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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of pyridobenzothiodiazepindioxides such as the 11-ethyl-6,8,9-trimethyl-6,11-dihydro-pyrido[2,3-f] [2,1,5]benzothiodiazepine-5,5-dioxide and arylpiridodiazepines such as the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b] pyrido(2',3'-4,5]furo[2,3-f][1,4]diazepin-6(12H)-thio and the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido- [2,3-4,5]thieno[2,3-f][1,4] diazepin-6(12H)-thione were found to inhibit human immunodeficiency virus type 1 [HIV-1(IIIB)] replication at a concentration of 0.003-0.04 microM without being cytotoxic at a 3,000- to 15,000-fold higher concentration. These compounds proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3' deoxythymidine (AZT), but not against HIV-2, simian immunodeficiency virus or herpes simplex virus. An HIV-1 strain containing the 188 Tyr-->His mutation in the reverse transcriptase displayed severely reduced sensitivity to the compounds. The specificity of these compounds is due to an interaction with the reverse transcription process. The 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido [2,3-4,5]thieno[2,3-f][1,4]diazepin-6(12H)-thione (MEN 10979) enhanced the anti-HIV-1 activity of AZT and dideoxyinosine (ddI) in a synergistic manner. The new arylpyrido-diazepine and -thiodiazepine derivatives appear to be drug candidates for the treatment of HIV-1 infection.
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PMID:New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase. 878 3

We have selected and plaque purified a mutant of feline immunodeficiency virus (FIV) that is resistant to 2',3'-dideoxycytidine (ddC). This mutant was selected in cultured cells in the continuous presence of 25 microM ddC. The mutant, designated DCR-5c, was fourfold resistant to ddC, threefold resistant to 2',3'-dideoxyinosine, and more than fourfold resistant to phosphonoformic acid. DCR-5c displayed little or no resistance to (-)-beta-2',3'-dideoxy-3'-thiacytidine, 3'-azido-3'-deoxythymidine, or 9-(2-phosphonylmethoxyethyl) adenine. Reverse transcriptase purified from DCR-5c was less susceptible to inhibition by ddCTP, phosphonoformic acid, ddATP, or azido-dTTP than the wild-type FIV reverse transcriptase. Sequence analysis of DCR-5c revealed a single base change (G to C at nucleotide 2342) in the reverse transcriptase-encoding region of FIV. This mutation results in substitution of His for Asp at codon 3 of FIV reverse transcriptase. The role of this mutation in ddC resistance was confirmed by site-directed mutagenesis.
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PMID:Selection and characterization of a mutant of feline immunodeficiency virus resistant to 2',3'-dideoxycytidine. 884 58

Two types of cDNAs encoding thyrotropin-releasing hormone (TRH) precursors (TRH-A and TRH-B) were amplified from hypothalamic mRNA of sockeye salmon by reverse transcriptase-polymerase chain reaction (RT-PCR). The amplification was achieved using two primers which correspond to TRH progenitor sequence (Lys/Arg-Arg-Gln-His-Pro-Gly-Lys/Arg-Arg). A full length cDNA encoding TRH-A was obtained by 5'- and 3'-RACE methods. It has a length of 1324 base pairs (bp) that contains sequences of 5' and 3' untranslated regions and an open reading frame of 259 codons. The sockeye salmon TRH-A deduced from the nucleotide sequence tandemly contains 8 copies of TRH progenitor sequences. Another cDNA which encodes a part of TRH-B consists of 242 bp, and the sequence homology between TRH-A and -B cDNAs is 90%. The result of Southern blot analysis of sockeye and masu salmon genomic DNAs supported the evidence that there are at least two TRH genes in the salmonid. A RT-PCR analysis of TRH gene expression in various tissues of sockeye salmon showed that strong expression was observed only in the brain. The primary structure of the sockeye salmon TRH-A shares low similarity to those of human, rat and Xenopus TRH precursors (35, 27 and 44%, respectively). However, their hydropathy profiles were almost the same with each other. The profile of sockeye salmon TRH-A showed the presence of two discrete hydrophobic regions, one in the N-terminal region which corresponds to the signal peptide and the other in the C-terminal region. All of the repetitive TRH progenitor sequences are included in three hydrophilic regions easily recognizable. The present results thus suggest that the three-dimensional structures of TRH precursors are highly conserved, although the primary structures of TRH precursors have diverged through the evolutionary pathway of vertebrates.
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PMID:Hydropathy profiles of predicted thyrotropin-releasing hormone precursors are highly conserved despite low similarity of primary structures. 887 18

Exposure to 3TC of HIV-1 mutant strains containing non-nucleoside reverse transcriptase inhibitor (NNRTI)-specific mutations in their reverse transcriptase (RT) easily selected for double-mutant viruses that had acquired the characteristic 184-Ile mutation in their RT in addition to the NNRTI-specific mutations. Conversely, exposure of 3TC-resistant 184-Val mutant HIV-1 strains to nine different NNRTIs resulted in the rapid emergence of NNRTI-resistant virus strains at a time that was not more delayed than when wild-type HIV-1(IIIB) was exposed to the same compounds. The RTs of these resistant virus strains had acquired the NNRTI-characteristic mutations in addition to the preexisting 184-Val mutation. Surprisingly, when the 184-Ile mutant HIV-1 was exposed to a variety of NNRTIs, the 188-His mutation invariably occurred concomitantly with the 184-Ile mutation in the HIV-1 RT. Breakthrough of this double-mutant virus was markedly accelerated as compared with the mutant virus selected from the wild-type or 184-Val mutant HIV-1 strain. The double (184-Ile + 188-His) mutant virus showed a much more profound resistance profile against the NNRTIs than the 188-His HIV-1 mutant. In contrast with the sequential chemotherapy, concomitant combination treatment of HIV-1-infected cells with 3TC and a variety of NNRTIs resulted in a dramatic delay of virus breakthrough and resistance development.
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PMID:Concomitant combination therapy for HIV infection preferable over sequential therapy with 3TC and non-nucleoside reverse transcriptase inhibitors. 891 60

Using the structured RNA encapsidation signal (D(epsilon)) and the reverse transcriptase (P protein) of duck hepatitis B virus (DHBV) as an example, we devised a sensitive mapping procedure that yields accurate information on the minimal RNA sequence required for interaction with a few nanograms of an RNA-binding protein. RNAs from pools of end-labeled, partially hydrolyzed transcripts that bound to in vitro translated His-tagged P protein were isolated using immobilized Ni2+-ions. Size analysis by PAGE is consistent with a gradual gain in binding-competence from a minimum of 5 to a maximum of 8 base pairs in the basal stem of D(epsilon). The procedure should be generally applicable to the convenient and precise fine mapping of RNA-protein interactions.
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PMID:A sensitive procedure for mapping the boundaries of RNA elements binding in vitro translated proteins defines a minimal hepatitis B virus encapsidation signal. 893 98

The initiation of reverse transcription of the human immunodeficiency virus type 1 (HIV-1) genome requires cellular tRNA(Lys,3) as a primer and occurs at a site in the viral RNA genome, designated as the primer binding site (PBS), which is complementary to the 3'-terminal 18 nucleotides of tRNA(Lys,3). We previously described an HIV-1 virus [designated as HXB2(His-AC)], which contained a sequence within the U5 region complementary to the anticodon region of tRNA(His) in addition to a PBS complementary to the 3'-terminal 18 nucleotides of the tRNA(His). That virus maintained a PBS complementary to tRNA(His) after extended in vitro culture (Wakefield et al., J. Virol. 70, 966-975, 1996). In the present study, we report that subcloning a 200-base-pair DNA fragment encompassing the U5 and PBS regions from an integrated provirus of HXB2(His-AC) back into the wild-type genome (pHXB2) resulted in an infectious virus, designated as HXB2(His-AC-gac), which again stably maintained a PBS complementary to tRNA(His). DNA sequence analysis of the 200-base-pair region revealed only three nucleotide changes from HXB2(His-AC): a T-to-G change at nucleotide 174, a G-to-A change at nucleotide 181, and a T-to-C change at nucleotide 200. The new mutant virus replicated in CD4+ Sup T1 cells similarly to the wild-type virus. Comparison of the nucleotide sequence of nucleocapsid gene of the wild-type and HXB2 (His-AC-gac) virus revealed no differences. Although we found numerous mutations in the reverse transcriptase gene in proviral clones derived from HXB2 (His-AC-gac), no common mutations were found among the 13 clones examined. Comparison of the virion-associated tRNAs of HXB2(His-AC-gac) with those of the wild type revealed that both viruses incorporated a similar subset of cellular tRNAs, with tRNA(Lys,3) being the predominant tRNA found within virions. There was no selective enrichment for tRNA(His) within virions of HXB2(His-AC-gac) virus which selectively use tRNA(His) to initiate reverse transcription. The results of these studies suggest that the U5 and PBS regions in the viral RNA genome are important determinants for HXB2(His-AC) viruses in the selective use of tRNA(His) to initiate reverse transcription.
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PMID:Nucleotide sequences within the U5 region of the viral RNA genome are the major determinants for an human immunodeficiency virus type 1 to maintain a primer binding site complementary to tRNA(His). 895 50

For bacterial expression of rat anaphylatoxin C5a, the cDNA was amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) using rat liver RNA and degenerate primers designed according to the published amino acid sequence [1]. Surprisingly, the amino acid sequence deduced from cDNA differed at positions 55 (N for K), 63 (K for H), 67 (E for N), 68 (S for E) and 69 (H for S) from the published sequence. The overall amino acid composition, however, was unchanged because these 5 amino acids were located at different positions compared to the published sequence. As a consequence, the proposed N-glycosylation site was absent, suggesting O-glycosylation of the mature molecule. Recombinant rat C5a with a 6 histidine tag at the N-terminus was expressed in bacteria, purified and renatured. The peptide was as potent as recombinant human C5a in eliciting lysosomal enzyme release from human granulocytes.
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PMID:Nucleotide and corrected amino acid sequence of the functional recombinant rat anaphylatoxin C5a. 911 48

cDNA clones encoding two new Arabidopsis thaliana peroxidases, ATP 1a and ATP 2a, have been identified by searching the Arabidopsis database of expressed sequence tags (dbEST). They represent a novel branch of hitherto uncharacterized plant peroxidases which is only 35% identical in amino acid sequence to the well characterized group of basic plant peroxidases represented by the horseradish (Armoracia rusticana) isoperoxidases HRP C, HRP E5 and the similar Arabidopsis isoperoxidases ATP Ca, ATP Cb, and ATP Ea. However ATP 1a is 87% identical in amino acid sequence to a peroxidase encoded by an mRNA isolated from cotton (Gossypium hirsutum). As cotton and Arabidopsis belong to rather diverse families (Malvaceae and Crucifereae, respectively), in contrast with Arabidopsis and horseradish (both Crucifereae), the high degree of sequence identity indicates that this novel type of peroxidase, albeit of unknown function, is likely to be widespread in plant species. The atp 1 and atp 2 types of cDNA sequences were the most redundant among the 28 different isoperoxidases identified among about 200 peroxidase encoding ESTs. Interestingly, 8 out of totally 38 EST sequences coding for ATP 1 showed three identical nucleotide substitutions. This variant form is designated ATP 1b. Similarly, six out of totally 16 EST sequences coding for ATP 2 showed a number of deletions and nucleotide changes. This variant form is designated ATP 2b. The selected EST clones are full-length and contain coding regions of 993 nucleotides for atp 1a, and 984 nucleotides for atp 2a. These regions show 61% DNA sequence identity. The predicted mature proteins ATP 1a, and ATP 2a are 57% identical in sequence and contain the structurally and functionally important residues, characteristic of the plant peroxidase superfamily. However, they do show two differences of importance to peroxidase catalysis: (1) the asparagine residue linked with the active site distal histidine via hydrogen bonding is absent; (2) an N-glycosylation site is located right at the entrance to the heme channel. The reverse transcriptase polymerase chain reaction (RT-PCR) was used to identify mRNAs coding for ATP 1a/b and ATP 2a/b in germinating seeds, seedlings, roots, leaves, stems, flowers and cell suspension culture using elongation factor 1alpha (EF-1alpha) for the first time as a positive control. Both mRNAs were transcribed at levels comparable to EF-1alpha in all plant tissues investigated which were more than two days old, and in cell suspension culture. In addition, the mRNA coding for ATP 1a/b was found in two day old germinating seeds. The abundant transcription of ATP 1a/b and ATP 2a/b is in line with their many entries in dbEST, and indicates essential roles for these novel peroxidases.
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PMID:Sequence and RT-PCR expression analysis of two peroxidases from Arabidopsis thaliana belonging to a novel evolutionary branch of plant peroxidases. 913 61

By using biochemical, immunological, and molecular strategies we have identified and cloned a cDNA encoding a protease from tomato (Lycopersicon esculentum) plants (P69B) that is part of a proteolytic system activated in the plant as a result of infection with citrus exocortis viroid. This new protease is closely related, in terms of amino acid sequence and structural organization, to the previously identified pathogenesis-related subtilisin-like protease (Tornero, P., Conejero, V., and Vera, P. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 6332-6337). The 745-residue amino acid sequence of P69B begins with a cleavable signal peptide, contains a prodomain and a 631-residue mature domain which is homologous to the catalytic modules of bacterial subtilisins and eukaryotic Kex2-like proteases. Within the catalytic domain, the essential Asp, His, and Ser residues that conform the catalytic triad of this family of proteases are conserved in P69B. Northern blot and reverse transcriptase-polymerase chain reaction analysis demonstrated widespread induced expression of the 2.5-kilobase hybridizing mRNA in plant tissues as a consequence of viroid infection. We propose that P69B is a member of a complex gene family of plant Kex2/subtilisin-like proteases presumably involved in a number of specific proteolytic events activated during pathogenesis in plants and that takes place in the extracellular matrix.
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PMID:Identification of a new pathogen-induced member of the subtilisin-like processing protease family from plants. 916 80

We have previously described the private or family platelet antigen, Gro(a), which was identified in a case of neonatal alloimmune thrombocytopenia. The Gro(a) antigen was found to be located on the GP IIIa (beta3) subunit of the GP IIb/IIIa complex, the most prominent fibrinogen receptor of platelets. Initial experiments to characterize the Gro(a) antigen at the molecular genetic level were unsuccessful. We therefore decided to use a different strategy to unravel the molecular basis of this antigen. Platelet GP IIIa mRNA of a Gro(a+) and a Gro(a-) donor was amplified with suitable primers in a reverse transcriptase-polymerase chain reaction (RT-PCR) and subjected to single-strand conformational polymorphism (SSCP) analysis. Three regions of the amplified GP IIIa cDNA derived from the Gro(a+) donor showed a different SSCP pattern when compared to that of the Gro(a-) donor. Direct nucleotide sequence analysis of these three segments revealed that two of them contained silent substitutions, A1163C, A1553G and G1565A. The first and the latter changes were described previously. In the third segment a G1996A mutation was found, predicting an arginine --> histidine substitution at position 633 of the mature glycoprotein. PCR-ASRA (allele-specific restriction enzyme analysis) performed on cDNA as well as on genomic DNA with the restriction enzyme MaeIII showed that the His633 form of GPIIIa is restricted to the Gro(a+) phenotype. The observed mutation is three amino acids upstream of the mutation underlying the HPA-8/Sr system (Arg636Cys), suggesting this region of GP IIIa to be susceptible for mutations. Moreover, the presence of a silent mutation and two low-frequency forms of the silent polymorphisms strongly suggests that the G1996A mutation did not occur in a direct ancestral allele.
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PMID:The Arg633His substitution responsible for the private platelet antigen Gro(a) unravelled by SSCP analysis and direct sequencing. 916 97


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