Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In four abnormal fibrinogens with a point mutation in the gamma chain, all characterized by impaired fibrin polymerization, we identified single base exchanges in the respective mutant gamma chain genes by polymerase chain reaction followed by DNA sequence analysis. These base exchanges accounted for the amino acid substitutions previously reported from our laboratory. They were exchanges of C to T (CGC for gamma Arg-275 to TGC for Cys) in fibrinogen Osaka II, T to G (AAT for gamma Asn-308 to AAG for Lys) in fibrinogen Kyoto I, T to C (ATG for gamma Met-310 to ACG for Thr) in fibrinogen Asahi, and G to T (GAT for gamma Asp-330 to TAT for Tyr) in fibrinogen Kyoto III. These base exchanges were found to reside in exon VIII of the gamma chain gene. Since many abnormal molecules are associated with polymerization defects, unless associated with the impaired release of fibrinopeptides A and/or B, exon VIII of the gamma chain gene may deserve careful study to define the structural alterations.
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PMID:Gene analyses of abnormal fibrinogens with a mutation in the gamma chain. 142 Nov 74

The complete amino acid sequence of the hen ovomacroglobulin (ovostatin) subunit has been determined from cDNA and partial peptide sequence analysis. Ovostatin is a tetrameric member of the alpha-macroglobulin (alpha M) family of proteins. The 4715 nt ovostatin cDNA encodes a 36- or a 16-residue signal peptide and a 1437-residue mature protein (162.2 kDa). At the protein level the overall score of sequence identity between ovostatin and mammalian alpha Ms is 39-44%, indicating an early divergence from the line leading to the mammalian alpha Ms. Ovostatin contains 56 mol glucosamine per mol subunit, and 12 of its Asn-residues are likely to be N-glycosylated. Including carbohydrate, the size of the ovostatin subunit is approx. 185 kDa. The ovostatin subunit is predicted to contain 12 intrachain disulfide bridges, and two subunits are predicted to be disulfide bound by two interchain bridges. One Cys residue may be unpaired or participate in dimer formation as a third interchain disulfide bridge. Ovostatin contains a unique 40-residue bait region. In contrast to other alpha Ms, ovostatin contains no internal beta-Cys-gamma-Glu thiol ester, as a result of a Cys-to-Asn replacement (TGC or TGT to AAT), but the Gln-moiety of the thiol ester is preserved. By comparing the sequences of the receptor binding domain in alpha Ms with the corresponding region of ovostatin possible determinants for receptor recognition of mammalian alpha Ms are proposed.
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PMID:Amino acid sequence of hen ovomacroglobulin (ovostatin) deduced from cloned cDNA. 753 98

To assess which residues of Oct-1 POU-specific (POUs) are important for DNA recognition and stimulation of adenovirus DNA replication we have mutated 10 residues of the POUs helix-turn-helix motif implicated in DNA contact. Seven of these turned out to have reduced DNA binding affinity. Of these, three alanine substituted proteins were found to have a changed specificity using a binding site selection procedure. Mutation of the first residue in the recognition helix, Gln44, to alanine led to a loss of specificity for the first two bases, TA, of the wild-type recognition site TATGC(A/T)AAT. Instead of the A, a T was selected, suggesting a new contact and a novel specificity. A change in specificity was also observed for the T45A mutant, which could bind to TATAC(A/T)AAT, a site hardly recognized by the wild-type protein. Mutation of residue Arg49 led to a relaxed specificity for three consecutive bases, TGC. This residue, which is critical for high affinity binding, is absent from the structurally homologous lambdoid helix-turn-helix motifs. Employing a reconstituted system all but two mutants could stimulate adenovirus DNA replication upon saturation. Mutation of residues Gln27 and Arg49 impairs the ability of the Oct-1 POU domain protein to enhance replication, with a concomitant loss of DNA contacts. Since the POU domain binds the precursor terminal protein-DNA polymerase complex and guides it to the origin, lack of stimulation may be caused by incorrect targetting of the DNA polymerase due to loss of specificity.
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PMID:Mutation of the Oct-1 POU-specific recognition helix leads to altered DNA binding and influences enhancement of adenovirus DNA replication. 766 96

Sixteen Escherichia coli clinical isolates which were resistant to ampicillin and amoxicillin-clavulanate but susceptible to cephalothin were studied. Eight strains showed the presence of a beta-lactamase which comigrates with reference OXA-1 enzyme. The eight other strains produced different TEM-1 derivatives which had in common a higher Km for penicillins and a higher 50% inhibitory concentration for the beta-lactamase inhibitors. By oligotyping and sequencing of PCR products, it was shown that Ser (AGC) (TEM-30; also called TRI-1) in three strains and Cys (TGC) (TEM-31; also called TRI-2) in one strain were substituted for Arg-241 (CGC), that Leu (CTG) (TEM-33) and Val (GTG) (TEM-34) in one strain each were substituted for Met-67 (ATG), and that in other mutants the two latter substitutions occurred together with the substitution of Asp (GAT) (TEM-35 and TEM-36) for Asn-272 (AAT). Therefore, different sets of amino acid substitutions of TEM-1 can be found in clinical isolates and lead to resistance to beta-lactamase inhibitors.
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PMID:Emergence of clinical isolates of Escherichia coli producing TEM-1 derivatives or an OXA-1 beta-lactamase conferring resistance to beta-lactamase inhibitors. 806 42

Three novel splice site mutations and two novel missense mutations were identified by molecular analysis of pyruvate kinase (PK) deficiency associated with hereditary nonspherocytic hemolytic anemia. A Nepalese PK variant, PK Kowloon, was found to have a homozygous transversion at the 5'-splice site of the seventh intervening sequence (IVS) of the L-type PK gene (Ivs7[+1]gt --> tt). Using a reverse transcription polymerase chain reaction (RT-PCR) assay, we showed that the R-type PK mRNA in the proband's reticulocytes included the seventh IVS between the seventh and eighth exon, introducing a stop codon 3 nucleotides downstream of the mutated site. Consequently, the translational product may lack 44% of the R-PK polypeptide. A transition at the last nucleotide of exon 9 (1269GCG --> GCA) was found in a Japanese PK variant, PK 'Kamata.' The mutation did not alter the amino acid sequence, but caused skipping of the ninth exonic sequence in the R-PK transcripts. As a result, the affected R-type PK lost 51 amino acid residues (373Met-423Ala del). A transversion at the splice acceptor site of the third IVS (Ivs 3[-2]ag --> tg) was identified in PK 'Aomori.' The mutation resulted in aberrant splicing at a cryptic splice site within exon 4, causing deletion of two codons in the aberrant R-PK transcript (95 Gly-96 Pro --> del). Both PK 'Kamata' and PK 'Aomori' had a missense mutation on the other allele, 1044AAG --> AAT (348Lys --> Asn) and 1075CGC --> TGC (359Arg --> Cys), respectively. Although both 348Lys and 359Arg were located in the sixth loop of A domain (beta/alpha)8 barrel, which has been shown to contain the substrate and cation binding sites, the degree of anemia was much more severe in PK 'Kamata' than PK 'Aomori,' possibly because the 51 amino acid deletion of PK 'Kamata' but the 2 amino-acid deletion of PK 'Aomori' may abolish PK catalytic activity.
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PMID:Frame shift mutation, exon skipping, and a two-codon deletion caused by splice site mutations account for pyruvate kinase deficiency. 916 66

Osteopontin (OPN) is an acidic phosphoprotein synthesized by osteoblasts and osteoclastic cells that are localized in the mineralized phase of bone matrix. OPN is thought to bind to the vitronection receptor on the osteoclast membrane and regulates bone resorption by the osteoclast. In this study, we investigated whether or not OPN can relate to osteoclast differentiation and bone resorption in a co-culture system. When C57Black/6N mouse bone marrow cells suspended on ivory slices coated with collagen were inoculated onto a MC3T3-G2/PA6 cell layer, colonies containing TRAP(+) mononuclear and multinuclear cells were formed in the presence of 1 alpha, 25-dihydroxyvitamin D3 and dexamethasone. At the end of culture period the number of TRAP(+) osteoclast-like cells were counted and the resorption pits were evaluated by reflected light microscopy. The mRNA of OPN was detected by in situ hybridization. Osteoclast-like cells expressed OPN mRNA. The addition of an OPN antisense oligomer (5' AAT CAC TGC CAA TCT CAT 3') at the start of the co-culture period decreased the number of TRAP(+) cells present after 7 d (30.3 +/- 3.4 vs 56.9 +/- 12.4), and the ratio of mononuclear and multinucleated cells was changed (77.6:23.2 vs 60.8:39.3). The total area of pits per ivory slice was also decreased by adding the OPN antisense oligomer (246813 vs 303139 microns2). These results showed that OPN can be an important mechanism for regulating differentiation and bone resorption.
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PMID:Osteopontin antisense deoxyoligonucleotides inhibit bone resorption by mouse osteoclasts in vitro. 937 15

Allele-specific competitive blocker PCR (ACB-PCR) amplification and quantification was developed for mouse p53 codon 270 CGT-->TGT base substitution and codon 244/245 AAC/CGC-->AAT/TGC tandem mutation. PCR products corresponding to p53 mutant and wild-type DNA sequences were generated. These DNAs were mixed in known proportions to construct samples with defined mutant fractions and the allele-specific detection of each mutation was systematically optimized. Each assay was used to analyze eight simulated solar light (SSL)-induced tumors. By analyzing mutant fraction (MF) standards in parallel with PCR products generated from tumor samples, p53 mutants could be quantified as subpopulations within the tumors. All eight tumors contained detectable levels of p53 codon 270 CGT-->TGT mutation. Three tumors had p53 MFs between 10(-4) and 10(-3). Five tumors had p53 MFs between 10(-3) and 10(-2). None of the eight mouse skin tumors had measurable levels of p53 codon 244/245 tandem mutation. Frequent detection of p53 codon 270 CGT-->TGT mutation provides additional evidence that a pyrimidine dinucleotide overlapping a methylated CpG site (Pyr(me)CG) is a susceptible target for SSL-induced mutagenesis. The absence of p53 codon 244/245 mutation in tumors may be explained by its mutant p53 phenotype and/or indicate that this site is not methylated. These initial results indicate that p53 codon 270 CGT-->TGT mutation may be a sensitive biomarker for SSL- or UV-induced mutagenesis. This mutational endpoint may be useful for evaluating the co-carcinogenicity of compounds administered in combination with UV or SSL.
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PMID:Quantifying levels of p53 mutation in mouse skin tumors. 1566 16

IL-6 plays a key role in local and systemic manifestation of RA. IL-6 is not only a pro-inflammatory cytokine, but also interacts in complex ways with the cells involved in bone remodeling. In RA, IL-6 may indirectly promote osteoclastogenesis by increasing the release of RANK-L by osteoblasts, and it diminishes the proliferation of osteoblasts at late differentiation stages. The aims of this work were to evaluate the level of serum IL-6 and to correlate it with the activity, severity, early development of osteoporosis, and early structural bone damage in RA patients. The following parameters were investigated in 40 RA patients and 20 healthy controls: IL-6 level, BMI, ESR, CRP, CBCs, serum ionized calcium, blood urea, serum creatinine, AST, ALT, anti-CCP, and RF. Bone mineral density was measured by dual-energy X-ray absorptiometry at lumbar spines and femoral neck. Drug history was taken stressing on steroid therapy. Data were processed and analyzed using computer-based program. IL-6 was significantly positively correlated with HAQ1, PTGA, grade of pain, ESR, platelet count, blood urea, AST level, and anti-CCP level; IL-6 showed an inverse significant correlation with T-score. IL-6 was positively correlated with TGC, DAS-28 score, and RF level. No correlation was found between T-score and morning stiffness duration, BMI, CRP, RBC, serum creatinine, and ALT. There was an inverse significant correlation between T-score and HAQ1, SJC, pain grade, DAS-28 score, PTGA, ESR, RF, anti-CCP, and IL-6. Patients with RA on steroid therapy had significantly higher TJC, SJC, and DAS-28 score, anti-CCP, and IL-6 than patients with RA not on steroid therapy. Patients with RA on steroid therapy had significantly lower T-score and lower serum ionized calcium than patients with RA not on steroid therapy. IL-6 has an important role in increasing osteoclastic activity and subsequent bone resorption in the patients with RA. Blocking IL-6 by using IL-6 inhibitors and anti-RANK-L therapy may be effective in inhibiting the inflammatory process and preventing the bone complications of RA disease.
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PMID:Relation of interleukin-6 in rheumatoid arthritis patients to systemic bone loss and structural bone damage. 2253 87

Eleusine indica (goosegrass) populations resistant to fluazifop, an acetyl-CoA carboxylase (ACCase: EC6.4.1.2)-inhibiting herbicide, were found in several states in Malaysia. Dose-response assay indicated a resistance factor of 87.5, 62.5 and 150 for biotypes P2, P3 and P4, respectively. DNA sequencing and allele-specific PCR revealed that both biotypes P2 and P3 exhibit a single non-synonymous point mutation from TGG to TGC that leads to a well known Trp-2027-Cys mutation. Interestingly, the highly resistant biotype, P4, did not contain any of the known mutation except the newly discovered target point Asn-2097-Asp, which resulted from a nucleotide change in the codon AAT to GAT. ACCase gene expression was found differentially regulated in the susceptible biotype (P1) and highly resistant biotype P4 from 24 to 72h after treatment (HAT) when being treated with the recommended field rate (198gha(-1)) of fluazifop. However, the small and erratic differences of ACCase gene expression between biotype P1 and P4 does not support the 150-fold resistance in biotype P4. Therefore, the involvement of the target point Asn-2097-Asp and other non-target-site-based resistance mechanisms in the biotype P4 could not be ruled out.
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PMID:Molecular basis for resistance to ACCase-inhibiting fluazifop in Eleusine indica from Malaysia. 2486 27

The detection of Trypanosoma evansi in blood is intricate, primarily in chronic stage of infection, as the parasitaemia is often low and fluctuating. The climatic conditions of the target area of Punjab (a province of India with a total of 34,000 horses and ponies used for sports and transport) are conducive for the parasite propagation. The objective of present investigation was to assess the prevalence of T. evansi in central and western Punjab by PCR and card agglutination test (CATT/T. evansi) in relation to clinico-haematobiochemical alterations and risk factors associated with latent trypanosomosis. A total of 169 equine blood and serum samples tested by CATT/T. evansi revealed 16 cases positive, with 6.8% from central plain and 13.63% from western zone. To assess the specificity of serological test, PCR1 was performed using established primer pair TR3 5'-GCG CGG ATT CTT TGC AGA CGA-3' and TR4 5'-TGC AGA CAC TGG AAT GTT ACT-3' for T. evansi. PCR2 applied with primer pair RoTat1.2F: 5'-ATG TCA ACG ATG CCT GTT ACA TTA CGC AC-3' and RoTat1.2R: 5'-TAA ATA TCA CTG TCA AGA CCT GCT GCG G-3' to rule out the consensus between the finding of the two PCR assays and agglutination test for T. evansi, which displayed results in concordance with PCR1. PCR assays showed 1.92 and 1.51% positive samples from central plain and western zone, respectively. With respect to PCR assay, CATT/T. evansi showed 100% sensitivity and 92.1% specificity. Microscopy showed a very low prevalence rate of 0.59% with only one sample positive with teaming parasitaemia. Comparison between sexes revealed higher positivity in mares by the three tests (BSE: 0.95%, PCR: 2.88%, CATT/T. evansi: 14.42%). The haemato-biochemical factors were found to be altered in PCR positive cases, while the mean value of vital parameters lied in normal range in seropositive cases. The female horse (RR=0.0937, 95% CI=1.388-190.223%) population was found to be at the highest risk of seropositivity for T. evansi, particularly in the unorganized farms (RR=19.726, 95% CI=2.918-400.221%).
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PMID:Equine trypanosomosis in central and western Punjab: prevalence, haemato-biochemical response and associated risk factors. 2493 Dec 85


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