with respect to ATP and uncompetitive behavior with respect to AMP resulting in improved binding constant in the presence of AMP, and (b) the binding of the peptide is not significantly altered by NADH [8].
• Furthermore, the reaction products of Y70A n-TCS and AMP incubated at various reaction times were analyzed using HPLC [9].
• Although we have yet to identify the specific abnormal genes in mood disorders, recent studies have implicated signal transduction pathways, in particular the stimulatory guanine nucleotide binding protein (Gs)/cyclic AMP and protein kinase C pathways, in the pathophysiology and treatment of mood disorders [10].

High impact information on APRT

• Homozygotes may be detected by their raised urinary adenine levels or absence of detectable erythrocyte adenine phosphoribosyltransferase activity (or both) [11].
• Wild-type S49 cells are killed by dexamethasone or dbc AMP, and adenosine (5 muM) in the presence of an ADA inhibitor (6 muM EHNA) also prevents the growth of and kills these S49 cells [12].
• All three mutants are resistant to killing by isoproterenol or cholera toxin and two are resistant to dbc AMP itself, but all are sensitive to killing by adenosine and EHNA [12].
• Binding of the competitive inhibitor 2'-phospho-AMP (AMP, adenosine monophosphate) places the NADP binding site at the carboxyl-terminal edge of the sheet in a manner similar to the nucleotide binding of the dehydrogenase family [13].
• Transforming genes coding for selectable functions, such as adenine phosphoribosyltransferase or thymidine kinase, have now been isolated by utilizing transformation in concert with molecular cloning [14].

Chemical compound and disease context of APRT

• Human adenine phosphoribosyltransferase has sequence homology with xanthine-guanine phosphoribosyltransferase from Escherichia coli in 110-amino acid region encompassing the NH2-terminal section of the enzyme [15].
• We found that adenosine, AMP, and ADP accumulated in high concentrations relative to ATP within the ASL covering polarized primary human normal or cystic fibrosis airway epithelial cells [16].
• Thus, the particularly high prevalence of MTAP codeletion in mesothelioma makes it an ideal candidate for trials of targeted therapy using inhibitors of de novo AMP synthesis (e.g., L-alanosine) [17].
• The concentrations of the erythrocyte adenine nucleotides, AMP, ADP and ATP, did not differ in Down's syndrome (n = 10) from those of control subjects (n = 10) [18].
• The activities of other erythrocyte enzymes, phosphoribosylpyrophosphate synthetase, adenine phosphoribosyltransferase, adenosine deaminase and purine nucleoside phosphorylase, were similar between Werner's syndrome and normal subjects [19].

Biological context of APRT

• Nucleotide sequence analysis of APRT genomic DNA from WR2, a Japanese-type homozygote, identified a T to C substitution in exon 5, giving rise to the substitution of threonine for methionine at position 136 [20].
• Among 141 defective APRT alleles from 72 different families, 96 (68%), 30 (21%), and 10 (7%) had an ATG to ACG missense mutation at codon 136 (APRT*J allele), TGG to TGA nonsense mutation at codon 98, and duplication of a 4-bp sequence in exon 3, respectively [1].
• Evidence for a crossover or gene conversion event within the APRT gene was observed in an APRT*J mutant allele [1].
• The promoter region of the human APRT gene, like that of several other "housekeeping" genes, lacks "TATA" and "CCAAT" boxes but contains five GC boxes that are potential binding sites for the Sp1 transcription factor [21].
• Comparative anatomy of the human APRT gene and enzyme: nucleotide sequence divergence and conservation of a nonrandom CpG dinucleotide arrangement [21].

Anatomical context of APRT

• In this paper, we report studies of 11 APRT-deficient lymphoblast cell lines [20].
• However, the latter increment was not observed in APRT deficient erythrocytes [22].
• At the APRT locus in CHO cells, 80-97% of spontaneous mutations are due to base-pair changes, the remainder being, mostly, partial deletions [23].
• The exceptions are APRT mutations in CHO cells (16-20% of mutants with deletions or other changes) and HPRT mutations in T lymphocytes from A-bomb survivors (15-25%); the latter finding is consistent with the occurrence of in vivo selection against HPRT mutant cells [23].
• Activities of HPRT, APRT and PNP were low before morula formation, and then increased until the blastocyst stage [24].

Associations of APRT with chemical compounds

• The mouse cells lacked HPRT and were also deficient in adenine phosphoribosyltransferase (APRT; AMP: pyrophosphate phosphoribosyltransferase; EC2.4.2.7) [25].
• Particularly striking is the distribution of CpG dinucleotides within human and rodent APRT genes [21].
• This suggests that in recipient cells incorporation is due to [3H]MTA, which has been shown previously to be the major 3H-labeled purine metabolite to accumulate in B82 medium, being cleaved by MTAP to [3H]adenine, which is phosphoribosylated by APRT to [3H]AMP [26].
• The core of APRT is similar to that of other phosphoribosyltransferases (PRTases), although the adenine-binding domain is quite different [2].
• To address the molecular basis of DHA-urolithiasis, the recombinant human APRT was crystallized in complex with adenosine 5'-monophosphate (AMP) [2].

Regulatory relationships of APRT

• The APRT subclone was used for in situ hybridization to chromosomes expressing FRA16D [27].
• We investigated the metabolism of some adenosine analogues in adenosine deaminase inhibited normal and adenine phosphoribosyltransferase (APRT) deficient human erythrocytes [22].

Other interactions of APRT

• Alanosine, an inhibitor of AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines [28].
• This study is apparently the first documentation of interstitial deletion of 16q24.3, involving GALNS and APRT genes [29].
• Using both simulations and analysis of real data from murids (APRT and LCAT nuclear genes), we show that comparing large numbers of species significantly improves the power of the test [30].
• Polyethylene glycol-1000 (PEG-1000) induced fusion of HPRT (E.C. 2.4.2.8) deficient Chinese hamster cells with alpha-galactosidase A (E.C. 2.3.1.22) deficient cells from a patient with Fabry's disease yielded hybrids which contained both human and hamster HPRT, G6PD (E.C. 1.1.1.49), and APRT (E.C. 2.4.2.7) and Chinese hamster alpha-galactosidase B [31].
• We describe methods both for targeted gene knockout of ERCC1, and for APRT targeted gene correction by homologous recombination, and some of our experimental results using these approaches [32].

Analytical, diagnostic and therapeutic context of APRT

• The five exons and flanking regions of APRT were amplified by PCR and then sequenced [3].
• The complete primary structure of human adenine phosphoribosyltransferase was established by sequence analysis of 19 peptide fragments [15].
• The adenine phosphoribosyltransferase gene allows for selection of chromosome 16 in somatic cell hybrids and a hybrid panel is available which segments the chromosome into six regions to facilitate gene mapping [33].
• Both TLC and HPLC confirmed that ATP and ADP were converted to AMP and ADO after their incubation with unstimulated or FMLP-activated neutrophils [34].
• To elucidate its mechanism, we examined the frequency of a 7.4-kb mtDNA deletion, the concentration of adenine nucleotides, and the activity of AMP catabolic enzymes in 10 human right atria obtained from cardiac surgery, using quantitative PCR, HPLC, and immunoprecipitations [35].

References