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: UMLS:C0679427 (myeloblastosis)
982 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The subsite requirements of the aspartic proteinase from the myeloblastosis-associated virus (MAV) for the cleavage of peptide substrates were studied with a series of synthetic peptides of general structure Ala-Thr-P4-P3-P2-P1*Nph-Val-Arg-Lys-Ala. The residues in positions P4, P3, P2 and P1 were varied and the kinetic parameters for the cleavage of substrates in 2.0 M NaCl were spectrophotometrically determined at pH 6.0 and 37 degrees C. The acceptance of amino acid residues in particular subsites is similar to that observed with the human immunodeficiency virus type 1 (HIV-1) proteinase in our earlier studies on the same substrate series: hydrophobic or aromatic residues are preferable in P1 position, a broad variety of residues are acceptable in P3 whereas the residues occupying P2 plays the decisive role in the substrate cleavage as evidenced by its dramatic influence on both kcat and Km values. The most remarkable difference between the two enzymes was found in P3 and P4 subsites. In P3, the introduction of negatively charged glutamate increases the substrate binding by the MAV proteinase 12-fold and decreases binding by the HIV-1 proteinase. In P4, Pro in this series is a favourable residue for the MAV proteinase and is strongly inacceptable for HIV-1 the proteinase. The pH profile of the cleavage was studied with a chromogenic substrate and differences between HIV-1 and MAV proteinases are discussed.
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PMID:Subsite specificity of the proteinase from myeloblastosis associated virus. 202 69

The 11-kD protease (PR) encoded by the human immunodeficiency virus 1 (HIV-1) is essential for the correct processing of viral polyproteins and the maturation of infectious virus, and is therefore a target for the design of selective acquired immunodeficiency syndrome (AIDS) therapeutics. To facilitate the identification of novel inhibitors of HIV-1 PR, as well as to permit detailed studies on the enzymology and inhibition of this enzyme, a continuous assay for its activity was developed that was based on intramolecular fluorescence resonance energy transfer (RET). The assay used the quenched fluorogenic substrate 4-(4-dimethylaminophenylazo)benzoic acid (DABCYL)--Ser Gln Asn Tyr Pro Ile Val Gln--5-[(2-aminoethyl)amino]naphthalene-1 sulfonic acid (EDANS), whose peptide sequence is derived from a natural processing site for HIV-1 PR. Incubation of recombinant HIV-1 PR with the fluorogenic substrate resulted in specific cleavage at the Tyr-Pro bond and a time-dependent increase in fluorescence intensity that was linearly related to the extent of substrate hydrolysis. An internally quenched fluorogenic substrate was also designed that was selectively cleaved by the related PR from avian myeloblastosis virus (AMV). The fluorescence quantum yields of the HIV-1 PR and AMV PR substrates in the RET assay increased by 40.0- and 34.4-fold, respectively, per mole of substrate cleaved. Because of its simplicity, rapidity, and precision in the determination of reaction rates required for kinetic analysis, this method offers many advantages over the commonly used high-performance liquid chromatography- or electrophoresis-based assays for peptide substrate hydrolysis by retroviral PRs.
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PMID:Novel fluorogenic substrates for assaying retroviral proteases by resonance energy transfer. 210 61

The virally encoded proteases from human immunodeficiency virus (HIV) and avian myeloblastosis virus (AMV) have been compared relative to their ability to hydrolyze a variant of the three-domain Pseudomonas exotoxin, PE66. This exotoxin derivative, missing domain I and referred to as LysPE40, is made up of a 13-kilodalton NH2-terminal translocation domain II connected by a segment of 40 amino acids to enzyme domain III of the toxin, a 23-kilodalton ADP-ribosyltransferase. HIV protease hydrolyzes two peptide bonds in LysPE40, a Leu-Leu bond in the interdomain region and a Leu-Ala bond in a nonstructured region three residues in from the NH2-terminus. Neither of these sites is cleaved by the AMV enzyme; hydrolysis occurs, instead, at an Asp-Val bond in another part of the interdomain segment and at a Leu-Thr bond in the NH2-terminal region of domain II. Synthetic peptides corresponding to these cleavage sites are hydrolyzed by the individual proteases with the same specificity displayed toward the protein substrate. Peptide substrates for one protease are neither substrates nor competitive inhibitors for the other. A potent inhibitor of HIV type 1 protease was more than 3 orders of magnitude less active toward the AMV enzyme. These results suggest that although the crystallographic models of Rous sarcoma virus protease (an enzyme nearly identical to the AMV enzyme) and HIV type 1 protease show a high degree of similarity, there exist structural differences between these retroviral proteases that are clearly reflected by their kinetic properties.
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PMID:Proteases from human immunodeficiency virus and avian myeloblastosis virus show distinct specificities in hydrolysis of multidomain protein substrates. 216 35

Aspartic proteinases from human immunodeficiency virus type 1 (HIV-1) and avian myeloblastosis virus (AMV) were found to interfere with microtubule assembly. Preincubation of the proteinases with purified brain microtubule proteins (tubulin and microtubule-associated proteins) at low ionic strength (pH 6.8), completely inhibited microtubule assembly. Analysis of microtubule proteins after incubation with proteinase showed no effect on tubulin but extensive cleavage of the microtubule-associated proteins 1 and 2 was observed. The digestion by the two proteinases differed. In the presence of HIV-1 proteinase, a fragment with an Mr of approximately 300, appeared, as well as at least three other new fragments, with Mr values of 188,000, 124,000 and 73,000. In the presence of AMV proteinase, the microtubule-associated proteins were extensively digested to many small fragments. The extending microtubule-associated proteins normally seen by electron microscopy on the microtubule surface disappeared after treatment with AMV proteinase. Our results show that retroviral proteinases are not restricted to cleavage of viral polyproteins in vitro. It is suggested that proteolysis of microtubular proteins by viral proteinases is an important step in viral pathogenicity and that it may be part of a mechanism causing degenerative effects in infected cells.
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PMID:Proteolytic cleavage of microtubule-associated proteins by retroviral proteinases. 221 89

The inhibitory effects of several polysaccharides, dextran, xylofuranan, and ribofuranan, and their sulfated counterparts on the infectivity and replication of human immunodeficiency virus (HIV) were examined by using an HTLV-I-carrying cell line, MT-4, in vitro. Dextran sulfate (Mw 34 X 10(3], xylofuranan sulfate, and ribofuranan sulfate completely prevented HIV-induced cytopathic effects (CPE) at concentrations greater than 10 micrograms/ml and dextran sulfate (Mw 7 X 10(3] at concentrations greater than 100 micrograms/ml. However, the non-sulfated compounds did not prevent them at any concentration tested. The anti-HIV effect of these polysaccharides was confirmed by measuring HIV-specific antigen expression in infected MT-4 cells. In cocultures with MOLT-4 and MOLT-4/HIVHTLV-IIIB cells, formation of multinucleated cells was completely inhibited in the presence of 100 micrograms/ml of these sulfated compounds. Dextran sulfate showed 20-30% growth inhibition of uninfected MT-4 cells at 1000 micrograms/ml but dextran sulfate, xylofuranan sulfate, and ribofuranan sulfate showed no effect on sulfated polysaccharides efficiently inhibited the reverse transcriptase activity of avian myeloblastosis virus and HIV.
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PMID:Sulfation of polysaccharides generates potent and selective inhibitors of human immunodeficiency virus infection and replication in vitro. 244 45

A new reverse transcriptase (RT) inhibitor was extracted and purified from the red alga Schizymenia pacifica. The chromatographic behavior and chemical properties of this sea algal extract (SAE) suggest that it is a sulfated polysaccharide having a molecular weight of approximately 2,000,000. SAE is composed of galactose (73%), sulfonate (20%), and 3,6-anhydrogalactose (0.65%). SAE is a member of the lambda-carrageenan family, based on its infrared spectrum and products of hydrolysis. SAE selectively inhibited human immunodeficiency virus (HIV) RT and replication in vitro. When MT-4 cells were treated with more than 10(4) inhibitory units (IU) of SAE per ml after HIV infection, significant inhibition of viral antigen synthesis was observed. Furthermore, more than 90% of cells were viable in the cultures exposed to 4 X 10(4) to 8 X 10(4) IU of SAE per ml, while almost all the MT-4 cells in the control culture had died by 10 days after HIV infection. The inhibitory effect of SAE on HIV replication was confirmed by plaque reduction assays. The 50% inhibitory dose of SAE was 9.5 x 10(3) IU/ml. Chondroitin sulfate A, dermatan sulfate, heparan sulfate, keratan polysulfate, and heparin also inhibited the RT of avian myeloblastosis virus. SAE immediately inhibited RT activity when added to an assay mixture after the start of the reaction.
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PMID:Purification and characterization of an avian myeloblastosis and human immunodeficiency virus reverse transcriptase inhibitor, sulfated polysaccharides extracted from sea algae. 244 20

A study was conducted to determine the fidelity of DNA synthesis catalyzed in vitro by the reverse transcriptase from a human immunodeficiency virus type 1 (HIV-1). Like other retroviral reverse transcriptases, the HIV-1 enzyme does not correct errors by exonucleolytic proofreading. Measurements with M13mp2-based fidelity assays indicated that the HIV-1 enzyme, isolated either from virus particles or from Escherichia coli cells infected with a plasmid expressing the cloned gene, was exceptionally inaccurate, having an average error rate per detectable nucleotide incorporated of 1/1700. It was, in fact, the least accurate reverse transcriptase described to date, one-tenth as accurate as the polymerases isolated from avian myeloblastosis or murine leukemia viruses, which have average error rates of approximately 1/17,000 and approximately 1/30,000, respectively. DNA sequence analyses of mutations generated by HIV-1 polymerase showed that base substitution, addition, and deletion errors were all produced. Certain template positions were mutational hotspots where the error rate could be as high as 1 per 70 polymerized nucleotides. The data are consistent with the notion that the exceptional diversity of the HIV-1 genome results from error-prone reverse transcription.
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PMID:The accuracy of reverse transcriptase from HIV-1. 246 Sep 25

The inhibition of human immunodeficiency virus (HIV) reverse transcriptase by certain antibiotics and related compounds was studied in comparison with that of avian myeloblastosis virus (AMV) reverse transcriptase and cellular DNA polymerases alpha and beta. In general, compounds that inhibited HIV reverse transcriptase also inhibited AMV reverse transcriptase. For example, 10 micrograms/ml of the isoquinoline quinones used in this study inhibited approximately 80% of the activity of reverse transcriptases of HIV and AMV, but did not inhibit the activity of DNA polymerases alpha and beta even at 50 micrograms/ml. AMV enzyme was more sensitive than HIV enzyme to colistin, enduracidins A and B, janiemycin, glysperin A, and thielavins A and B. The streptonigrin alkyl esters, however, inhibited HIV reverse transcriptase only. Sakyomicin A, luzopeptins, ellagic acid and suramine inhibited the activities of reverse transcriptases and cellular DNA polymerases.
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PMID:Comparative studies of the inhibitory properties of antibiotics on human immunodeficiency virus and avian myeloblastosis virus reverse transcriptases and cellular DNA polymerases. 246 28

A series of test substrates have been synthesized to establish the effect of termini on the putative exoribonuclease H activity of reverse transcriptase. Recombinant reverse transcriptase from human immunodeficiency virus, natural enzyme from avian myeloblastosis virus, and a known endonuclease, Escherichia coli ribonuclease H, cleaved relaxed, circular, covalently closed plasmids in which 770 consecutive residues of one strand were ribonucleotides. The avian enzyme also deadenylated capped globin mRNA with a covalently attached oligo(dT) tail at the 3' end. These results resolve a long-standing controversy--that the viral enzymes are obligatory exonucleases in vitro, based on their failure to cleave certain substrates for E. coli ribonuclease H, including circular poly(A).linear poly(T) and ribonucleotide-substituted supercoiled plasmids, but resemble endonucleases in vivo, based on their ability to degrade RNA in complex DNA.RNA hybrids. The data strongly suggest that the viral enzymes are endonucleases with exquisite sensitivity to the conformation of heteroduplexes. Inhibition of viral, but not cellular, ribonuclease H with ribonucleoside-vanadyl complexes further distinguishes these enzymes.
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PMID:Ribonuclease H activities associated with viral reverse transcriptases are endonucleases. 247 Nov 88

Feline immunodeficiency virus (FIV), formerly called feline T-lymphotropic lentivirus, causes an immune deficiency in cats that is very similar to the acquired immune deficiency syndrome in humans (N. C. Pedersen, E. M. Ho, M. L. Brown, and J. K. Yamamoto, Science 235:790-793, 1987). We have examined the reverse transcriptase of this virus to determine whether it is similar enough to the reverse transcriptase of the human immunodeficiency virus type 1 (HIV-1) to enable its use as a model for chemotherapy for acquired immune deficiency syndrome. The FIV reverse transcriptase is similar to that of HIV-1 in sensitivity to the noncompetitive inhibitor phosphonoformate (Ki, 0.3 microM) and relative insensitivity to phosphonoacetate. This enzyme was also sensitive to two competitive inhibitors, the 5'-triphosphates of 2', 3'-dideoxythymidine (Ki, 3.4 nM) and 3'-azido-3'-deoxythymidine (AZT; Ki, 6.2 nM). The ratios of Ki/Km for these two competitive inhibitors are similar to the ratios calculated from previously reported data for the HIV-1 enzyme assayed under identical conditions. In contrast, the FIV enzyme is different from the reverse transcriptase of avian myeloblastosis virus in sensitivity to those inhibitors. The replication of FIV in Crandell feline kidney cells was inhibited by AZT; virus production was inhibited more than 95% by 1.0 microM AZT.
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PMID:Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome. 247 68


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