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:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 60-year-old white male (KH) was diagnosed to suffer from severe type III hyperlipoproteinemia (HLP) and premature cardiovascular disease. Biochemical analysis revealed an unusual apolipoprotein (apo) E phenotype and genotype. All clinical characteristics of type III HLP were present in the patient. His very low density lipoprotein (VLDL) cholesterol to plasma triglyceride (TG) ratio was elevated at 0.97 without therapy which is unusually high (normal ratio about 0.18). By contrast his plasma apo E level was only moderately elevated (6.8 mg dl-1). The patient's apo E migrated in the apo E1 position on isoelectric focusing gels. Chemical modification with cysteamine and treatment with neuraminidase confirmed the presence of two cysteine residues in the patient's apo E and a normal sialylation pattern. Pedigree analysis suggested that the patient was a compound heterozygote with one apo epsilon 1 allele and another allele whose product did not appear in the plasma compartment ('null' allele). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo E gene as well as restriction fragment length polymorphism (RFLP) analysis with the endonuclease Taq I identified an adenosine for guanosine (G-->A) exchange in the second base of codon 127 that is predictive for an Asp for Gly substitution in the encoded apo E amino acid sequence. This mutation is the structural basis for the apo E1 isoform identified upon isoelectric focusing. Five other family members are also carriers of the mutant apo epsilon 1 allele. Two of those were hyperlipidemic and exhibited biochemical characteristics of type III HLP. A second mutation, a deletion of a G in codon 31, is predictive for a reading frameshift that encodes for a premature stop in codon 60. Our inability to identify the product of a second apo E allele in the plasma of the patient and two other members of the KH family corresponds with the heterozygous presence of this mutation in the affected individuals. Both relatives (like the index case) had an increased VLDL cholesterol to plasma TG ratio, which indicates the presence of cholesterol-enriched VLDL particles. We propose that the single base deletion in the apo E gene which is the cause of a non-functional 'null' allele in addition to a probably dominant apo E1 (Gly127-->Asp, Arg158-->Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to severe dysbetalipoproteinemia.
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PMID:Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/'null' genotype. 136 Aug 98

Using two different techniques, phenotyping and genotyping, we have studied allelic variation at amino acids 112 and 158 of the apolipoprotein E gene locus in 52 patients with insulin-dependent diabetes and in 58 non-diabetic controls. Phenotypes were determined by isoelectric focusing and immunoblotting of delipidated, neuraminidase-treated plasma. Genotypes were determined by using the polymerase chain reaction to amplify a 227 base pair fragment of the apolipoprotein E gene spanning both allelic sites. This was then digested with the restriction endonuclease CfoI and the alleles identified by polyacrylamide gel electrophoresis. Discrepancies between phenotype and genotype were observed in 16 (15%) of the individuals studied, 7 (13%) in the diabetics and 9 (17%) in the controls. From these results it is concluded that isoelectric focusing can lead to the erroneous assignment of apolipoprotein E phenotype even after pretreatment with neuraminidase. It is suggested that genotyping by DNA analysis is the method of choice in determining apolipoprotein E status.
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PMID:Apolipoprotein E phenotyping: a word of caution. 177 11

A cosmid gene bank of Vibrio cholerae 395, classical Ogawa, was screened in Escherichia coli HB101 for expression of the vibrio neuraminidase (NANase) gene nanH (N-acylneuraminate glycohydrolase). Positive clones were identified by their ability to cleave the fluorogenic NANase substrate 2'-(4-methylumbelliferyl)-alpha-D-N-acetylneuraminic acid. Seven NANase-positive clones were detected after screening 683 cosmid isolates with a rapid, qualitative plate assay method. The nanH gene was subcloned from one of the cosmids and was located within a 4.8-kilobase-pair BglII restriction endonuclease fragment. Evidence that nanH was the NANase structural gene was obtained by transposon mutagenesis and by purification and comparison of the cloned gene product with the secreted NANase purified from the parent V. cholerae strain. The sequence of the first 20 amino-terminal amino acids of the secreted NANase purified from V. cholerae was determined by automated Edman degradation and matched perfectly with the amino acid sequence predicted from nucleotide sequencing of nanH. The sequence data also revealed the existence of a potential signal peptide that was apparently processed from NANase in both V. cholerae and E. coli. In contrast to V. cholerae, E. coli nanH+ clones did not secrete NANase into the growth medium, retaining most of the enzyme in the periplasmic compartment. Kinetic studies in V. cholerae showed that nanH expression and NANase secretion were temporally correlated as cells in batch culture entered late-exponential-phase growth. Similar kinetics were observed in at least one of the E. coli nanH+ clones, suggesting that nanH expression in E. coli might be controlled by some of the same signals as in the parent V. cholerae strain.
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PMID:Cloning and expression of the Vibrio cholerae neuraminidase gene nanH in Escherichia coli. 283 65

Apolipoprotein E (apo E) genotypes have been determined in 460 Danish men, with the use of the polymerase chain reaction (PCR) to amplify a 244 base pair fragment spanning the first-base polymorphic sites in the codons of amino acids 112 and 158 followed by restriction endonuclease cleavage. The results were compared with the apo E phenotypes previously determined by isoelectric focusing (IEF) of delipidated plasma, not pretreated with neuraminidase, followed by apo E specific immunoblotting. Conflicting results were found in only 9 cases (2.0%) and in each case only with respect to one allele. Five of the discrepancies can be explained, post hoc, by technical difficulties with the IEF method ('faint bands'). A possible cause of the other 4 discrepancies is the presence of rare mutations. Our findings in this large study are reassuring, since, if appreciable and systematic misclassification of genotypes do occur by using IEF, as has been reported from some laboratories, it may influence the validity of genetic epidemiological studies.
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PMID:Genotyping compared with protein phenotyping of the common apolipoprotein E polymorphism. 800 83

Influenza is worldwide one of the deadliest infectious diseases. Lethal influenza mutants can unpredictably arise, as in the 1918 pandemic, or in the 1997 Hong Kong influenza outbreak. Vaccines are today the only protective prophylactic agents, and development of potent new anti-influenza drugs of therapeutic effectiveness appears urgent. It is the aim of the present review, to summarize and discuss the different investigational approaches to this goal. In Medline- and several internet virology database-searches, numerous citations were compiled, and selected according to their relevance to the different topics discussed. The antiviral agents are classified according to their target in the viral replication cycle: proteolytic activation of haemagglutinin, attachment of the virus to specific cell-surface receptors, endocytosis and fusion with the endosomal membrane, uncoating of the nucleocapsid, multiplication, i.e. synthesis of viral RNA and mRNA, and release of the new virus generation from the host cell surface. Potential drugs, directed towards each of these replication steps are described with respect to their mechanism of action, antiviral activity, toxic side effects and induction of resistance. The most promising candidates for safe and potent new influenza drugs, are antiviral agents, directed towards a virus-specific, well conserved target, such as inhibitors of virus-cell fusion, inhibitors of RNA transcriptase and endonuclease, and inhibitors of neuraminidase. It can be hoped that in the near future potent and therapeutically effective anti-influenza drugs will be available.
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PMID:Influenza chemotherapy: a review of the present state of art and of new drugs in development. 1120 14

In an avian flu pandemic, which drugs could be used to treat or prevent infection with influenza A (H5N1) virus? Foremost are the viral neuraminidase inhibitors oseltamivir and zanamivir, which have already been used to treat human influenza A (H1N1 and H3N2) and B virus infections. The use of the M2 ion channel blockers amantadine and rimantadine is compounded by the rapid development of drug resistance. Although formally approved for other indications (i.e. treatment of hepatitis C), ribavirin and pegylated interferon might also be useful for controlling avian flu. Combined use of the currently available drugs should be taken into account and attempts should be made to develop new strategies directed at unexplored targets such as the viral proteins hemagglutinin, the viral polymerase (and endonuclease) and the non-structural protein NS1. As has been shown for other viral infections, RNA interference could be a powerful means with which to suppress the replication of avian H5N1.
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PMID:Avian influenza A (H5N1) infection: targets and strategies for chemotherapeutic intervention. 1748 39

In this review, we will discuss drug design based on proven and potential anti-influenza drug targets including viral hemagglutinin (HA), neuraminidase (NA), M2 ion channel, 3P polymerase complex, and host factors such as kinases. We have summarized influenza inhibitors based on their mode of actions. For instance, included are descriptions of (1) inhibitors of HA cleavage, such as nafamostat, camostat, gabexate, epsilon-aminocapronic acid and aprotinin, (2) inhibitors of fusion and entry, such as benzoquinones and hydroquinones, CL 385319, BMY-27709, stachyflin, and their analogues, (3) inhibitors of viral RNPs/polymerase/endonuclease, such as T-705, L-735,822, flutimide and their analogues, (4) inhibitors of MEK, such as PD 0325901, CI-1040 and ARRY-142886, and (5) inhibitors of NA such as DANA, FANA, zanamivir, and oseltamivir, etc. Although amantadine and rimantadine are not recommended for treating influenza virus infections because of drug resistance problem, these viral M2 ion channel blockers established a proof-of-concept that the endocytosis of virion into host cells can be a valid drug target because M2 protein is involved in the endocytosis process. The influenza polymerase complex not only catalyzes RNA polymerization but also encodes the "cap snatching" activity. After being exported from the nucleus to the cytoplasm, the newly synthesized vRNPs are assembled into virions at the plasma membrane. The progeny virions will then leave the host cells through the action of NA. The strategies for discovery of small molecule inhibitors of influenza virus replication based on each particular mechanism will be discussed. Finally, the lessons learned from the design of NA inhibitors (NAI) are also included. Many exciting opportunities await the cadre of virologists, medicinal chemists, and pharmacologists to design novel influenza drugs with favorable pharmacological and pharmacokinetic properties to combat this threatening infectious disease.
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PMID:Strategies of development of antiviral agents directed against influenza virus replication. 1822 Jul 89

Influenza, especially pandemic influenza, poses great threat to health and humans life of. Due to the antigenic drift and shift of the influenza virus, there is a constant requirement to accurately adjust contents of the vaccine to current subtype of the virus. As there is always a long period of time between the moment of detection of a new kind of influenza virus till a new vaccine is produced, the only protection for the people are antiviral drugs. Some examples of antiviral compounds that can be used in treatment in near future have been presented. A review of the researches on the substances that are active against influenza viruses has been carried out and their mechanism of action was described. We have taken into account the chemical compounds that seem to be active in the process of virus adsorption; hemagglutinin and neuraminidase inhibitors; M2 ion channel blockers; polymerase, endonuclease, transcriptase, proteine kinase and signaling cascade inhibitors. The potential of oligonucleotide antiviral therapeutics and the substances that are extracted from different plants were presented. The future direction of research were shown.
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PMID:[The substances active against influenza virus. Possibilities and prospects of application]. 2012 Sep 45

The emergence of pandemic H1N1 influenza viruses in April 2009 and the continuous evolution of highly pathogenic H5N1 influenza viruses underscore the urgency of novel approaches to chemotherapy for human influenza infection. Anti-influenza drugs are currently limited to the neuraminidase inhibitors (oseltamivir and zanamivir) and to M2 ion channel blockers (amantadine and rimantadine), although resistance to the latter class develops rapidly. Potential targets for the development of new anti-influenza agents include the viral polymerase (and endonuclease), the hemagglutinin, and the non-structural protein NS1. The limitations of monotherapy and the emergence of drug-resistant variants make combination chemotherapy the logical therapeutic option. Here we review the experimental data on combination chemotherapy with currently available agents and the development of new agents and therapy targets.
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PMID:Combination chemotherapy for influenza. 2199 92

As an attempt to increase the resistance to Newcastle Disease Virus (NDV) and so further reduction of its risk on the poultry industry. This work aimed to build the eukaryotic gene co-expression plasmid of neuraminidase (NA) gene and myxo-virus resistance (Mx) and detect the gene expression in transfected mouse fibroblasts (NIH-3T3) cells, it is most important to investigate the influence of the recombinant plasmid on the chicken embryonic fibroblasts (CEF) cells. cDNA fragment of NA and mutant Mx gene were derived from pcDNA3.0-NA and pcDNA3.0-Mx plasmid via PCR, respectively, then NA and Mx cDNA fragment were inserted into the multiple cloning sites of pVITRO2 to generate the eukaryotic co-expression plasmid pVITRO2-Mx-NA. The recombinant plasmid was confirmed by restriction endonuclease treatment and sequencing, and it was transfected into the mouse fibroblasts (NIH-3T3) cells. The expression of genes in pVITRO2-Mx-NA were measured by RT-PCR and indirect immunofluorescence assay (IFA). The recombinant plasmid was transfected into CEF cells then RT-PCR and the micro-cell inhibition tests were used to test the antiviral activity for NDV. Our results showed that co-expression vector pVITRO2-Mx-NA was constructed successfully; the expression of Mx and NA could be detected in both NIH-3T3 and CEF cells. The recombinant proteins of Mx and NA protect CEF cells from NDV infection until after 72 h of incubation but the individually mutagenic Mx protein or NA protein protects CEF cells from NDV infection till 48 h post-infection, and co-transfection group decreased significantly NDV infection compared with single-gene transfection group (P<0. 05), indicating that Mx-NA jointing contributed to delaying the infection of NDV in single-cell level and the co-transfection of the jointed genes was more powerful than single one due to their synergistic effects.
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PMID:Partial antiviral activities detection of chicken Mx jointing with neuraminidase gene (NA) against Newcastle disease virus. 2397 11


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