Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Pas1 protein (Pas1p) is required for peroxisome biogenesis in Saccharomyces cerevisiae and contains two putative ATP-binding sites, each within a domain which is conserved among members of the recently characterized AAA-family. To elucidate whether both putative ATP-binding sites are essential for Pas1p function, lysine 467 of the first and lysine 744 of the second putative ATP-binding site were each changed to glutamate by site-directed mutagenesis. While replacement of lysine 744 abolished the function of the Pas1 protein in peroxisome biogenesis, replacement of lysine 467 had no obvious effect.
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PMID:Effect of site-directed mutagenesis of conserved lysine residues upon Pas1 protein function in peroxisome biogenesis. 772 96

Two lysine isoacceptor tRNAs corresponding to the codons AAA and AAG, respectively, were isolated from squid (Loligo bleekeri), and their nucleotide sequences were determined. During this analysis, we discovered that the tRNA with the anticodon CUU was efficiently cleaved at a specific site in the presence of magnesium ions, whereas the tRNA with the anticodon UUU was not. Cleavage occurred almost exclusively at the phosphodiester linkage between G15 and D16 (p16). The most remarkable feature of this cleavage reaction is that the end product was not a 2',3'-cyclic phosphate but was mainly a 3'-phosphate. Thus, this reaction was distinct from the well characterized cleavage of yeast tRNA(Phe) by lead and from reactions catalyzed by various other metalloribozymes. The presence of a cytidine residue at position 60 was required for efficient cleavage but was not crucial for the reaction, and the entire tRNA molecule had to be intact for this specific and efficient cleavage reaction. The present study provides evidence that there exists a new catalytic mechanism for cleavage of tRNA that exploits biologically ubiquitous ions rather than toxic, nonessential ions such as lead.
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PMID:Highly specific and efficient cleavage of squid tRNA(Lys) catalyzed by magnesium ions. 773 Mar 14

Three unrelated families have been identified with mutations involving asparagine 187. Two of these families are asymptomatic and were identified during the screening of random blood donors, whilst the third has a history of recurrent thromboembolic disease. In two families the mutation (6460 AAC-->GAC) results in an asparagine to aspartate substitution and is associated with normal immunological levels of antithrombin but a reduction in functional activity. In the third family the mutation (6462 AAC-->AAA) results in an asparagine to lysine substitution at residue 187 and is associated with a parallel reduction in both immunological and functional antithrombin levels. Asparagine 187 is located in the middle of the F helix of antithrombin and forms the major link between the F helix and strand 3 of the A sheet. The F helix is seen to overlie the A sheet of the molecule and moves with strands 2 and 3 of this sheet as they open to allow entry of the reactive site loop to form strand 4. Substitutions of asparagine 187 are, therefore, likely to disrupt this sliding movement leading to a loss of inhibitory activity.
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PMID:Two novel antithrombin variants, Asn187Asp and Asn187Lys, indicate a functional role for asparagine 187. 779 54

A 6.4-kb DNA fragment containing the DNA gyrase gyrA and gyrB genes was cloned and sequenced from the quinolone-susceptible Staphylococcus aureus type strain ATCC 12600. An expression plasmid was constructed by inserting the cloned genes into the Escherichia coli-S. aureus shuttle vector pAT19, and deletion plasmids carrying only functional gyrA and gyrB genes were derived from this plasmid. An efficient transformation system for S. aureus RN4220 was established by using these plasmids. Quinolone-resistant mutants of S. aureus RN4220 were isolated by three-step selection with quinolones. The first- and second-step mutants were considered to be transport mutants, and the third-step mutants were divided into five groups with respect to their resistance patterns and transformation results with gyrA and gyrB genes. Sequencing analysis of the resulting mutant gyrase genes showed that they had the following point mutations: group 1, Ser-84 (TCA) to Leu (TTA) in GyrA; group 2, Ser-84 (TCA) to Ala (GCA), Ser-85 (TCT) to Pro (CCT), or Glu-88 (GAA) to Lys (AAA) in GyrA; group 3, Asp-437 (GAC) to Asn (AAC) in GyrB; group 4, Arg-458 (CGA) to Gln (CAA) in GyrB; and group 5, Ser-85 (TCT) to Pro (CCT) in GyrA and Asp-437 (GAC) to Asn (AAC) in GyrB. When the gyrA and/or gyrB mutants were transformed with the wild-type gyrA and/or gyrB plasmids, they became quinolone susceptible, but transformants with the plasmids having the same mutations on the gyrA and/or gyrB genes did not confer susceptibility. These results indicate that mutations in both gyrA and gyrB can be responsible for quinolone resistance in S. aureus.
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PMID:Quinolone resistance mutations in the DNA gyrase gyrA and gyrB genes of Staphylococcus aureus. 781 Oct 12

Streptomyces clavuligerus produces the beta-lactam antibiotics penicillin N, O-carbamoyldeacetylcephalosporin C and cephamycin C. We characterized a wild-type DNA region which restores antibiotic formation to a mutant strain named NP1, previously shown to exhibit depressed activities for two early enzymes of cephalosporin synthesis, delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS) and isopenicillin N synthase (IPNS). L-Lysine epsilon-aminotransferase (LAT) assays and alpha-AAA feeding experiments suggested that strain NP1 is a lat mutant. NP1 recovered LAT, ACVS and IPNS activities when transformed with the cloned region. DNA sequencing showed that this region encodes the entire LAT gene (lat), required for the conversion of L-lysine to the beta-lactam precursor L-alpha-aminoadipic acid (alpha-AAA), as well as the upstream half of the ACVS gene (pcbAB). The activities of ACVS and IPNS appear to depend upon LAT expression. Gene fusions constructed to investigate promoter activities in the cloned region support a model of interdependence in the expression of the genes for LAT, ACVS and IPNS (pcbC).
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PMID:Possible involvement of the lysine epsilon-aminotransferase gene (lat) in the expression of the genes encoding ACV synthetase (pcbAB) and isopenicillin N synthase (pcbC) in Streptomyces clavuligerus. 788 54

Albumin Ortonovo is a slow moving variant of human serum albumin which has been found only in people coming from the small villages of Ortonovo and Nicola (Liguria, Italy) and reaches polymorphic frequency (> or = 1%) in the poorly admixed population group living in that area. This is the first report of a 'private' variant detected in a Caucasian population. It probably originated as a mutation in a founder individual many generations ago. Isoelectric focusing analysis of CNBr fragments from the purified variant localized the mutation in fragment CNBr VI (residues 447-548). This fragment was isolated on a preparative scale by reversed-phase HPLC and subjected to V8 proteinase digestion. Sequence analysis of the abnormal V8 peptide revealed that the variant arises from a previously unreported substitution at position 505 where glutamic acid has been replaced by lysine. The protein data were confirmed by DNA sequence analysis which indicated a single nucleotide change of GAA-->AAA in the corresponding codon of the structural gene. Since the amino acid substitution found in albumin Ortonovo accords with its electrophoretic mobility on cellulose acetate, residue 505 is probably exposed to the solvent. The clustering of the mutations in the intersubdomain connection linking subdomains IIIA and IIIB (residues 492-511) accords with the fact that this region lies on the molecular surface and is accessible to solvent.
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PMID:Protein and DNA sequence analysis of a 'private' genetic variant: albumin Ortonovo (Glu-505-->Lys). 790 34

Hb O-Arab [beta 121(GH4)Glu-->Lys] was detected in two Mediterranean families, one from Southern Italy and the other from Albania. The GAA-->AAA mutation at codon 121 was characterized by DNA sequencing. The mutant genes were associated with the same beta-globin gene framework variant and with the rare Hpa I/3' beta polymorphic restriction site generating a 7.0 kb fragment. However, at 5' the gene of the Italian family was associated with the restriction fragment length polymorphism subhaplotype [+ - - - +] and the Taq I/3'G gamma polymorphic site, while that of the Albanian family was associated with subhaplotype [- - - - +] but not with the Taq I/3'G gamma site. The particular features of these polymorphisms support the hypothesis of an African origin for the Hb O-Arab gene and a subsequent recombination event leading to the haplotype found in the Italian family.
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PMID:Hb O-Arab [beta 121(GH4)Glu-->Lys]: association with DNA polymorphisms of African ancestry in two Mediterranean families. 790 81

An electrophoretic variant of lactate dehydrogenase (LD) M(A) subunit was discovered in a female patient with chest pain. Her LD activity in serum was within the normal reference interval, and analysis of her LD isoenzyme pattern showed an abnormal migration indicating a fast-type LD-M(A) subunit variant. DNA analysis of the mutant LD-M gene detected a single base substitution, an A to G transition at codon 220 (AAA-->GAA). This mutation resulted in the replacement of a lysine by a glutamic acid (mutation K220E) and produced a subunit variant (electrophoretic fast type). This missense mutation was also observed in the patient's son, and genotypes of mother and son were consistent with their biochemical phenotypes, as evaluated by LD isoenzyme analysis.
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PMID:Fast-type electrophoretic variant of lactate dehydrogenase M(A) and comparison with other missense mutations in lactate dehydrogenase M(A) and H(B) genes. 790 13

Mutations in N-ras exon 2 codon 61 were studied in formalin-fixed human melanoma metastases. DNA fragments including codon 61 were amplified by polymerase chain reaction (PCR) and mutational analysis was performed by oligonucleotide hybridization (ODN), allele specific PCR and PCR combined with single strand conformation polymorphism analysis (SSCP). Thirty metastases from 25 patients with 'spontaneous' cutaneous melanoma were compared with 35 metastases from 17 patients with 'hereditary' cutaneous melanoma. The frequency of mutations as measured by PCR/ODN was significantly higher in patients with hereditary melanoma (mutations in 24% versus 59%, p < 0.05). The most frequent mutations were C/A transversions to lysine (AAA). The occurrence of lysine mutations was, in addition, studied by allele specific polymerase chain reaction. Again, the mutation frequency was significantly higher in metastases from patients with hereditary melanoma. PCR/SSCP finally enabled the isolation of lysine mutant alleles and nucleotide sequence analysis which confirmed the presence of the mutated codon 61. The relatively higher frequency of N-ras mutations in tumours from patients with hereditary melanoma may be related to the hypermutability described in hereditary melanoma and dysplastic naevus syndrome. The results support an involvement of N-ras mutations in the molecular pathogenesis of melanoma.
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PMID:Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations. 791 62

Protein 4.1 has been defined as a major component of the subcortical skeleton of erythrocytes. It binds the spectrin--actin scaffold through a 10-kD internal domain. This binding requires an essential 21-amino acid sequence motif, Motif I, which is retained by alternative splicing at the late stage of erythroid differentiation. We here analyze the molecular basis of heterozygous 4.1(-) hereditary elliptocytosis, associated with protein 4.1 partial deficiency, in nine related French families. cDNA sequencing revealed a single codon deletion (AAA) resulting in a lysine residue deletion within the 10-kD binding domain, 3' of Motif I. The mutated allele was designated allele 4.1 Aravis. In order to assess the functional effect of the codon deletion, recombinant 10-kD constructs were made and various binding assays were performed using spectrin, purified spectrin-actin complex, or red cell membranes. These experiments demonstrated that the deletion of the Lys residue clearly prevents the binding capacity. Similar results were obtained with a construct containing the Lys residue but lacking Motif I. These data strongly suggest that the binding site to the spectrin-actin complex must contain the Lys 447 (or 448), and therefore resides not only on Motif I but extends 3' of this essential motif.
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PMID:Protein 4.1 deficiency associated with an altered binding to the spectrin-actin complex of the red cell membrane skeleton. 792 42


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