Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
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African swine fever virus (ASFV) encodes a novel DNA polymerase, constituted of only 174 amino acids, belonging to the polymerase (pol) X family of DNA polymerases. Biochemical analyses of the purified enzyme indicate that ASFV pol X is a monomeric DNA-directed DNA polymerase, highly distributive, lacking a proofreading 3'-5'-exonuclease, and with a poor discrimination against dideoxynucleotides. A multiple alignment of family X DNA polymerases, together with the extrapolation to the crystal structure of mammalian DNA polymerase beta (pol beta), showed the conservation in ASFV pol X of the most critical residues involved in DNA binding, nucleotide binding, and catalysis of the polymerization reaction. Therefore, the 20-kDa ASFV pol X most likely represents the minimal functional version of an evolutionarily conserved pol beta-type DNA polymerase core, constituted by only the "palm" and "thumb" subdomains. It is worth noting that such an "unfingered" DNA polymerase is able to handle templated DNA polymerization with a considerable high fidelity at the base discrimination level. Base excision repair is considered to be a cellular defense mechanism repairing modified bases in DNA. Interestingly, the fact that ASFV pol X is able to conduct filling of a single nucleotide gap points to a putative role in base excision repair during the ASFV life cycle.
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PMID:Characterization of an African swine fever virus 20-kDa DNA polymerase involved in DNA repair. 938 36

DNA viruses as their host cells require a DNA-dependent DNA polymerase (Pol) to faithfully replicate their genomic information. Large eukaryotic DNA viruses as well as bacterial viruses encode a specific Pol equipped with a proofreading 3'-5'-exonuclease, and other replication proteins. All known viral Pol belong to family A and family B Pol. Common to all viral Pol is the conservation of the 3'-5'-exonuclease domain manifested by the three sequence motifs Exo I, Exo II, and Exo III. The polymerase domain of family A and B Pol is clearly distinguishable. Family A Pol share 9 distinct consensus sequences, only two of them are convincingly homologous to sequence motif B of family B Pol. The putative sequence motifs A, B, and C of the polymerase domain are located near the C-terminus in family A Pol and more central in family B Pol. Thus, family A Pol show a significant greater spacing between the Exo III motif and the Pol motif A that is especially extended in the case of the mitochondrial Pol gamma. From each host and virus family whenever possible the consensus sequences of two distantly related polymerase species were aligned for assessment of phylogenetic trees, using both maximum parsimony and distance methods, and evaluated by bootstrap analysis. Three alternative methods yielded trees with identical major groupings. A subdivision of viral family B Pol was achieved resulting in a branch with Pol carrying out a protein-primed mechanism of DNA replication, including adenoviruses, bacteriophages and linear plasmids of plant and fungal origin. Archaebacterial Pol and cellular Pol epsilon were consistently found at the base of this branch. Another major branch comprised alpha- and delta-like viral Pol from mammalian herpesviruses, fish lymphocystis disease virus, insect ascovirus, and chlorella virus. Due to a lower branch integrity Pol of T-even bacteriophages, poxviruses, African swine fever virus, fish herpesvirus, and baculoviruses were not clearly resolved and placed in alternate groupings. A composite and rooted tree of family A and B Pol shows that viral Pol with a protein-priming requirement represent the oldest viral Pol species suggesting that the protein-primed mechanism is one of the earliest modes of viral DNA replication.
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PMID:Evolution of viral DNA-dependent DNA polymerases. 956 90

We recently demonstrated that African swine fever virus DNA polymerase X (Pol X) is extremely error-prone during single-nucleotide gap-filling and that the downstream ASFV DNA ligase seals 3' mismatched nicks with high efficiency. To further assess the credence of our hypothesis that these proteins may promote viral diversification by functioning within the context of an aberrant DNA repair pathway, herein we characterize the third protein expected to function in this system, a putative AP endonuclease (APE). Assays of the purified protein using oligonucleotide substrates unequivocally establish canonical APE activity, 3'-phosphatase and 3'-phosphodiesterase activities (in the context of a single-nucleotide gap), 3' --> 5' exonuclease activity (in the context of a nick), and nucleotide incision repair activity against 5,6-dihydrothymine. The 3' --> 5' exonuclease activity is shown to be highly dependent upon the identity of the nascent 3' base pair and to be inhibited when 2-deoxyribose-5-phosphate, rather than phosphate, constitutes the 5' moiety of the nick. ASFV APE retains activity when assayed in the presence of EDTA but is inactivated by incubation with 1,10-phenanthroline in the absence of a substrate, suggesting that it is an endonuclease IV homologue possessing intrinsic metal cofactors. The activities of ASFV APE, when considered alongside those of Pol X and ASFV DNA ligase, provide an enhanced understanding of (i) the types of damage that are likely to be sustained by the viral genome and (ii) the mechanisms by which the minimalist ASFV DNA repair pathway, consisting of just these three proteins, contributes to the fitness of the virus.
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PMID:Contributions of an endonuclease IV homologue to DNA repair in the African swine fever virus. 1650 34