Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.27.5 (RNase)
 17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenin, a member of the pancreatic-like ribonuclease family with a special biological action (RISBAses), is a basic protein that induces blood vessel formation. Another member of these special ribonucleases, bovine seminal ribonuclease (BS RNase), displays biological properties, including aspermatogenic, embryotoxic, antitumor and immunosuppressive activities. The effects of two angiogenin preparations tested on the biological activities mentioned above are reported and compared with those of BS RNase and RNase A. In contrast to RNase A, which was ineffective in all biological activities tested, angiogenin suppressed significantly the proliferation of human lymphocytes stimulated by phytohemagglutinin or concanavalin A or by allogenic human lymphocytes (mixed lymphocyte culture). However, angiogenin did not affect the growth of human tumor cell lines, development of cow and mouse embryos and spermatogenicity in mice. On the basis of these results, angiogenin is the first monomeric ribonuclease described so far that displays immunosuppressive activity similar to that of the dimeric BS RNase. The immunosuppressive activity of angiogenin might synergize with the effect on neovascularization of tumor tissues and thus contribute to the development of tumor.
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PMID:Immunosuppressive activity of angiogenin in comparison with bovine seminal ribonuclease and pancreatic ribonuclease. 758 54

Angiogenin (ANG) promotes the formation of blood vessels in animals. This hormone is a small, monomeric protein that is homologous to bovine pancreatic ribonuclease A (RNase). ANG is a poor ribonuclease but its ribonucleolytic activity is essential for its angiogenic activity. RNase is not angiogenic. A hybrid protein was produced in which 13 residues of a divergent surface loop of ANG were substituted for the analogous 15 residues of RNase. The value of kcat/Km for the cleavage of uridylyl(3'-->5')adenosine by this hybrid protein was 20-fold less than that of RNase but 10(5)-fold greater than that of ANG. The thermal stability of the hybrid protein was also less than that of RNase. Nevertheless, the RNase/ANG hybrid protein promotes angiogenesis in mice at least as extensively as does authentic ANG. Thus we present a protein endowed with a noncognate biological activity simply by replacing a single element of secondary structure. In addition, a 13-residue peptide corresponding to the surface loop of ANG inhibits endogenous angiogenesis in mice. These results support a model in which both a surface loop and a catalytic site are necessary for the promotion of blood vessel formation by ANG or RNase. The dissection of structure/function elements in ANG reveals a unique opportunity to develop new molecules that modulate neovascularization.
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PMID:Replacing a surface loop endows ribonuclease A with angiogenic activity. 761 14

Angiogenin, a potent inducer of neovascularization, is the only angiogenic molecule known to exhibit ribonucleolytic activity. Its overall structure, as determined at 2.4 A, is similar to that of pancreatic ribonuclease A, but it differs markedly in several distinct areas, particularly the ribonucleolytic active center and the putative receptor binding site, both of which are critically involved in biological function. Most strikingly, the site that is spatially analogous to that for pyrimidine binding in ribonuclease A differs significantly in conformation and is "obstructed" by glutamine-117. Movement of this and adjacent residues may be required for substrate binding to angiogenin and, hence, constitute a key part of its mechanism of action.
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PMID:Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease. 815 79

Angiogenin, a homologue of pancreatic ribonuclease, is a potent inducer of blood vessel formation. As an initial step toward investigating the in vivo functional role of this protein via gene disruption, we undertook the isolation of the angiogenin gene (Ang) from the 129 strain mouse, which will be used for generating targeting constructs. Unexpectedly, screening of a genomic library with an Ang gene probe obtained previously from the BALB/c strain yielded two new genes closely similar to Ang rather than Ang itself. One of these encodes a protein with 78% sequence identity to angiogenin and is designated "Angrp" for "angiogenin-related protein." The ribonucleolytic active site of angiogenin, which is critical for angiogenic activity, is completely conserved in Angrp, whereas a second essential site, thought to bind cellular receptors, is considerably different. Thus, the Angrp product may have a function distinct from that of angiogenin. The second gene obtained by library screening is a pseudogene, designated "Ang-ps1," that contains a frameshift mutation in the early part of the coding region. Although the Ang gene was not isolated from this library, it was possible to amplify this gene from 129 mouse genomic DNA by the polymerase chain reaction (PCR). Sequence analysis showed that the 129 strain Ang gene is identical to the BALB/c gene throughout the coding region. PCR cloning also yielded a second Ang-like pseudogene, designated "Ang-ps2." Southern blotting of genomic DNA confirmed the presence of Ang, Angrp, and at least one of the pseudogenes in an individual mouse and suggested that the mouse Ang gene family may contain more than the four members identified here.
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PMID:The mouse angiogenin gene family: structures of an angiogenin-related protein gene and two pseudogenes. 853 72

The similarities and differences among members of the RNase A superfamily provide an ideal opportunity to examine the molecular basis for differences in their pharmacokinetics and biodistribution. Plasma clearances in BALB/c mice are similar among the five RNases studied: human pancreatic RNase, angiogenin, eosinophil-derived neurotoxin, onconase, and bovine seminal RNase. The average clearance is 0.13 ml/min or 60% of the glomerular filtration rate (measured by [14C]inulin clearance during continuous infusion from an i.p. implanted osmotic pump). Angiogenin has a higher volume of distribution and plasma-to-muscle transport rate than the other RNases, suggestive of binding to endothelial cells. Organ distribution differs dramatically among these RNases. The RNase most toxic to tumor cells, onconase, exhibits the longest retention in the kidneys: at 180 min, 50% of the injected dose is found in the kidneys, whereas only 1% or less of the other RNases is retained in the kidneys. Slower elimination of onconase from the kidneys may be due to a higher degree of binding in the kidney or a resistance to proteolytic degradation. To elucidate the molecular determinants involved in tissue uptake, we examined the biodistribution of recombinant onconase and two onconasepancreatic RNase chimeric proteins. The tissue retention property of onconase appears to be located in at least two regions, one of which is in the NH2-terminal 9-amino acid alpha-helix. The NH2-terminal pyroglutamate of onconase, a residue essential for ribonucleolytic activity and cytotoxicity, does not play a role in kidney retention.
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PMID:Molecular determinants in the plasma clearance and tissue distribution of ribonucleases of the ribonuclease A superfamily. 879 89

Angiogenin stimulates both [3H]thymidine incorporation and proliferation of human endothelial cells in sparse cultures. Under these conditions, a 170-kDa cell surface protein can be detected that binds angiogenin specifically. Angiogenin-stimulated cell growth is concentration-dependent and is completely inhibited by an anti-angiogenin monoclonal antibody, but not by a nonimmune control antibody. It is not affected by the nonangiogenic homolog, RNase A, nor by other angiogenic proteins, such as basic fibroblast growth factor and its antibody. Results suggest that under specific conditions, endothelial cells express an angiogenin receptor that may mediate angiogenin-stimulated DNA synthesis and proliferation and play an important role in angiogenin-induced angiogenesis.
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PMID:A putative angiogenin receptor in angiogenin-responsive human endothelial cells. 912 72

The RNA population in cells is controlled post-transcriptionally by ribonucleases (RNases) of varying specificity. Angiogenin, neurotoxins, and plant allergens are among many proteins with RNase activity or significant homology to known RNases. RNase activity in serum and cell extracts is elevated in a variety of cancers and infectious diseases. RNases are regulated by specific activators and inhibitors, including interferons. Many of these regulatory molecules are useful lead compounds for the design of drugs to control tumor angiogenesis, allergic reactions, and viral replication. One RNase (Onconase) and several RNase activators are now in clinical trials for cancer treatment or inhibition of chronic virus infections. Several others, alone or conjugated with specific cell binding molecules, are being developed for their antifungal, antiviral, and antitumor cell activity.
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PMID:From housekeeper to microsurgeon: the diagnostic and therapeutic potential of ribonucleases. 918 74

Our search for an angiogenesis-inducing factor in culture medium conditioned by human colon adenocarcinoma cells (HT-29) was inspired by the 'organizer' hypothesis originally postulated by Spemann. It led us to the isolation of angiogenin, a 14 kD protein homologous to pancreatic ribonuclease and one of the most potent stimulators of blood vessel formation known. This review summarizes the properties of angiogenin, its enzymatic and three-dimensional relationship to ribonuclease A (RNase A), those aspects of its structure that are critical for its biological function, and the therapeutic potential of angiogenin inhibition. Despite having the same arrangement of catalytic residues as RNase A, angiogenin has very low enzymatic activity. It lacks one of the four disulphide loops of RNase A; instead, the corresponding residues form part of a cell binding region. Both the catalytic activity and cell binding site are essential for angiogenesis. Angiogenin binds to cell-surface actin in confluent endothelial cells and to an as yet uncharacterized receptor on proliferating cells. Internalization and translocation to the nucleolus are also required for activity. Inhibitors of angiogenin can block angiogenesis in vitro and prevent tumour growth in vivo. Thus, a noncytotoxic neutralizing monoclonal antibody prevents the establishment of HT-29 human tumour xenografts in up to 65% of treated athymic mice. In those tumours that develop, the number of vascular elements is reduced. Actin also prevents the establishment of tumours while exhibiting no toxic effects at daily doses > 50 times the molar amount of circulating mouse angiogenin. These antagonists also inhibit the appearance of tumours derived from two other human tumour cell lines. Inhibition of the action of angiogenin may prove to be an effective therapeutic approach for the treatment of malignant disease.
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PMID:Organogenesis and angiogenin. 941 51

Angiogenin belongs to the Ribonuclease superfamily and has a weak enzymatic activity that is crucial for its biological function of stimulating blood vessel growth. Structural studies on ligand bound Angiogenin will go a long way in understanding the mechanism of the protein as well as help in designing drugs against it. In this study we present the first available structure of nucleotide ligand bound Angiogenin obtained by computer modeling. The importance of this study in itself notwithstanding, is a precursor to modeling a full dinucleotide substrate onto Angiogenin. Bovine Angiogenin, the structure of which has been solved at a high resolution, was earlier subjected to Molecular Dynamics simulations for a nanosecond. The MD structures offer better starting points for docking as they offer lesser obstruction than the crystal structure to ligand binding. The MD structure with the least serious short contacts was modeled to obtain a steric free Angiogenin - 3' mononucleotide complex structure. The structures were energetically minimized and subjected to a brief spell of Molecular Dynamics. The results of the simulation show that all the ligand-Angiogenin interactions and hydrogen bonds are retained, redeeming the structure and docking procedure. Further, following ligand - protein interactions in the case of the ligands 3'-CMP and 3'-UMP we were able to speculate on how Angiogenin, a predominantly prymidine specific ribonuclease prefers Cytosine to Uracil in the first base position.
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PMID:Modeling of angiogenin - 3-NMP complex. 1005 27

Targeted toxins represent a new approach to specific cytocidal therapy. Immunotoxins based on plant and microbial toxins are very immunogenic. To develop a targeted therapy that is less immunogenic and easily invades target tissues, four fusion proteins containing human angiogenin targeted by human EGF have been constructed. EGF is a single chain polypeptide, which binds to epidermal growth factor receptor (EGFR) and is known to be internalized by endocytosis. Angiogenin has been separately fused either at the amino terminus or the carboxyl terminus of EGF via linkers, giving rise to angiogenin-gly-EGF, angiogenin-(gly)4ser-EGF and EGF-angiogenin, EGF-gly-angiogenin, respectively. The fusion proteins were over-expressed in Escherichia coli and purified from periplasmic eluents by affinity chromatography. EGF-angiogenin and EGF-gly-angiogenin maintained receptor-binding activity of EGF and RNase activity of angiogenin in a single peptide and actively inhibited growth of human EGFR-positive target cells in culture. They are expected to have a very low immunogenic potential in humans because of their endogenous origin and also to have another potential therapeutic advantage because these fusion proteins may have overcome conventional immunotoxin and possess increased ability to penetrate because of their small size.
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PMID:Cloning and cytotoxicity of fusion proteins of EGF and angiogenin. 1032 23


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