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:2.6.1.44 (AGT)
770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported the isolation of a genomic clone encoding human liver-specific peroxisomal alanine:glyoxylate aminotransferase (AGT, EC 2.6.1.44), the deficient enzyme in primary hyperoxaluria type 1 (PH1) (P. E. Purdue, Y. Takada, and C. J. Danpure, J. Cell Biol. 111: 2341-2351, 1990). This clone has now been characterized, revealing that the coding sequence is distributed among 11 exons covering 10 kb. The nucleotide sequences of each exon have been determined, confirming that this clone corresponds to previously characterized AGT cDNA (Y. Takada, N. Kaneko, H. Esumi, P. E. Purdue, and C. J. Danpure, Biochem. J. 268: 517-520, 1990). In addition, to provide sequence data for the design of exon-specific PCR primers, the intron sequences immediately flanking each exon have been determined. Furthermore, in an attempt to identify putative transcriptional control sequences we have determined the sequence of 1.25 kb directly upstream of the cDNA 5' end. The results of genomic Southern blotting indicate that human AGT is probably encoded by a single copy gene, and a combination of in situ hybridization and PCR analysis of rodent/human somatic cell hybrids suggests that this gene is located on chromosome 2q36-q37. The gene symbol AGXT has been assigned for this locus.
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PMID:Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase. 204 8

Our previous studies have shown that human skin cancers occurring on sun-exposed body sites frequently contain activated Ha-ras oncogenes capable of inducing morphologic and tumorigenic transformation of NIH 3T3 cells. In this study, we analyzed human primary squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) occurring on sun-exposed body sites for mutations in codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction, followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to the primary human skin cancers, we also analyzed Ha-ras-positive NIH 3T3 transformants for mutations in the Ha-ras oncogene. The results indicated that all three NIH 3T3 transformants, 11 of 24 (46%) SCCs, and 5 of 16 (31%) BCCs contained mutations at the second position of Ha-ras codon 12 (GGC----GTC), predicting a glycine-to-valine amino acid substitution, whereas only 1 of 40 skin cancers (an SCC) displayed a mutation in the first position of Ki-ras codon 12 (GGT----AGT), predicting a glycine-to-serine amino acid change. In addition, three of the SCCs contained highly amplified copies of the N-ras oncogene in their genomic DNA. Interestingly, two of the SCCs containing amplified N-ras sequences also had G----T mutations in codon 12 of the Ha-ras oncogene. These studies demonstrate that mutations in codon 12 of the Ha-ras oncogene occurred at a high frequency in human skin cancers originating on sun-exposed body sites, whereas mutation in codon 12 of Ki-ras or amplification of N-ras occurred at a low frequency. Since the mutations in the Ha-ras and Ki-ras oncogenes were located opposite potential pyrimidine dimer sites (C-C), it is likely that these mutations were induced by ultraviolet radiation present in sunlight.
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PMID:Ras gene mutation and amplification in human nonmelanoma skin cancers. 206 25

Direct double-strand breaks in DNA have been implicated in cellular lethality of the antitumor antibiotic neocarzinostatin, but the mechanism of their formation has not been elucidated. Evidence is presented that neocarzinostatin causes sequence-specific direct double-strand breaks whose formation is strongly influenced by the activating thiol. Seven-fold more double-strand breaks result when glutathione rather than 2-mercaptoethanol is used to activate the drug to its putative diradical form, while the sequence specificity of cleavage remains the same. These data explain earlier inconsistencies in the ratios of double-strand to single-strand breaks obtained from in vitro and in vivo studies. Double-strand cleavage sites, occurring predominantly at GT steps, especially AGT.ACT, consist of trinucleotide sequences with a two-nucleotide 3'-stagger of the cleaved residues. The chemical structures of the cleavage sites suggest a model in which a neocarzinostatin-induced double-strand break results from abstraction of a C5' hydrogen atom from the T of ACT and the C4' hydrogen atom of the T of AGT by a single molecule of the diradical form of the drug. Single-strand breaks at these sites occur as separate events with attack at the C5' hydrogens. These findings permit the generalization that single-strand breaks produced by neocarzinostatin show a base preference but no clear sequence specificity, while bistranded lesions are sequence-specific in nature.
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PMID:Sequence-specific double-strand breakage of DNA by neocarzinostatin involves different chemical mechanisms within a staggered cleavage site. 214 79

The reaction of a histidine-containing peptide (angiotensin I) with copper (II)/ascorbate under physiological conditions has been studied chemically. In the presence of a catalytic amount of copper(II) ion, ascorbate mediated the oxidative damage to the peptide via selective loss of the histidine residue. Furthermore, the reaction of copper(II)/ascorbate with the peptide gave two products (AGT-1 and AGT-2) selectively. From amino acid analysis of the modified peptides, it was found that either of the two histidine residues within the native peptide was modified. Amino-terminal sequence analysis indicated that AGT-1 and AGT-2 were modified at the His9 and the His6, respectively. In addition, the data of FAB-MS and 1H NMR suggested that the unknown residues (modified histidine) within AGT-1 and AGT-2 should have the 2-imidazolone structure. In order to confirm the 2-imidazolone residue in both modified peptides, they were hydrolyzed and analyzed by reverse-phase HPLC. The result demonstrated that the acid hydrolysis of modified peptides gave a product which was identical to authentic 2-imidazolone residue. Consequently, it was confirmed that the reaction of Cu(II)/ascorbate occurs specifically at the C-2 position of the imidazole ring of the histidine residue within a peptide.
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PMID:Site-specific oxidation of angiotensin I by copper(II) and L-ascorbate: conversion of histidine residues to 2-imidazolones. 224 Nov 71

Concerning the signals which direct excision of introns from mRNA precursors in higher eukaryotic genes, consensus 9-nucleotide sequence, (CA)AG/GT(AG)AGT, has been proposed with the 5'-splice site, but actual 5'-splice site sequences differ from it in a greater or lesser degree. We analyzed 5'-splice site sequence of human beta-globin gene by quantification method (categorical discriminant analysis) proposed previously. Analysis of 13-nucleotide sequences and deleted sequences showed that 9-nucleotide sequences in the consensus region are almost sufficient to define 5'-splice signal. To confirm this view, we examined a number of beta-globin mutant genes, where nucleotide changes occur at the authentic 5'-splice site of the first intron and cause beta-thalassemia phenotype. Our method could explain why such mutations abolish the 5'-splice site and cryptic 5'-splice sites are activated.
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PMID:Quantification analysis of 5'-splice signal sequences in mRNA precursors. Mutations in 5'-splice signal sequence of human beta-globin gene and beta-thalassemia. 224

pBR322 contains the amp gene encoding beta-lactamase. When Escherichia coli carrying this plasmid is exposed to heat shock, beta-lactamase synthesis is repressed transiently at the translational level. To identify the DNA element responsible for this translational repression, DNA segments containing the translation start region of the amp gene were excised from pAT153 and fused in frame with the lacZ reading frame in the open reading frame vector pORF1. These constructs were introduced into E. coli, and the effect of heat shock of the cells on the synthesis of beta-galactosidase starting from the amp start codon was examined. As is the case for pBR322-encoded synthesis of beta-lactamase, the synthesis of beta-galactosidase encoded by the fused genes also ceased transiently upon heat shock. It is concluded that the heat shock-induced repression of the amp gene occurs at the initiation step of translation. As far as the present study is concerned, the minimum DNA segment responsible for the repression is AT TGA AAA AGG AAG AGT ATG AG, which includes the Shine-Dalgarno sequence (AAGGA) and the initiation codon (ATG).
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PMID:The translation start signal region of TEM beta-lactamase mRNA is responsible for heat shock-induced repression of amp gene expression in Escherichia coli. 250 25

We followed patients with pregnancy and diabetes in an outpatient clinic. 240 had gestational diabetes, 16 had type II and 5 type I diabetes. 85% of 110 patients with gestational diabetes had normal glucose tolerance test post partum (AGT). Type I patients were younger (25 years old) than AGT (32) or type II (33) patients. Complications frequently observed among diabetics included hypertension, premature membrane rupture and polyhydroamnios (the latter only among AGT and type II patients). Insulin was required for diabetes control in 14% of cases. Cesarean section was more frequent in diabetics than in a control population (21%): AGT 45%, type II 45% and type I 60%. Larger newborns occurred in 21% of AGT and 22% of type II as compared to 6% in controls. Neonatal mortality was 2.1% in AGT patients (0.8% in controls). Hyperbilirrubinemia, polyglobulia and hypocalcemia were more frequent among newborns of diabetic patients.
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PMID:[Clinical experience in diabetes and pregnancy]. 251 61

Virus inducible elements (IE) in promoters of mouse alpha-interferon and human beta 1-interferon genes contain multiple copies of the hexanucleotide sequence AGT-GAA or its variants which are also found in the interferon-stimulated response element of genes transcriptionally induced by interferon. We have examined the similarities between virus and interferon induction of gene expression and the role of AGTGAA and AAT-GAA hexamers in these responses. Hybrid plasmids were constructed by inserting the IE region, the alpha 4 promoter, or the multiple copies of AGTGAA or AAT-GAA 5' to the inactive-45 human immunodeficiency-chloramphenicol acetyltransferase hybrid gene, and their inducible expression was studied in a transient expression assay. In L-cells, multiple hexamers were efficiently induced both by infection with Newcastle disease virus and by interferon treatment; while the alpha 4 promoter and the IE inducible region were induced predominantly by virus rather than by interferon. In order to dissociate the effect of virus and endogenous interferon on the induction process, we examined the gene expression in Vero cells, which have undergone homozygous deletion of type 1 interferon genes, and in VNPT-159 cells, which were derived from Vero cells by insertion of an inducible human interferon beta 1 gene. The results show that while the alpha 4 promoter was efficiently induced only by virus in both cell types, the constructs containing shorter segments of the IE were induced by both virus and interferon in Vero cells. However, the inducibility by interferon was not detected in VNPT-159 cells, suggesting that the presence of endogenous interferon suppresses interferon-induced expression of hexanucleotide repeats and the short inducible region. In contrast, virus inducibility of endogenous interferon-stimulated genes, ISG-15 and ISG-54, was about 100-fold more efficient in VNPT-159 cells than in Vero cells, suggesting that this induction is largely mediated through synthesis of endogenous interferon. Hence, endogenous interferon may play a role in the autoregulation of both interferon genes and interferon-stimulated genes.
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PMID:Virus infection and interferon can activate gene expression through a single synthetic element, but endogenous genes show distinct regulation. 255 Apr 51

Limited tryptic digestion of spectrin (Sp) from seven related individuals manifesting hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP) phenotypes revealed the presence of a novel peptide with a molecular weight of 78 Kd and a concomitant decrease in the alpha I domain (80-Kd peptide), which is the domain involved in the dimer self-association process. Sp from the normal members of this white family exhibited a normal peptide pattern, as compared with controls. The abnormal peptide pattern was associated with a decreased ability of Sp dimer to self-associate. In this kindred in which three generations were available for study, the clinical manifestations were quite variable and ranged from the asymptomatic HE carrier state to hemolytic HE or to severe anemia requiring splenectomy. The severity of the disease appeared to be correlated both with the amount of mutant spectrin (31% to 69%) and with the excess of the Sp dimer found in the membrane (26% to 60%, compared with a normal value of 5.6% +/- 2.2%). Partial amino acid sequencing showed that the alpha I/78-Kd peptide resulted from cleavage at lysine residue 10 of the alpha I/80-Kd domain. Knowledge of the exon/intron structure of cloned genomic DNA encoding the alpha I domain allowed us to amplify in vitro a DNA fragment containing the third exon of the alpha-spectrin gene. The amplified fragment was subcloned and sequenced. A G to T transversion was found in the 39th codon (AGT for AGG), which changed the normal arginine to a serine. Hybridization of amplified DNAs with allele-specific oligonucleotides corresponding to the normal and mutant sequences confirmed the presence of the mutation in three other HE members of the family (the propositus mother, brother, and sister).
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PMID:Sp alpha I/78: a mutation of the alpha I spectrin domain in a white kindred with HE and HPP phenotypes. 256 62

Two sisters presented with severe insulin resistance and markedly decreased insulin binding to erythrocytes, cultured fibroblasts and transformed lymphocytes. The dose-response curve of insulin-stimulated amino acid uptake in the fibroblasts was shifted to the right. The molecular weight of the insulin receptor on the transformed lymphocytes from the patients was 210,000 and could not be dissociated to alpha- and beta-subunits by dithiothreitol treatment. However, the proreceptor was cleaved by trypsin and this led to the production of alpha-subunit with normal insulin binding. We performed cDNA sequence analysis of the cleavage site of the insulin proreceptor from the patients. The polymerase chain reaction was used to obtain a large amount of cDNA coding for the region including the interconnecting site. A thermostable DNA polymerase, Taq polymerase, successfully produced enough cDNA for the region to be sequenced. The results showed an AGG (Arg) to AGT (Ser) point mutation, resulting in the change of the interconnecting sequence of the two subunits from -Arg-Lys-Arg-Arg- to -Arg-Lys-Arg-Ser-. These results suggest that the tertiary structure change of the cleavage site leads to production of unprocessed insulin proreceptors.
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PMID:Unprocessed insulin proreceptors due to point mutation at the cleavage site. 268 Mar 65


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