Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenin is a potent blood-vessel-inducing polypeptide with a molecular weight of 14,000 that has a unique ribonucleolytic activity. First isolated from the conditioned medium of tumour cells, angiogenin has since been purified from normal plasma, which suggested that its propensity to induce neovascularization should be strictly controlled. Modulation of that activity might involve interaction of angiogenin with cell-surface receptors and extracellular matrix of endothelial cells, tight-binding inhibition of both its ribonucleolytic activity and cell binding property by ribonuclease inhibitor, as well as the overall influence of divalent copper, a modulator of angiogenesis.
 ...
PMID:In vivo and in vitro studies of angiogenin--a potent angiogenic factor. 172 10

The amino acid sequence and disulfide bond pairing of human tumor derived angiogenin, the first tumor angiogenesis factor to be isolated in pure form from human sources, have been determined by conventional sequencing techniques adapted and applied to nanomole and subnanomole levels of material. Angiogenin, obtained from conditioned media of a human colonic adenocarcinoma cell line, is a single-chain protein consisting of 123 amino acids with the following sequences: less than Glu1-Asp-Asn-Ser-Arg-Tyr-Thr-His- Phe-Leu-Thr-Gln-His-Tyr-Asp15-Ala-Lys-Pro-Gln-Gly-Arg-Asp-Asp- Arg-Tyr-Cys-Glu-Ser-Ile-Met30- Arg-Arg-Arg-Gly-Leu-Thr-Ser-Pro-Cys-Lys-Asp-Ile-Asn-Thr- Phe45-Ile-His-Gly-Asn-Lys-Arg-Ser -Ile-Lys-Ala-Ile-Cys-Glu-Asn-Lys60-Asn-Gly-Asn-Pro-His-Arg-Glu-Asn -Leu-Arg-Ile -Ser-Lys-Ser-Ser75 -Phe-Gln-Val-Thr-Thr-Cys-Lys-Leu-His-Gly-Gly-Ser-Pro-Trp-Pro90-Pro -Cys-Gln-Tyr -Arg-Ala-Thr-Ala -Gly-Phe-Arg-Asn-Val-Val-Val105-Ala-Cys-Glu-Asn-Gly-Leu-Pro-Val- His-Leu-Asp-Gln-Ser-Ile-Phe120-Arg-Arg-Pro123-OH. Three disulfide bonds link the half-cystinyl residues 26-81, 39-92, and 57-107. The sequence is homologous to that of the pancreatic ribonucleases with 35% identity and many of the remaining residues conservatively replaced. Similarities are especially apparent around the major active-site residues His-12, Lys-41, and His-119 of ribonuclease which are conserved as are three of the four disulfide bonds.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Amino acid sequence of human tumor derived angiogenin. 286 94

The primary structures of the blood vessel inducing protein human angiogenin and human pancreatic ribonuclease (RNase) are 35% identical. Angiogenin catalyzes the limited cleavage of ribosomal RNA (18 and 28 S), yielding a characteristic pattern of polynucleotide products, but shows no significant activity toward conventional pancreatic RNase substrates [Shapiro, R., Riordan, J. F., & Vallee, B. L. (1986) Biochemistry 25, 3527-3532]. Angiogenin/RNase hybrid enzymes--wherein particular regions of primary structure in RNase are replaced by the corresponding segments of angiogenin--serve to explore the structural features underlying angiogenin's characteristic activities. Herein we show that synthetic angiogenin peptides, Ang(1-21) and Ang(108-123), form noncovalent complexes with inactive fragments of bovine RNase A--RNase(21-124) (i.e., S-protein) and RNase(1-118), respectively--with regeneration of activity toward conventional RNase substrates. Maximal activities for the Ang(1-21)/S-protein complex (Kd = 1.0 microM) are 52%, 45%, and 15% toward cytidine cyclic 2',3'-phosphate, cytidylyl(3'----5')adenosine, and yeast RNA, respectively. In contrast, activities of the RNase(1-118)/Ang(108-123) hybrid (Kd = 25 microM) are 1-2 orders of magnitude lower toward cyclic nucleotides and dinucleoside phosphates. However, substitution of phenylalanine for Leu-115 in Ang(108-123) increases activity up to 100-fold. Both His-13 and His-114 in the angiogenin peptides are required for activity since their substitution by alanine yields inactive complexes. Importantly, the pattern of polynucleotide products formed during cleavage of ribosomal RNA by the Ang(1-21)/S-protein hybrid shows a striking resemblance to that formed by angiogenin, demonstrating that the hybrid retains features of both angiogenin and RNase A.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Enzymatically active angiogenin/ribonuclease A hybrids formed by peptide interchange. 334 27

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.
 ...
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.
 ...
PMID:Replacing a surface loop endows ribonuclease A with angiogenic activity. 761 14

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.
 ...
PMID:Modeling of angiogenin - 3-NMP complex. 1005 27

The antitumor effect of ribonucleases was studied with animal ribonucleolytic enzymes, bovine pancreatic RNase A, bovine seminal RNase (BS-RNase), onconase and angiogenin. While bovine pancreatic RNase A exerts a minor antitumor effect, BS-RNase and onconase exert significant effects. Angiogenin, as RNase, works in an opposite way, it initiates vascularization of tumors and subsequent tumor growth. Ribonunclease inhibitors are not able to inhibit the antitumor effectiveness of BS-RNase or onconase. However, they do so in the case of pancreatic RNases. Conjugation of BS-RNase with antibodies against tumor antigens (preparation of immunotoxins) like the conjugation of the enzyme with polymers enhances the antitumor activity of the ribonuclease. After conjugation with polymers, the half-life of BS-RNase in blood is extended and its immunogenicity reduced. Recombinant RNases have the same functional activity as the native enzymes. The synthetic genes have also been modified, some of them with gene sequences typical for the BS-RNase parts. Recent experimental efforts are directed to the preparation of 'humanized antitumor ribonuclease' that would be structurally similar to human enzyme with minimal immunogenicity and side effects. The angiogenesis of tumors is attempted to be minimized by specific antibodies or anti-angiogenic substances.
 ...
PMID:Ribonucleases and their antitumor activity. 1146 35

Angiogenin and ribonuclease A share 33% sequence identity but have distinct functions. Angiogenin is a potent inducer of angiogenesis that is only weakly ribonucleolytic, whereas ribonuclease A is a robust ribonuclease that is not angiogenic. A chimera ("ARH-I"), in which angiogenin residues 58-70 are replaced with residues 59-73 of ribonuclease A, has intermediate ribonucleolytic potency and no angiogenic activity. Here we report a crystal structure of ARH-I that reveals the molecular basis for these characteristics. The ribonuclease A-derived (guest) segment adopts a structure largely similar to that in ribonuclease A, and successfully converts this region from a cell-binding site to a purine-binding site. At the same time, its presence causes complex changes in the angiogenin-derived (host) portion that account for much of the increased ribonuclease activity of ARH-I. Guest-host interactions of this type probably occur more generally in protein chimeras, emphasizing the importance of direct structural information for understanding the functional behavior of such molecules.
 ...
PMID:Guest-host crosstalk in an angiogenin-RNase A chimeric protein. 1217 35

Angiogenin is a member of the ribonuclease superfamily, which shows an ever expanding collection of molecules being identified and cloned. It was initially isolated from the conditioned medium of cultured tumour cells. Its angiogenic activity appears to be critical for the maintenance and support of tumour growth. Angiogenin also plays a role in a number of non-malignant vasculoproliferative pathological conditions. Along with other related molecules, it has been identified in a wide variety of somatic tissues in adult and embryonic stages of vertebrate development. This suggests that angiogenin and related molecules are likely to play a vital role in normal physiology. Angiogenin is detectable in serum and to date has been implicated as a mitogen for vascular endothelial cells, an immune modulator with suppressive effects on polymorphonuclear leukocytes, an activator of certain protease cascades such as matrix metalloproteases and plasminogen-activated plasmin pathways, as well as an adhesion molecule. However, the role of the angiogenin family in both normal and abnormal physiology and in development will only fully be realised by genetic approaches involving gene deletion.
 ...
PMID:The angiogenins: an emerging family of ribonuclease related proteins with diverse cellular functions. 1451 18

Human ribonuclease inhibitor (hRI) is an acid protein with a molecular weight of 50 kDa. It can inhibit the activity of pancreatic RNase (RNase A). Angiogenin (Ang) is a member of the ribonuclease super family. It has 35% identity with RNase A and contains ribonucleolytic activity. The substrate specificity of angiogenin seems, however, to be more restricted than that of the pancreatic RNase. Since Ang is an important angiogenic factor and RI is a highly efficient inhibitor of Ang, it can be hypothesized that RI may be a latent antiangiogenic drug. This study focuses on the feasibility of transfecting the ri gene into mice hematopoietic cells and inducing the expression of the ri gene to block the angiogenesis of solid tumors. First, the cDNA gene of the ri from human placenta was cloned and inserted in a retroviral vector, pLNCX. The combined vector pLNCX-ri was transfected into retroviral packaging cells, PA317, and a clone producing a high titer of virus was obtained. Next, isolated hematopoietic cells from mice bone marrow were infected with viruses carrying the pLNCX-ri. The infected cells were then injected into lethally irradiated mice. The expression and the contribution of RI were assayed in vivo. After administration of hematopoietic cells carrying the ri gene, mice were implanted with B16 melanomas for 21 days. The results showed that tumors of control groups became large and well vascularized. In contrast, tumors from mice groups treated with hematopoietic cells carrying the ri gene were small and possessed a relatively low density of blood vessels. The inhibited growth rate of the tumors was 47%. This study demonstrated the potential utility of gene therapy for systemic delivery of a novel antiangiogenic agent--hRI.
 ...
PMID:Anti-tumor effect of hematopoietic cells carrying the gene of ribonuclease inhibitor. 1559 48


1 2 3 4 Next >>