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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Computer-assisted comparison of the nonstructural polyprotein of hepatitis E virus (HEV) with proteins of other positive-strand RNA viruses allowed the identification of the following putative functional domains: (i) RNA-dependent RNA polymerase, (ii) RNA helicase, (iii) methyltransferase, (iv) a domain of unknown function ("X" domain) flanking the papain-like protease domains in the polyproteins of animal positive-strand RNA viruses, and (v) papain-like cysteine protease domain distantly related to the putative papain-like protease of rubella virus (RubV). Comparative analysis of the polymerase and helicase sequences of positive-strand RNA viruses belonging to the so-called "alpha-like" supergroup revealed grouping between HEV, RubV, and beet necrotic yellow vein virus (BNYVV), a plant furovirus. Two additional domains have been identified: one showed significant conservation between HEV, RubV, and BNYVV, and the other showed conservation specifically between HEV and RubV. The large nonstructural proteins of HEV, RubV, and BNYVV retained similar domain organization, with the exceptions of relocation of the putative protease domain in HEV as compared to RubV and the absence of the protease and X domains in BNYVV. These observations show that HEV, RubV, and BNYVV encompass partially conserved arrays of distinctive putative functional domains, suggesting that these viruses constitute a distinct monophyletic group within the alpha-like supergroup of positive-strand RNA viruses.
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PMID:Computer-assisted assignment of functional domains in the nonstructural polyprotein of hepatitis E virus: delineation of an additional group of positive-strand RNA plant and animal viruses. 151 55

The 5'-most gene, gene 1, of the genome of murine coronavirus, mouse hepatitis virus (MHV), is presumed to encode the viral RNA-dependent RNA polymerase. We have determined the complete sequence of this gene of the JHM strain by cDNA cloning and sequencing. The total length of this gene is 21,798 nucleotides long, which includes two overlapping, large open reading frames. The first open reading frame, ORF 1a, is 4488 amino acids long. The second open reading frame, ORF 1b, overlaps ORF 1a for 75 nucleotides, and is 2731 amino acids long. The overlapping region may fold into a pseudoknot RNA structure, similar to the corresponding region of the RNA of avian coronavirus, infectious bronchitis virus (IBV). The in vitro transcription and translation studies of this region indicated that these two ORFs were most likely translated into one polyprotein by a ribosomal frameshifting mechanism. Thus, the predicted molecular weight of the gene 1 product is more than 800,000 Da. The sequence of ORF 1b is very similar to the corresponding ORF of IBV. In contrast, the ORF 1a of these two viruses differ in size and have a high degree of divergence. The amino acid sequence analysis suggested that ORF 1a contains several functional domains, including two hydrophobic, membrane-anchoring domains, and three cysteine-rich domains. It also contains a picornaviral 3C-like protease domain and two papain-like protease domains. The presence of these protease domains suggests that the polyprotein is most likely processed into multiple protein products. In contrast, the ORF 1b contains polymerase, helicase, and zinc-finger motifs. These sequence studies suggested that the MHV gene 1 product is involved in RNA synthesis, and that this product is processed autoproteolytically after translation. This study completes the sequence of the MHV genome, which is 31 kb long, and constitutes the largest viral RNA known.
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PMID:The complete sequence (22 kilobases) of murine coronavirus gene 1 encoding the putative proteases and RNA polymerase. 184 89

Computer-assisted analysis of the putative polypeptide products encoded by the two open reading frames present in a large virus-like double-stranded RNA, L-dsRNA, associated with hypovirulence of the chestnut blight fungus, Cryphonectria parasitica, revealed five distinct domains with significant sequence similarity to previously described conserved domains within plant potyvirus-encoded polyproteins. These included the putative RNA-dependent RNA polymerase, RNA helicase, two papain-like cysteine proteases related to the potyvirus helper-component protease, and a cysteine-rich domain of unknown function similar to the N-terminal portion of the potyvirus helper-component protein. Phylogenetic trees derived from the alignment of the polymerase domains of L-dsRNA, a subset of positive-stranded RNA viruses, and double-stranded RNA viruses, using three independent algorithms, suggested that the hypovirulence-associated dsRNA and potyvirus genomes share a common ancestry. However, comparison of the organization of the conserved domains within the encoded polyproteins of the respective viruses indicated that the proposed subsequent evolution involved extensive genome rearrangement.
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PMID:Evidence for common ancestry of a chestnut blight hypovirulence-associated double-stranded RNA and a group of positive-strand RNA plant viruses. 196 31

The 5' most gene of the murine coronavirus genome, gene 1, is presumed to encode the viral RNA-dependent RNA polymerase. cDNA clones representing this gene encompass more than 22 kilobases, suggesting that this region may encode multifunctional polyprotein(s). It has previously been shown that the N-terminal portion of this gene product is cleaved into a protein of 28 kilodaltons (p28). To identify possible functional domains of gene 1 and further understand the mechanism of synthesis of the p28 protein, cDNA clones representing the 5'-most 5.3 kilobases of the murine coronavirus mouse hepatitis virus strain JHM were subcloned into pT7 vectors from which RNAs were transcribed and translated in vitro. Although p28 is encoded from the first 1 kilobase at the 5'-end of the genome, translation of in vitro transcribed RNAs indicated that this protein was not detected unless the product of the entire 5.3 kilobase region was synthesized. This result suggests that the region close to 5.3 kilobases from the 5'-end of the genomic RNA is essential for the proteolytic cleavage and may contain an autoproteolytic activity. Addition of the protease inhibitor ZnCl2 blocked cleavage of the p28 protein. Site-directed mutagenesis of Cys residue 1137 significantly reduced the cleavage of the p28 protein, indicating that this residue, probably in conjunction with a downstream domain, plays an essential role in the cleavage of p28. This Cys residue may be part of a papain-like autoprotease encoded by gene 1.
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PMID:Murine coronavirus gene 1 polyprotein contains an autoproteolytic activity. 196 14

The sequence of the entire genome of citrus tristeza virus (CTV), Florida isolate T36, was completed. The 19,296-nt CTV genome encodes 12 open reading frames (ORFs) potentially coding for at least 17 protein products. The 5'-proximal ORF 1a starts at nucleotide 108 and encodes a large polyprotein with calculated MW of 349 kDa containing domains characteristic of (from 5' to 3') two papain-like proteases (P-PRO), a methyltransferase (MT), and a helicase (HEL). Alignment of the putative P-PRO sequences of CTV with the related proteases of beet yellows closterovirus (BYV) and potyviruses allowed the prediction of catalytic cysteine and histidine residues as well as two cleavage sites, namely Val-Gly/Gly for the 5' proximal P-PRO domain and Met-Gly/Gly for the 5' distal P-PRO domain. The autoproteolytic cleavage of the polyprotein at these sites would release two N-terminal leader proteins of 54 and 55 kDa, respectively, and a 240-kDa C-terminal fragment containing MT and HEL domains. The apparent duplication of the leader domain distinguishes CTV from BYV and accounts for most of the size increase in the ORF 1a product of CTV. The downstream ORF 1b encodes a 57-kDa putative RNA-dependent RNA polymerase (RdRp), which is probably expressed via a +1 ribosomal frameshift. Sequence analysis of the frameshift region suggests that this +1 frameshift probably occurs at a rare arginine codon CGG and that elements of the RNA secondary structure are unlikely to be involved in this process. The complete polyprotein resulting from this frameshift event has a calculated MW of 401 kDa and after cleavage of the two N-terminal leaders would yield a 292-kDa protein containing the MT, HEL, and RdRp domains. Phylogenetic analysis of the three replication-associated domains, MT, HEL, and RdRp, indicates that CTV and BYV form a separate closterovirus lineage within the alpha-like supergroup of positive-strand RNA viruses. Two gene blocks or modules can be easily identified in the CTV genome. The first includes the replicative MT, HEL, and RdRp genes and is conserved throughout the entire alpha-like superfamily. The second block consists of five ORFs, 3 to 7, conserved among closteroviruses, including genes for the CTV homolog of HSP70 proteins and a duplicate of the coat protein gene. The 3'-terminal ORFs 8 to 11 encode a putative RNA-binding protein (ORF 11), and three proteins with unknown functions; this gene array is poorly conserved among closteroviruses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Complete sequence of the citrus tristeza virus RNA genome. 774 24

The sequence of 8734 nucleotides (nt) from the 5'-end of the beet yellows closterovirus (BYV) RNA was determined to complete the 15,480-nt sequence of the virus genome. The 5'-terminal two-thirds of the sequence are occupied by two overlapping open reading frames (ORFs) 1a and 1b, encoding products with calculated M(r) of 295K and 48K, respectively. The RNA sequence surrounding the stop codon in ORF 1a shows structural elements typical of ribosomal frameshifting signals in a number of animal and plant viruses. It is predicted that the ORF 1b product is expressed via a +1 ribosomal frameshifting as the 348K ORF 1a/1b fusion protein. This putative protein contains the array of methyltransferase, RNA helicase, and RNA-dependent RNA polymerase domains that is conserved in the Sindbis-like supergroup of positive-strand RNA viruses. The 348K protein of BYV is longer than the putative replicases of the most closely related viruses (tobra- and tobamoviruses) by about 1300 amino acids distributed between two unique regions, one at the N-terminus, and the other in the central portion. The N-terminal domain showed sequence similarity to the helper component papain-like protease of potyviruses. By using in vitro translation of the T7 transcripts encoding the N-terminal 92K peptide of the BYV ORF 1a product, we found that the N-terminal fragment of 588 amino acids is released from the translation product by cleavage at the Gly-Gly dipeptide. Site-directed mutagenesis of either of the predicted catalytic residues Cys-509 and His-569 or of the Gly-588 at the cleavage site completely abolished the cleavage. The central unique region of the 348K protein contains a domain distantly resembling the aspartic protease of HIV and other lentiviruses. As shown previously, the 3'-terminal portion of the BYV genome encompasses seven more ORFs, one of which codes for a protein related to the HSP70 cell heat shock proteins, whereas two others encode the capsid protein and its diverged copy. Thus, despite the apparent evolutionary relationship with Sindbis-like viruses, BYV comprises a collection of genomic modules absorbed from different sources and has a unique expression strategy.
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PMID:Beet yellows closterovirus: complete genome structure and identification of a leader papain-like thiol protease. 825 66

Despite the rapid mutational change that is typical of positive-strand RNA viruses, enzymes mediating the replication and expression of virus genomes contain arrays of conserved sequence motifs. Proteins with such motifs include RNA-dependent RNA polymerase, putative RNA helicase, chymotrypsin-like and papain-like proteases, and methyltransferases. The genes for these proteins form partially conserved modules in large subsets of viruses. A concept of the virus genome as a relatively evolutionarily stable "core" of housekeeping genes accompanied by a much more flexible "shell" consisting mostly of genes coding for virion components and various accessory proteins is discussed. Shuffling of the "shell" genes including genome reorganization and recombination between remote groups of viruses is considered to be one of the major factors of virus evolution. Multiple alignments for the conserved viral proteins were constructed and used to generate the respective phylogenetic trees. Based primarily on the tentative phylogeny for the RNA-dependent RNA polymerase, which is the only universally conserved protein of positive-strand RNA viruses, three large classes of viruses, each consisting of distinct smaller divisions, were delineated. A strong correlation was observed between this grouping and the tentative phylogenies for the other conserved proteins as well as the arrangement of genes encoding these proteins in the virus genome. A comparable correlation with the polymerase phylogeny was not found for genes encoding virion components or for genome expression strategies. It is surmised that several types of arrangement of the "shell" genes as well as basic mechanisms of expression could have evolved independently in different evolutionary lineages. The grouping revealed by phylogenetic analysis may provide the basis for revision of virus classification, and phylogenetic taxonomy of positive-strand RNA viruses is outlined. Some of the phylogenetically derived divisions of positive-strand RNA viruses also include double-stranded RNA viruses, indicating that in certain cases the type of genome nucleic acid may not be a reliable taxonomic criterion for viruses. Hypothetical evolutionary scenarios for positive-strand RNA viruses are proposed. It is hypothesized that all positive-strand RNA viruses and some related double-stranded RNA viruses could have evolved from a common ancestor virus that contained genes for RNA-dependent RNA polymerase, a chymotrypsin-related protease that also functioned as the capsid protein, and possibly an RNA helicase.
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PMID:Evolution and taxonomy of positive-strand RNA viruses: implications of comparative analysis of amino acid sequences. 826 9

Gene 1, the putative RNA replicase gene of coronaviruses, is expressed via two large overlapping open reading frames (ORF 1a and ORF 1b). We have determined the nucleotide sequence of ORF 1a, encoded within the first 13.7 kb of gene 1, for the coronavirus mouse hepatitis virus strain A59 (MHV-A59). Putative papain-like protease domains, a picornavirus 3C-like protease domain, two hydrophobic domains, and a domain "X" of unknown function, previously identified in other coronaviruses (1-3), are also present in ORF 1a of MHV-A59. Comparison between the ORF 1a sequence of MHV-A59 and the published sequence of the JHM strain of MHV (2) showed a high degree of similarity with the exception of several short regions. We sequenced one region of MHV-JHM that contained an 18 amino acid insertion relative to A59 and four other regions in which the sequences of the two strains differed. The MHV-2 and MHV-3 strains were also sequenced in some of these regions. Our analysis confirmed the presence of only one heterogeneous region in ORF 1a of MHV-A59 and MHV-JHM which is also present in MHV-2. Our findings indicate the need to modify the published sequence of MHV-JHM.
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PMID:Mouse hepatitis virus strain A59 RNA polymerase gene ORF 1a: heterogeneity among MHV strains. 829 Dec 54

The apparently complete sequence of the RNA genome of the neurovirulent isolate of lactate dehydrogenase-elevating virus (LDV-C) has been determined. The LDV-C genome is at least 14,222 nucleotides in length and contains eight open reading frames (ORFs). ORF 1a, which encodes a protein of 242.8 kDa and is located at the 5' end of the genome, contains at least two putative papain-like cysteine protease domains, and one putative chymotrypsin-like serine protease domain. This ORF terminates with a UAG stop codon that can be bypassed if a -1 frameshift occurs. The frameshift region consists of a heptanucleotide "slippery" sequence, 5'-UUUAAAC-3', followed by a putative pseudoknot. ORF 1b encodes a protein of 155.4 kDa containing, in its N-terminal portion, an RNA-dependent RNA polymerase and an RNA helicase domain separated by a Zn finger domain. Another domain of unknown function that is also conserved in coronaviruses and toroviruses is located at the C-terminus of the ORF 1b product. Three cleavage sites in the ORF 1a polyprotein and three in the ORF 1b polyprotein were predicted for the chymotrypsin-like protease and tentatively delimit the mature nonstructural proteins of LDV. Six small, overlapping 3' ORFs (ORFs 2 through 7) encode proteins with calculated sizes of 25.8, 21.6, 19.8, 23.9, 18.9, and 12.3 kDa. ORF 7 encodes the virion nucleocapsid protein Vp-1, while ORF 6 encodes the nonglycosylated envelope protein Vp2. ORFs 5, 4, 3, and 2 each encode glycoproteins which may be virion envelope proteins. LDV is closely related to equine arteritis virus, Lelystad virus (LV), and simian hemorrhagic fever virus. These four viruses belong to a new group of positive-strand RNA viruses and are related to coronaviruses and toroviruses.
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PMID:Complete genomic sequence and phylogenetic analysis of the lactate dehydrogenase-elevating virus (LDV). 838 75

The entire genome of grapevine leafroll-associated closterovirus-2 (GLRaV-2), except the exact 5' terminus, was cloned and sequenced. The sequence encompasses nine open reading frames (ORFs) which include, in the 5' to 3' direction, an incomplete ORF1a encoding a putative viral polyprotein and eight ORFs that encode proteins of 52 kDa (ORF1b), 6 kDa (ORF2), 65 kDa (ORF3), 63 kDa (ORF4), 25 kDa (ORF5), 22 kDa (ORF6), 19 kDa (ORF7) and 24 kDa (ORF8) respectively, and 216 nucleotides of the 3' untranslated region. An incomplete ORF1a potentially encoded a large polyprotein containing the conserved domains characteristic of a papain-like protease, methyltransferase and helicase. ORF1b potentially encoded a putative RNA-dependent RNA polymerase. The expression of ORF1b may be via a +1 ribosomal frameshift mechanism, similar to other closteroviruses. A unique gene array, which is conserved in other closteroviruses, was also identified in GLRaV-2; it includes genes encoding a 6 kDa small hydrophobic protein, 65 kDa heat shock protein 70, 63 kDa protein of function unknown, 25 kDa coat protein duplicate and 22 kDa coat protein. Identification of ORF6 (22 kDa) as the coat protein gene was further confirmed by in vivo expression in E. coli and immunoblotting. Phylogenetic analysis comparing different genes of GLRaV-2 with those of other closteroviruses demonstrated a close relationship with beet yellows virus (BYV), beet yellow stunt virus and citrus tristeza virus. GLRaV-2 is the only closterovirus, so far, that matches the genome organization of the type member of the group, BYV, and thus can be unambiguously classified as a definitive member of the genus Closterovirus.
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PMID:Nucleotide sequence and genome organization of grapevine leafroll-associated virus-2 are similar to beet yellows virus, the closterovirus type member. 960 45


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