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排序方式: 共有126条查询结果,搜索用时 18 毫秒
71.
Tchigvintsev A Singer A Brown G Flick R Evdokimova E Tan K Gonzalez CF Savchenko A Yakunin AF 《The Journal of biological chemistry》2012,287(3):1874-1883
The β-hydroxyacid dehydrogenases form a large family of ubiquitous enzymes that catalyze oxidation of various β-hydroxy acid substrates to corresponding semialdehydes. Several known enzymes include β-hydroxyisobutyrate dehydrogenase, 6-phosphogluconate dehydrogenase, 2-(hydroxymethyl)glutarate dehydrogenase, and phenylserine dehydrogenase, but the vast majority of β-hydroxyacid dehydrogenases remain uncharacterized. Here, we demonstrate that the predicted β-hydroxyisobutyrate dehydrogenase PA0743 from Pseudomonas aeruginosa catalyzes an NAD+-dependent oxidation of l-serine and methyl-l-serine but exhibits low activity against β-hydroxyisobutyrate. Two crystal structures of PA0743 were solved at 2.2–2.3-Å resolution and revealed an N-terminal Rossmann fold domain connected by a long α-helix to the C-terminal all-α domain. The PA0743 apostructure showed the presence of additional density modeled as HEPES bound in the interdomain cleft close to the predicted catalytic Lys-171, revealing the molecular details of the PA0743 substrate-binding site. The structure of the PA0743-NAD+ complex demonstrated that the opposite side of the enzyme active site accommodates the cofactor, which is also bound near Lys-171. Site-directed mutagenesis of PA0743 emphasized the critical role of four amino acid residues in catalysis including the primary catalytic residue Lys-171. Our results provide further insight into the molecular mechanisms of substrate selectivity and activity of β-hydroxyacid dehydrogenases. 相似文献
72.
Evdokimova V Ruzanov P Imataka H Raught B Svitkin Y Ovchinnikov LP Sonenberg N 《The EMBO journal》2001,20(19):5491-5502
mRNA silencing and storage play an important role in gene expression under diverse circumstances, such as throughout early metazoan development and in response to many types of environmental stress. Here we demonstrate that the major mRNA-associated protein YB-1, also termed p50, is a potent cap-dependent mRNA stabilizer. YB-1 addition or overexpression dramatically increases mRNA stability in vitro and in vivo, whereas YB-1 depletion results in accelerated mRNA decay. The cold shock domain of YB-1 is responsible for the mRNA stabilizing activity, and a blocked mRNA 5' end is required for YB-1-mediated stabilization. Significantly, exogenously added YB-1 destabilizes the interaction of the cap binding protein, eIF4E, with the mRNA cap structure. Conversely, sequestration of eIF4E from the cap increases the association of endogenous YB-1 with mRNA at or near the cap, and significantly enhances mRNA stability. These data support a model whereby down-regulation of eIF4E activity or increasing the YB-1 mRNA binding activity or concentration in cells activates a general default pathway for mRNA stabilization. 相似文献
73.
Cyclooxygenases (COXs) catalyze the rate-limiting step in the production of prostaglandins, bioactive compounds involved in
processes such as fever and sensitivity to pain, and are the target of aspirin-like drugs. COX genes have been cloned from coral, tunicates and vertebrates, and in all the phyla where they are found, there are two genes
encoding two COX isoenzymes; it is unclear whether these genes arose from an early single duplication event or from multiple
independent duplications in evolution. The intron-exon arrangement of COX genes is completely conserved in vertebrates and mostly conserved in all species. Exon boundaries largely define the four
functional domains of the encoded protein: the amino-terminal hydrophobic signal peptide, the dimerization domain, the membrane-binding
domain, and the catalytic domain. The catalytic domain of each enzyme contains distinct peroxidase and cyclooxygenase active
sites; COXs are classified as members of the myeloperoxidase family. All COXs are homodimers and monotopic membrane proteins
(inserted into only one leaflet of the membrane), and they appear to be targeted to the lumenal membrane of the endoplasmic
reticulum, where they are N-glycosylated. In mammals, the two COX genes encode a constitutive isoenzyme (COX-1) and an inducible isoenzyme (COX-2); both are of significant pharmacological
importance. 相似文献
74.
Savchenko A Krogan N Cort JR Evdokimova E Lew JM Yee AA Sánchez-Pulido L Andrade MA Bochkarev A Watson JD Kennedy MA Greenblatt J Hughes T Arrowsmith CH Rommens JM Edwards AM 《The Journal of biological chemistry》2005,280(19):19213-19220
A combination of structural, biochemical, and genetic studies in model organisms was used to infer a cellular role for the human protein (SBDS) responsible for Shwachman-Bodian-Diamond syndrome. The crystal structure of the SBDS homologue in Archaeoglobus fulgidus, AF0491, revealed a three domain protein. The N-terminal domain, which harbors the majority of disease-linked mutations, has a novel three-dimensional fold. The central domain has the common winged helix-turn-helix motif, and the C-terminal domain shares structural homology with known RNA-binding domains. Proteomic analysis of the SBDS sequence homologue in Saccharomyces cerevisiae, YLR022C, revealed an association with over 20 proteins involved in ribosome biosynthesis. NMR structural genomics revealed another yeast protein, YHR087W, to be a structural homologue of the AF0491 N-terminal domain. Sequence analysis confirmed them as distant sequence homologues, therefore related by divergent evolution. Synthetic genetic array analysis of YHR087W revealed genetic interactions with proteins involved in RNA and rRNA processing including Mdm20/Nat3, Nsr1, and Npl3. Our observations, taken together with previous reports, support the conclusion that SBDS and its homologues play a role in RNA metabolism. 相似文献
75.
76.
Sabaté M Ligthart J Deshpande N DeFeyter P Serruys P 《International journal of cardiovascular interventions》1998,1(2):109-112
We report a case of implantation of a new design of stent which allows creation of a double-hemispheric lumen for the treatment of a bifurcational stenosis. The unfavourable outcome following the implantation of this stent is described. 相似文献
77.
78.
V. N. Evdokimova T. V. Nikitina I. N. Lebedev N. N. Sukhanova S. A. Nazarenko 《Russian Journal of Developmental Biology》2000,31(4):204-210
The problem of the functioning specificity of sex chromosomes during the early stages of embryogenesis in man and the associated
problem of the sex ratio in spontaneous and induced abortions, as well as in newborns, remains open. We have conducted a cytogenetic
examination of 342 spontaneous abortions divided into three clinical groups on the basis of the severity of the developmental
disturbances of the embryo: spontaneous abortionssensu stricto with a developed embryo without any significant intrauterine delay of development (n=100), nondeveloping pregnancies (n=176), and anembryonic fetuses (n=66). The frequency of chromosomal mutations in these groups was 22.0, 48.3, and 48.5%, respectively. Statistical analysis
has demonstrated significant differences between the studied groups in the frequencies of the normal and abnormal karyotypes:
the major contributions to these differences were associated with autosomal trisomy, triploidy, and the 46.XY karyotype. The
presence of 46.XY may reflect the specific genetic mechanisms of the prenatal mortality of embryos with the normal karyotype,
associated with sex and/or with the imprinting of X-chromosomes. The sex ratio in spontaneous abortions with the normal karyotype
was as follows: 0.77 for spontaneous abortions with well-developed embryos without any significant intrauterine delay of development;
0.60 for nondeveloping pregnancies; and 0.31 for anembryonic fetuses. An analysis of DNA from the embryos and their parents
has demonstrated a low probability of contamination of cell cultures with mother cells as a possible source of the prevalence
of embryos with the 46.XX karyotype among spontaneous abortions. Nondeveloping pregnancies and anembryonic fetuses showed
statistically significant differences in the sex ratio from the control group consisting of medical abortions (1,11). Differences
in the sex ratio were due to an increasingly lower proportion of embryos with karyotype 46.XY (relative to the expected one)
among the fetuses with an increased severity of developmental disturbances. The statistical “chances ratio” index also provided
evidence that embryos with the 46.XY karyotype had a higher propensity to produce a well-formed fetus as compared with the
female embryos. We propose that the expression of genes of the maternal X-chromosome in XY embryos supports a more stable
development during early embryogenesis as compared with XX embryos. In the latter case, normal development is coupled with
the operation of an additional mechanism for compensation of the dose of X-linked genes. Operation of this mechanism increases
the probability of disturbances in female embryos. A higher viability of XY embryos during the early stages of ontogenesis
in man appears to explain their underrepresentation in samples of spontaneously aborted embryos and appears to be the major
factor responsible for the deviation of the sex ratio from the theoretically expected value. 相似文献
79.
Zhang Rg Andersson CE Savchenko A Skarina T Evdokimova E Beasley S Arrowsmith CH Edwards AM Joachimiak A Mowbray SL 《Structure (London, England : 1993)》2003,11(1):31-42
Ribose-5-phosphate isomerase A (RpiA; EC 5.3.1.6) interconverts ribose-5-phosphate and ribulose-5-phosphate. This enzyme plays essential roles in carbohydrate anabolism and catabolism; it is ubiquitous and highly conserved. The structure of RpiA from Escherichia coli was solved by multiwavelength anomalous diffraction (MAD) phasing, and refined to 1.5 A resolution (R factor 22.4%, R(free) 23.7%). RpiA exhibits an alpha/beta/(alpha/beta)/beta/alpha fold, some portions of which are similar to proteins of the alcohol dehydrogenase family. The two subunits of the dimer in the asymmetric unit have different conformations, representing the opening/closing of a cleft. Active site residues were identified in the cleft using sequence conservation, as well as the structure of a complex with the inhibitor arabinose-5-phosphate at 1.25 A resolution. A mechanism for acid-base catalysis is proposed. 相似文献
80.
Sanishvili R Yakunin AF Laskowski RA Skarina T Evdokimova E Doherty-Kirby A Lajoie GA Thornton JM Arrowsmith CH Savchenko A Joachimiak A Edwards AM 《The Journal of biological chemistry》2003,278(28):26039-26045
Structural proteomics projects are generating three-dimensional structures of novel, uncharacterized proteins at an increasing rate. However, structure alone is often insufficient to deduce the specific biochemical function of a protein. Here we determined the function for a protein using a strategy that integrates structural and bioinformatics data with parallel experimental screening for enzymatic activity. BioH is involved in biotin biosynthesis in Escherichia coli and had no previously known biochemical function. The crystal structure of BioH was determined at 1.7 A resolution. An automated procedure was used to compare the structure of BioH with structural templates from a variety of different enzyme active sites. This screen identified a catalytic triad (Ser82, His235, and Asp207) with a configuration similar to that of the catalytic triad of hydrolases. Analysis of BioH with a panel of hydrolase assays revealed a carboxylesterase activity with a preference for short acyl chain substrates. The combined use of structural bioinformatics with experimental screens for detecting enzyme activity could greatly enhance the rate at which function is determined from structure. 相似文献