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:3.1.27.4 (ribonuclease)
6,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated two independent models of eosinophil differentiation for their ability to synthesize the ribonuclease toxins eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP). Cells from the clone 15 subline of HL-60 (human promyelocytic leukemia) produced both EDN and ECP; production of EDN increased in response to butyric acid (BA). CD34+ peripheral blood progenitor cells (PBPCs) grown with cytokines promoting eosinophil differentiation also produced EDN. EDN from both the clone 15 and PBPCs was more heterogeneous and heavily glycosylated (approximately 22-45 kDa) than EDN from the mature peripheral blood eosinophils (18-25 kDa). The heterogeneity of EDN from the clone 15 cells was not altered by endoglycosidase Hf, whereas treatment with peptide-N-glycosidase F (PNGase F) produced a single-band immunoreactive band (approximately 15 kDa). In contrast, only the highest molecular weight forms of EDN from differentiated PBPCs were eliminated by PNTGase F (reduced to 22-35 kDa), suggesting the presence of uncharacteristic forms of posttranslational modification. Synthesis of hyperglycosylated proteins has not been previously reported in PBPCs and is a feature shared with tumor cells and cell lines.
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PMID:Hyperglycosylation of eosinophil ribonucleases in a promyelocytic leukemia cell line and in differentiated peripheral blood progenitor cells. 761 5

We have traced the rapid molecular evolution of eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP), two host defense proteins that are members of the mammalian ribonuclease gene family. The EDN/ECP gene pair arose from a recent duplication event that occurred after the divergence of New World and Old World monkeys. Since duplication, the genes encoding EDN and ECP have accumulated non-silent mutations at rates exceeding those of all other functional coding sequences studied in primates, while retaining both the structural and catalytic components required for ribonuclease activity. These results suggest that both EDN and ECP may be responding to unusual evolutionary constraints, which has prompted a reexamination of their physiologic function.
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PMID:Rapid evolution of a unique family of primate ribonuclease genes. 766 19

Human eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are members of a unique subfamily of rapidly evolving primate ribonuclease genes that emerged via a gene duplication event occurring after the divergence of Old World from New World monkeys (Rosenberg, H. F., Dyer, K. D., Tiffany, H. L., and Gonzalez, M. (1995) Nature Genet. 10, 219-223). In this work, we studied the activity of the protein encoded by the EDN/ECP homolog of the New World monkey, Saguinus oedipus (marmoset), a representative of the "ancestral" single sequences. Although the nucleotide sequence of the single marmoset gene (mEDN) was equally homologous (82%) to both human genes, the encoded amino acid sequence, calculated isoelectric point, and immunoreactivity all suggested a closer relationship with EDN. Furthermore, mEDN (at 0.3-1.0 microM concentrations) had no measurable anti-staphylococcal activity, suggesting functional as well as structural similarity to EDN. However, with yeast tRNA as substrate, mEDN had significantly less ribonuclease activity than EDN; Michaelis constants were nearly identical (Km (mEDN) = 0.67 microM; Km (EDN) = 0.70 microM), while turnover numbers differed by a factor of 100 (kcat (mEDN) = 0.91 s-1; kcat (EDN) = 0.64 x 10(-2) s-1). Thus, evolutionary constraints appear to have promoted two novel functions: increased cationicity/toxicity (ECP) and enhanced ribonuclease activity (EDN). The latter result is particularly intriguing, as it suggests a crucial role for ribonuclease activity in the (as yet to be determined) physiologic function of EDN.
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PMID:Eosinophil cationic protein and eosinophil-derived neurotoxin. Evolution of novel function in a primate ribonuclease gene family. 853 Apr 35

The biochemistry, the molecular biology and the biological activity of the eosinophil granule proteins, major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO) are reviewed. MBP is present in the core of the eosinophil granule and is toxic to parasite and host cells. ECP and EDN are proteins in the matrix of the granule and share sequence similarity and ribonuclease activity. These two proteins can provoke the Gordon phenomenon in rabbits and are toxic to parasites. EPO consists of two polypeptide and is a toxin for parasite and host cells with or without H2O2. The common characteristics of these proteins are their high isoelectric points and cytotoxic activities.
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PMID:[Biochemistry and biological activities of eosinophil granule proteins]. 768 96

Eosinophil cationic protein (ECP) is a toxin secreted by activated human eosinophils that has anti-parasitic, antibacterial, and neurotoxic activities; ECP also has ribonuclease activity and structural homology to other mammalian ribonucleases. To determine the relationship between the ribonuclease activity and cytotoxicity of ECP, a method for producing recombinant ECP (rECP) in a prokaryotic expression system was devised. Periplasmic isolates from induced bacterial transfectants contained enzymatically active rECP; micromolar concentrations of rECP were shown to be toxic for Staphylococcus aureus (strain 502A). In contrast, recombinant eosinophil-derived neurotoxin, with 67% amino acid sequence identity to ECP, had little to no toxicity for S. aureus; these findings are analogous to those obtained with purified, granule-derived ECP and eosinophil-derived neurotoxin. Two single base pair mutations were introduced into the coding sequence of rECP (Lys38 to Arg and His128 to Asp) to convert ribonuclease active-site residues into non-functional counterparts. These mutations eliminated the ribonuclease activity of rECP but had no discernible effect on the antibacterial activity of this protein, demonstrating that ribonuclease activity and cytotoxicity are, in this case, independent functions of ECP.
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PMID:Recombinant human eosinophil cationic protein. Ribonuclease activity is not essential for cytotoxicity. 771 81

Two stimuli that have been associated with nutrient remobilization in plants are phosphate (P(i)) starvation and senescence. Little is known about how the nutrient remobilization machinery is induced at the molecular level, but in the case of P(i) starvation, ribonucleases are considered to play important roles in the remobilization process. Here, the control of two closely related ribonuclease genes of Arabidopsis, RNS1 and RNS3 is investigated. The RNS1 gene is sharply induced during starvation for P(i), an effect specific among the major macronutrients, whereas RNS3 transcript levels remain relatively constant. RNS1 and RNS3 produced in yeast co-migrate with Arabidopsis ribonuclease activities that exhibit the same induction properties as the transcripts in both wild-type plants and the pho1 mutant, which is defective in xylem loading of P(i). In contrast to what occurs during P(i) starvation, both RNS1 and RNS3 are modestly induced during senescence, indicating that the two stimuli could trigger different signal transduction pathways. The characterization of RNS1, in particular, provides an important first step towards elucidating the mechanisms by which plants sense and respond to P(i) limitation, a prominent condition in many soil types.
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PMID:The Arabidopsis ribonuclease gene RNS1 is tightly controlled in response to phosphate limitation. 800 Apr 25

Although ribonucleases fold into correct tertiary conformation in vitro guided solely by information contained in the primary amino acid sequence (Sela, M., White, F. H., and Anfinsen, C. B. (1957) Science 124, 691-693), it is not clear whether folding of these proteins proceeds unassisted in a complex intracellular environment. We describe here the specific and high affinity binding of groEL, the prokaryotic homolog of the heat shock protein 60 family of molecular chaperones, to recombinant eosinophil cationic protein and eosinophil-derived neurotoxin, two members of the human ribonuclease gene family. We have determined that groEL binds to a unique peptide sequence near the amino terminus of nascent eosinophil cationic protein that includes the first of eight cysteine residues. This binding site functions independently and can confer groEL binding activity on an unrelated carrier protein. GroEL dissociates from the binding site upon addition of ATP and Mg2+; no other cations or cofactors are necessary. These findings suggest the possibility that interaction with a groEL-like molecular chaperone may be a requirement for correct folding and/or translocation of eukaryotic ribonucleases in vivo.
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PMID:Characterization of a distinct binding site for the prokaryotic chaperone, GroEL, on a human granulocyte ribonuclease. 809 49

A ribonuclease (RNase) that cleaves specifically on the 3' side of uridine [Shapiro, R., Fett, J. W., Strydom, D. J. & Vallee, B. L. (1986a) Biochemistry 25, 7255-7264] was purified from human plasma and its amino acid sequence was determined. This protein is a 119-residue single-chain polypeptide cross-linked by four disulfide bonds and has an amino-terminal pyroglutaminyl residue. No post-translational modifications were observed during extensive sequence studies on peptide fragments, except for the amino-terminal pyroglutamic acid and a possible deamidation of Asn66. The protein is homologous to the pancreatic ribonucleases and angiogenin, but differs substantially from both of these proteins; the protein sequence has 43% identity with human pancreatic ribonuclease and 39% identity with human angiogenin, as compared to 35% identity between human angiogenin and pancreatic ribonuclease. It is referred to as RNase 4, based on the nomenclature currently used for the genes of pancreatic RNase (RNase 1) and the eosinophil-derived RNases (RNase 2 and RNase 3). Virtually all of the RNase active-site components, including the catalytic residues His12, His119 and Lys41, are preserved. However, some invariant residues of RNase 1 are replaced, e.g. Lys7 by arginine, Asp14 by histidine, and Pro42 by arginine. RNase 4 contains a unique two-residue deletion at the position corresponding to amino acids 77 and 78 of pancreatic RNase, and its carboxyterminal sequence is truncated at position 122. The deletion in angiogenin at position 21 is also found in RNase 4. RNase 4 is very similar to two RNases isolated from bovine and porcine liver, and together they form a new family in the RNase superfamily. The degree of inter-species similarity (90%) is much greater than within the pancreatic RNase and angiogenin families, which suggests that this ribonuclease could possess a physiologically important function other than general RNA catabolism.
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PMID:The amino acid sequence of human ribonuclease 4, a highly conserved ribonuclease that cleaves specifically on the 3' side of uridine. 822 79

Purkinje cell toxicity is one of the characteristic features of the Gordon phenomenon, a syndrome manifested by ataxia, muscular rigidity, paralysis, and tremor that may lead to death (Gordon, 1933). Two members of the RNase superfamily found in humans, EDN (eosinophil-derived neurotoxin) and ECP (eosinophil cationic protein), cause the Gordon phenomenon when injected intraventricularly into guinea pigs or rabbits. We have found that another member of the RNase superfamily, an antitumor protein called onconase, isolated from Rana pipiens oocytes and early embryos, will also cause the Gordon phenomenon when injected into the cerebrospinal fluid of guinea pigs at a dose similar to that of EDN (LD50, 3-4 micrograms). Neurologic abnormalities of onconase-treated animals were indistinguishable from those of EDN-treated animals, and histology showed dramatic Purkinje cell loss in the brains of onconase-treated animals. The neurotoxic activity of onconase correlates with ribonuclease activity. Onconase modified by iodoacetic acid to eliminate 70% and 98% of the ribonuclease activity of the native enzyme displays a similar decrease in ability to cause the Gordon phenomenon. In contrast, the homologous bovine pancreatic RNase A injected intraventricularly at a dose 5000 times greater than the LD50 dose of EDN or onconase is not toxic and does not cause the Gordon phenomenon. A comparison of the RNase activities of EDN, onconase, and bovine pancreatic RNase A using three pancreatic RNA substrates demonstrates that onconase is orders of magnitude less active enzymatically than EDN and RNase A. Thus, another member of the RNase superfamily in addition to EDN and ECP can cause the Gordon phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Toxicity of an antitumor ribonuclease to Purkinje neurons. 830 53

The allergic pig can be used as a large-animal model for studies of allergic reactions in the airways and the role of eosinophils in such reactions. To measure the activation of eosinophils, the release of eosinophil-derived cationic proteins can be used. The purpose of this study was to isolate and characterize cationic proteins derived from porcine eosinophils. Pigs were infested with live Ascaris suum eggs to induce eosinophilia (greater than or = 40% of leukocytes). Blood was collected and leukocytes were prepared by dextran sedimentation. Granules were obtained from the homogenized leukocytes by ultracentrifugation and cationic proteins were extracted and separated by gel filtration, cation exchange and zinc affinity chromatography. Using these methods, three cationic proteins were isolated from pig granulocytes, two of which were shown to originate from the eosinophil. The proteins were characterized according to molecular weight, amino acid composition, N-terminal sequence, isoelectric point, peroxidase and ribonuclease activity and antigenicity. One eosinophil protein was identified as eosinophil peroxidase and the other showed great similarities with human eosinophil cationic protein. The third protein was not specific for eosinophils, and had no obvious equivalent in human granulocytes. The eosinophil-derived proteins may be useful in the studies of eosinophil activation, e.g. in late-phase asthmatic reactions, where the pig represents a new candidate model for large-animal allergy research.
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PMID:Isolation and characterization of porcine cationic eosinophil granule proteins. 864 90


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