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)

Analogues of the 2',5'-linked adenylate trimers monophosphate (p5'A2'p5'A2'p5'A) containing 8-hydroxypropyladenosine, 8-bromoadenosine, and 8-hydroxyadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. p5'AHPr2'p5'AHPr2'p5'AHPr (pAHPr3) (1b) and p5'ABr2'p5'ABr2'p5'ABr (pABr3) (1d) were markedly decreased in ability to bind to the 2-5A dependent endonuclease. On the other hand, analogue of the 2',5'-linked adenylate trimer monophosphate substituted by 8-hydroxyadenosine in the first, second, and third nucleotide position was bound about as well as parent 2-5A [pppA(2'p5'A)2] (p3A3) (1e) to RNase L. Additionally, p5'AOH2'p5'AOH2'p5'AOH (pAOH3) (1c) was as active as parent 2-5A in the rRNA cleavage assay, while pAHPr3 (1b) and pABr3 (1d) were devoid of activity. The 8-substituted analogues of 2-5A were more resistant to the degradation by the (2',5') phosphodiesterase. Finally of particular interest was monophosphate, pAOH3 (1c) which possessed nearly 100% of the translation inhibitory activity of 2-5A triphosphate itself. These results suggest that changes in the base-sugar torsion angles of 2-5A may modulate both binding to and activation of mouse L cell RNase L.
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PMID:Purine 8-substitution modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. 202 89

The stereoconfiguration of the diester bond of phosphorothioate analogs of 2-5A strongly influenced lability to enzymatic hydrolysis by cellular and serum phosphodiesterases. Bonds containing the Sp configuration were extremely resistant to hydrolysis compared to the corresponding Rp configuration linkages. The rate of hydrolysis of the diester bond was influenced by chain length of the adenylate oligomer, with a stability ranking of dimer greater than trimer greater than tetramer; as well as by the stereo-configuration of the diester bond adjacent to the one undergoing hydrolysis. The anti-proliferative and anti-viral activities of these various phosphorothioate 2-5A core analogs were assessed. The most stable analogs possessed the greatest biological activities (at 25-50 microM), which were not readily attributable to 2-5A degradation products or endonuclease activation. A 5'-triphosphate analog of 2-5A containing a phosphorothioate substituent in the gamma-position was obtained in good yield by enzymatic synthesis from ATP-gamma S. This gamma-thio 2-5A analog showed full biological activity.
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PMID:2-5A analogs as mechanistic probes of the 2-5A system: stereoconfiguration of phosphorothioate analogs of 2-5A markedly influences metabolic stability. 300 74

Analogs of the 2',5'-linked adenylate trimer diphosphate (pp5'A2'p5'A2'p5'A or 2-5A) containing 8-bromoadenosine in the first, second, third, first and third, or second and third nucleotide positions (from the 5' terminus) were synthesized and found to vary dramatically in their ability to bind to and activate the RNase L of mouse L cells. Whenever the 8-bromoadenosine residue was substituted for adenosine in the first or 5'-terminal residue, there resulted a marked decrease in ability to bind to the 2-5A-dependent endonuclease. A similar result was obtained when the second adenosine nucleotide was replaced by 8-bromoadenosine. To the contrary, all analogs that bore an 8-bromoadenosine (br8A) in the third or 2'-terminal position were bound about as well as parent 2-5A to RNase L. Additionally, the 5'-diphosphate pp5'A2'p5'A2'p5' (br8A) was 10 times more effective than 2-5A as an inhibitor of translation. An increase in stability could not explain this significantly enhanced ability since the 2'-terminally brominated analog showed a similar half-life to 2-5A itself. Finally of particular interest was the analog monophosphate p5'A2'p5'(br8A)2'p5'(br8A) which possessed nearly 10% of the translational inhibitory activity of 2-5A triphosphate itself. These results suggest that changes in the base-sugar torsion angles of 2-5A may modulate both binding to and activation of mouse L cell RNase L.
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PMID:Purine 8-bromination modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. Possible influence of glycosyl torsion angle. 381 84

Analogs of the triphosphate 2'-5'-linked adenylate trimer (ppp5'A2'p5'A2'p5'A, called 2-5A) which contain 3'-deoxyadenosine (cordycepin) instead of adenosine either in positions one and two, or in all three positions, are 10-100-fold less potent than is parent 2-5A in inhibition of protein synthesis in intact cells, when utilizing calcium co-precipitation techniques to introduce the 5'-triphosphate oligonucleotides into the cells. That the inhibition of protein synthesis was a consequence of activation of the 2-5A-dependent endonuclease by the 3'-deoxyadenosine analogs of 2-5A was demonstrated in obtaining the ribosomal RNA cleavage pattern that is characteristic of endonuclease activation by parent 2-5A. Additional results (i.e. lack of activity by the dimer species ppp5'(3'dA)2'p5'-(3'dA) or the monomer 3'dA) as well as kinetic analysis both in intact cells and in cell-free extracts provided further evidence that the inhibition of protein synthesis observed with these 3'-deoxyadenosine 2-5A analogs was not due to their degradation to the antimetabolite monomer unit 3'-deoxyadenosine.
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PMID:Cordycepin analogs of ppp5'A2'p5'A2'p5'A (2-5A) inhibit protein synthesis through activation of the 2-5A-dependent endonuclease. 397 41

Synthesis of a complementary strand on the circular viral (+)-DNA of phage phiX174, coated with single-stranded DNA binding protein, is primed by the synthesis of an oligonucleotide by the primosome. Processive primosome movement on the lagging strand with the replication fork was proposed as a model for the discontinuous portion of Escherichia coli chromosome replication (Arai, K. and Kornberg, A. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 69-73; Arai, K., Low, R. L., and Kornberg, A. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 707-711). RNA primers covalently bound to the 5'-end of a DNA chain are heterogeneous with respect to both size and nucleotide composition. The chain length of the DNA-linked RNA primers is shorter than a decanucleotide, predominantly ranging from 1 to 9 residues. The primers start with adenylate followed mainly by a purine nucleotide (Pu) at the second position suggesting that pppA-Pu is a preferred initiation sequence. The inner sequences are more heterogeneous and no consensus or preferred sequence was found beyond the third position. The size distribution of the primer is influenced by the relative concentration of ribo- and deoxyribonucleoside triphosphates; the proportion of mononucleotide (riboadenylate) primer increases upon decreasing the relative ribonucleoside triphosphate concentration. Mapping of the transition sites from RNA to DNA on HaeIII endonuclease fragments suggest they are distributed randomly and occur frequently on the phiX174 genome. These results suggest that the selection of RNA priming sites is affected by primase at the preferred sequence 3'-T-pyrimidine nucleotide-5' on the template within the DNA domain generated by the dnaB protein. These properties of RNA priming have important implications for site selection by the primosome on the lagging strand at the replication fork of the E. coli chromosome.
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PMID:Site selection and structure of DNA-linked RNA primers synthesized by the primosome in phage phi X174 DNA replication in vitro. 619 63

Kinetic studies on the two major isoforms of Serratia marcescens nuclease, Sm2 and Sm1, have revealed them to be functionally equivalent. Both isoforms display marked substrate inhibition by DNA and RNA. They both require magnesium for optimal activity, but retain low catalytic activity in its absence. Both are moderately inhibited by mononucleotides including 5'-ATP, 5'-AMP, 5'-TTP and 3'5'-pTp. The two strongest mononucleotide inhibitors studied, 5'-ATP and 5'-AMP, display inhibition constants, KI, on the order of 10(-5) M. In assessing the strength of mononucleotide inhibition the type of nucleotide base appears to be more important than the number of phosphate moieties.
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PMID:Kinetic studies of the Serratia marcescens extracellular nuclease isoforms. 780 50

Analogues of the 2',5'-linked adenylate trimer 5'-monophosphates (p5'A2'p5'A2'p5'A) containing 8-hydroxyadenosine and 8-mercaptoadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. The ability of p5'ASH2'p5'ASH2'p5'ASH (pASH3) (1c) to bind 2-5A dependent endonuclease was markedly decreased. On the other hand, an analogue of the 2',5'-linked adenylate trimer monophosphate substituted by 8-hydroxyadenosine in the first, second, and third nucleotide positions bound almost as well as parent 2-5A [pppA(2'p5'A)2] (p3A3) (1d) to RNase L. The 8-substituted analogues of 2-5A were more resistant to the degradation by the (2',5') phosphodiesterase. Of particular interest is monophosphate, pASH3 (1c) which possessed higher anti-HIV activity than pA3 (1a) or pAOH3 (1b).
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PMID:Characterization and biological activity of 8-substituted analogues of 2',5'-oligoadenylates. 846 24

Mutations in mitochondrial DNA (mtDNA) cause a variety of relatively rare human diseases and may contribute to the pathogenesis of other, more common degenerative diseases. This stimulates interest in the capacity of mitochondria to repair damage to mtDNA. Several recent studies have shown that some types of damage to mtDNA may be repaired, particularly if the lesions can be processed through a base excision mechanism that employs an abasic site as a common intermediate. In this paper, we demonstrate that a combination of enzymes purified from Xenopus laevis mitochondria efficiently repairs abasic sites in DNA. This repair pathway employs a mitochondrial class II apurinic/apyrimidinic (AP) endonuclease to cleave the DNA backbone on the 5' side of an abasic site. A deoxyribophosphodiesterase acts to remove the 5' sugar-phosphate residue left by AP endonuclease. mtDNA polymerase gamma fills the resulting 1-nucleotide gap. The remaining nick is sealed by an mtDNA ligase. We report the first extensive purification of mtDNA ligase as a 100-kDa enzyme that functions with an enzyme-adenylate intermediate and is capable of ligating oligo(dT) strands annealed to poly(rA). These properties together with preliminary immunological evidence suggest that mtDNA may be related to nuclear DNA ligase III.
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PMID:Efficient repair of abasic sites in DNA by mitochondrial enzymes. 948 40

Kinetoplast DNA (kDNA), the form of mitochondrial DNA in trypanosomatids, consists of thousands of interlocked circular DNAs organized into a compact disk structure. A type II DNA topoisomerase, a DNA polymerase beta, and a structure-specific endonuclease have been localized to antipodal sites flanking the kDNA disk along with nascent DNA minicircles. We have cloned a gene (LIG k) encoding a mitochondrial DNA ligase in the trypanosomatid Crithidia fasciculata, and we show that an epitope-tagged form of the ligase colocalizes with the other replication proteins at the antipodal sites and also at the two faces of the kDNA disk. DNA LIG k becomes adenylated in reactions with ATP, and the adenylate moiety is removed by incubation with pyrophosphate or nicked DNA. The ligase interacts physically with the beta polymerase and is proposed to be involved in the repair of gaps in the newly synthesized minicircles. In yeast and mammals, a single gene encodes both nuclear and mitochondrial forms of DNA ligase. The LIG K protein sequence has low similarity to mitochondrial DNA ligases in other eukaryotes and is distinct from the C. fasciculata nuclear DNA ligase (LIG I).
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PMID:Mitochondrial DNA ligase in Crithidia fasciculata. 1507 Jul 15