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Query: UNIPROT:P06889 (Mol)
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The activities of carbamoylphosphate synthase, aspartate transcarbamoylase, dihydroorotase, orotate phosphoribosyl transferase and orotidine-5'-phosphate decarboxylase, five of the six enzymes of pyrimidine biosynthesis, have been measured in Crithidia fasciculata, Trypanosoma cruzi, Leishmania major, Trichomonas vaginalis, Eimeria tenella, Toxoplasma gondii, Plasmodium berghei, Fasciola gigantica, Schistosoma mansoni, Hymenolepis diminuta, Nippostrongylus brasiliensis and Trichuris muris. The majority of organisms contained all five enzyme activities. However, in T. vaginalis only carbamoylphosphate synthetase activity and in E. tenella only orotate phosphoribosyl transferase and orotidine-5'-phosphate decarboxylase activities could be detected. It appears therefore that the ability to synthesise pyrimidines by the de novo route is probably both common and widespread amongst parasitic organisms.
Mol Biochem Parasitol 1981 Feb
PMID:The enzymes of pyrimidine biosynthesis in a range of parasitic protozoa and helminths. 611 50

The rudimentary (r) locus of Drosophila melanogaster encodes the first three enzymes for the de novo synthesis of pyrimidines: carbamyl phosphate synthase (CPSase), aspartyl transcarbamylase (ATCase), and dihydroorotase (DHOase). Revertants of leaky r mutants deficient in CPSase have been recovered. Of those examined, most (28/30) appear to result from reversion of the original mutation or a second site mutation in the mutant gene: They map to the r locus, have levels of CPSase and Km's for glutamine similar to wild type, and have comparatively little change in ATCase and DHOase activity. Two of the revertants appear to involve regulatory mutations that lead to an increase in defective CPSase molecules: They map to the r locus, have Km's for glutamine like that of the CPSase in the progenitor stock, and lead to relatively small increases in CPSase activity that are roughly paralleled by increases in ATCase and DHOase. The recovery of these putative regulatory mutations increasing the activity of the three enzymes supports the conclusion that the three activities are part of a trifunctional polypeptide or that their genes are transcribed together as parts of a multicistronic transcript.
Mol Gen Genet 1981
PMID:Genetic and biochemical properties of revertants at the rudimentary locus in Drosophila melanogaster. 612 Apr 39

In the studies reported here, we have examined the molecular organization of the rudimentary gene of Drosophila melanogaster. rudimentary encodes a 220,000 Mr polypeptide catalyzing the first three steps in pyrimidine biosynthesis: carbamyl phosphate synthetase, aspartate transcarbamylase and dihydroorotase. We have determined the direction of transcription of the gene relative to the genetic map of the locus. The 5' end maps to the distal end of the locus (relative to the centromere) and transcription proceeds through the domains encoding dihydroorotase, carbamyl phosphate synthetase and finally aspartate transcarbamylase. The rudimentary transcription unit spans a DNA segment of 13.2 X 10(3) base-pairs and encodes a mature messenger RNA of 7.3 X 10(3) base-pairs. Three intervening sequences have been identified, one of which is over 4 X 10(3) base-pairs in length. Finally, we have compared the DNA sequence organization of the Drosophila rudimentary gene with the corresponding loci of yeast and hamster.
J Mol Biol 1984 May 05
PMID:The rudimentary locus of Drosophila melanogaster. 614 99

A pyrimidine auxotroph of Escherichia coli was isolated which contained a defect in its ability to synthesize both oroate phosphoribosyl transferase, the product of the gene pyrE, and orotidine monophosphate decarboxylase, product of the gene pyrF. A single location on the E. coli linkage map was found to be responsible for the loss of both enzyme activities. This gene was located near cysE at 80.55 min by a combination of Hfr crosses and P1 transductions. The pyrimidine requirement was also corrected by episome F'140 which was found not to carry any pyrimidine structural genes. These data confirm the existence of a new gene, pyrS, unlinked to any previously mapped pyrimidine structural gene, responsible for partial control of pyrimidine biosynthesis. A spontaneous revertant of the mutant strain was also identified which displayed constitutive levels of aspartate transcarbamylase, dihydroorotase, dihydroorotate dehydrogenase, orotidine monophosphate decarboxylase, and limited levels of orotate phosphoribosyl transferase. A model is proposed in which the pyrS gene product is an activator protein, necessary for the transcription of the pyrE and pyrF genes. This activator protein is nonfunctional in the original mutant strain, and partially functional in the revertant strain. The data presented here cannot rule out an alternative mechanism involving a repressor.
Mol Gen Genet 1983
PMID:Identification of a trans-acting regulatory factor involved in the control of the pyrimidine pathway in E. coli. 635 97

All six enzymes of the de novo biosynthetic pathway leading to the biosynthesis of UMP have been characterized in Toxoplasma gondii. The first three enzymes of the pathway, carbamyl phosphate synthetase-II (CPS-II), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase) could be consistently separated by sucrose gradient centrifugation. Their molecular weights were estimated to be approximately 540 000, 140 000 and 70 000, respectively. The last two enzymes, orotate phosphoribosyltransferase (OPRTase) and orotidylate decarboxylase (ODCase), cosedimented at the same position, corresponding also to a molecular weight of approximately 70 000. The fourth enzyme, dihydroorotate dehydrogenase (DHO-DHase), was associated with the particulate fraction. Apparent Km values for the respective enzymes were: CPS-II, MgATP2- (19.7 1.2 mM), L-glutamine (12.0 +/- 1.7 microM), ammonia (15.5 +/- 2.7 mM); ATCase, carbamyl phosphate (26.2 +/- 3.5 microM), L-aspartate (17.6 +/- 8.5 mM); DHOase (reverse direction) dihydroorotate (1.6 +/- 0.08 microM); ODCase, orotidine 5'-monophosphate (0.41 +/- 0.04 microM). MgUTP2- was found to act as an inhibitor of CPS-II, with an apparent Ki of 0.41 mM. However, 5-phospho-alpha-D-ribosyl-1-diphosphate, dimethyl sulphoxide and glycerol had no effect on the Km value for MgATP2-. The effect of some inhibitors, including pyrimidine and purine nucleotides and analogs and respiratory chain inhibitors, was also determined for the enzymes of the pathway.
Mol Biochem Parasitol 1983 Feb
PMID:Enzymes of the de novo pyrimidine biosynthetic pathway in Toxoplasma gondii. 685 12

The pyrimidine metabolism of Giardia lamblia trophozoites (Portland I strain) was studied using whole trophozoites and trophozoite homogenates. Pyrimidines and pyrimidine nucleosides were readily incorporated into nucleic acids. Orotic and aspartic acid incorporations were below the level of detection. Enzymes of the pyrimidine salvage pathway (i.e., thymidine and uridine phosphorylases and thymidine and uridine kinases) were detected in trophozoite homogenates, but the activities of de novo pyrimidine synthesis enzymes (i.e., carbamoyl-phosphate synthase, aspartate transcarbamoylase, dihydroorotase and dihydroorotate dehydrogenase) were below the level of detection in these same homogenates. The evidence presented supports the conclusion that G. lamblia trophozoites appear incapable of synthesizing pyrimidines de novo but are capable of salvaging preformed pyrimidines and pyrimidine nucleosides from the growth medium and the enzymes of this pyrimidine salvage pathway are not organelle associated.
Mol Biochem Parasitol 1982 May
PMID:Pyrimidine metabolism in Giardia lamblia trophozoites. 709 5

The construction of a transcriptional map for human chromosome 21 requires the generation of a specific catalogue of genes, together with corresponding mapping information. Towards this goal, we conducted a pilot study on a pool of random chromosome 21 cosmids representing 2 Mb of non-contiguous DNA. Exon-amplification and cDNA selection methods were used in combination to extract the coding content from these cosmids, and to derive expressed sequences libraries. These libraries and the source cosmid library were arrayed at high density for hybridisation screening. A strategy was used which related data obtained by multiple hybridisations of clones originating from one library, screened against the other libraries. In this way, it was possible to integrate the information with the physical map and to compare the gene recovery rate of each technique. cDNAs and exons were grouped into bins delineated by EcoRI cosmid fragments, and a subset of 91 cDNAs and 29 exons have been sequenced. These sequences defined 79 non-overlapping potential coding segments distributed in 24 transcriptional units, which were mapped along 21q. Northern blot analysis performed for a subset of cDNAs indicated the existence of a cognate transcript. Comparison to databases indicated three segments matching to known chromosome 21 genes: PFKL, COL6A1 and S100B and six segments matching to unmapped anonymous expressed sequence tags (ESTs). At the translated nucleotide level, strong homologies to known proteins were found with ATP-binding transporters of the ABC family and the dihydroorotase domain of pyrimidine synthetases. These data strongly suggest that bona fide partial genes have been isolated. Several of the newly isolated transcriptional units map to clinically important regions, in particular those involved in Down's syndrome, progressive myoclonus epilepsia and auto-immune polyglandular disease. The study presented here illustrates the complementarity of exon-amplification and cDNA selection techniques for generating a large resource of new expressed landmarks, which contribute to the construction of a chromosome 21 transcript map.
Hum Mol Genet 1995 Aug
PMID:Model for a transcript map of human chromosome 21: isolation of new coding sequences from exon and enriched cDNA libraries. 758 66

Most DNA replication origins in eukaryotes localize to nontranscribed regions, and there are no reports of origins within constitutively expressed genes. This observation has led to the proposal that there may be an incompatibility between origin function and location within a ubiquitously expressed gene. The biochemical and functional evidence presented here demonstrates that an origin of bidirectional replication (OBR) resides within the constitutively expressed housekeeping gene CAD, which encodes the first three reactions of de novo uridine biosynthesis (carbamoyl-phosphate synthetase, aspartate carbamoyltransferase, and dihydroorotase). The OBR was localized to a 5-kb region near the center of the Syrian hamster CAD transcriptional unit. DNA replication initiates within this region in the single-copy CAD gene in Syrian baby hamster kidney cells and in the large chromosomal amplicons that were generated after selection with N-phosphonacetyl-L-aspartate, a specific inhibitor of CAD. DNA synthesis also initiates within this OBR in autonomously replicating extrachromosomal amplicons (CAD episomes) located in an N-phosphonacetyl-L-aspartate-resistant clone (5P20) of CHOK1 cells. CAD episomes consist entirely of a multimer of Syrian hamster CAD cosmid sequences (cCAD1). These data limit the functional unit of replication initiation and timing control to the 42 kb of Syrian hamster sequences contained in cCAD1. In addition, the data indicate that the origin recognition machinery is conserved across species, since the same OBR region functions in both Syrian and Chinese hamster cells. Importantly, while cCAD1 exhibits characteristics of a complete replicon, we have not detected autonomous replication directly following transfection. Since the CAD episome was generated after excision of chromosomally integrated transfected cCAD1 sequences, we propose that prior localization within a chromosome may be necessary to "license" some biochemically defined OBRs to render them functional.
Mol Cell Biol 1995 Aug
PMID:Identification of an origin of bidirectional DNA replication in the ubiquitously expressed mammalian CAD gene. 762 8

To better understand the signaling pathways which lead to DNA synthesis in mammalian cells, we have studied the transcriptional activation of genes needed during the S phase of the cell cycle. Transcription of the gene encoding a pyrimidine biosynthetic enzyme, carbamoyl-phosphate synthase (glutamine-hydrolyzing)/aspartate carbamoyltransferase/dihydroorotase (cad), increases at the G1/S-phase boundary. We have mapped the growth-dependent response element in the hamster cad gene to the extended palindromic E-box sequence, CCACGTGG, which is centered at +65 in the 5' untranslated sequence. Mutation of the E box abolished growth-dependent transcription, and an oligonucleotide corresponding to the cad sequence at +55 to +75 (+55/+75) restored growth-dependent regulation to nonresponsive cad promoter mutants when placed down-stream of the transcription start site. The same oligonucleotide conferred less G1/S-phase induction when placed upstream of basal promoter elements. An analogous oligonucleotide containing the mutant E box had no effect in either location. Nuclear proteins bound the cad +55/+75 element in a cell cycle-dependent manner in electromobility shift assays; antibodies specific to USF and Max blocked the DNA-binding activity of different growth-regulated protein-DNA complexes. Expression of c-Myc mutants which have been shown to dominantly interfere with the function of c-Myc and Max significantly inhibited cad transcription during S phase but had no effect on transcription from another G1/S-phase-activated promoter, dhfr. These data support a model whereby E-box-binding proteins activate serum-induced transcription from the cad promoter at the G1/S-phase boundary and suggest that a Max-associated protein complex contributes to the serum response.
Mol Cell Biol 1995 May
PMID:An E-box-mediated increase in cad transcription at the G1/S-phase boundary is suppressed by inhibitory c-Myc mutants. 773 36

Carbamoylphosphate is a common intermediate in the metabolic pathways leading to the biosynthesis of arginine and pyrimidines. The amino acid sequences of all available proteins that catalyze the formation of carbamoylphosphate were retrieved from Genbank and aligned to estimate their mutual phylogenetic relations. In gram-negative bacteria carbamoylphosphate is synthesized by a two-subunit enzyme with glutaminase and carbamoylphosphate synthetase (CPS) activity, respectively. In gram-positive bacteria and lower eukaryotes this two-subunit CPS has become dedicated to arginine biosynthesis, while in higher eukaryotes the two subunits fused and subsequently lost the glutaminase activity. The CPS dedicated to pyrimidine synthesis is part of a multifunctional enzyme (CPS II), encoding in addition dihydroorotase and aspartate transcarbamoylase. Evidence is presented to strengthen the hypothesis that the two "kinase" subdomains of all CPS isozymes arose from a duplication of an ancestral gene in the progenote. A further duplication of the entire CPS gene occurred after the divergence of the plants and before the divergence of the fungi from the eukaryotic root, generating the two isoenzymes involved in either the synthesis of arginine or that of pyrimidines. The mutation rate was found to be five- to tenfold higher after the duplication than before, probably reflecting optimization of the enzymes for their newly acquired specialized function. We hypothesize that this duplication arose from a need for metabolic channeling for pyrimidine biosynthesis as it was accompanied by the tagging of the CPS gene with the genes for dihydroorotase and aspartate transcarbamoylase, and as the duplication occurred independently also in gram-positive bacteria. Analysis of the exon-intron organization of the two "kinase" subdomains in CPS I and II suggests that ancient exons may have comprised approx. 19 amino acids, in accordance with the prediction of the "intron-early" theory.
J Mol Evol 1995 Dec
PMID:Evolutionary relationships of the carbamoylphosphate synthetase genes. 858 26


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