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Critical Reviews in Biochemistry and... Jun 2022Pancreatic-type ribonucleases (ptRNases) are a large family of vertebrate-specific secretory endoribonucleases. These enzymes catalyze the degradation of many RNA... (Review)
Review
Pancreatic-type ribonucleases (ptRNases) are a large family of vertebrate-specific secretory endoribonucleases. These enzymes catalyze the degradation of many RNA substrates and thereby mediate a variety of biological functions. Though the homology of ptRNases has informed biochemical characterization and evolutionary analyses, the understanding of their biological roles is incomplete. Here, we review the functions of two ptRNases: RNase 1 and angiogenin. RNase 1, which is an abundant ptRNase with high catalytic activity, has newly discovered roles in inflammation and blood coagulation. Angiogenin, which promotes neovascularization, is now known to play roles in the progression of cancer and amyotrophic lateral sclerosis, as well as in the cellular stress response. Ongoing work is illuminating the biology of these and other ptRNases.
Topics: Endoribonucleases; RNA; Ribonuclease, Pancreatic; Ribonucleases
PubMed: 34886717
DOI: 10.1080/10409238.2021.2004577 -
Bioconjugate Chemistry Jan 2021Since its conception, the ribonuclease S complex (RNase S) has led to historic discoveries in protein chemistry, enzymology, and related fields. Derived by the...
Since its conception, the ribonuclease S complex (RNase S) has led to historic discoveries in protein chemistry, enzymology, and related fields. Derived by the proteolytic cleavage of a single peptide bond in bovine pancreatic ribonuclease (RNase A), RNase S serves as a convenient and reliable model system for incorporating unlimited functionality into an enzyme. Applications of the RNase S system in biomedicine and biotechnology have, however, been hindered by two shortcomings: (1) the bovine-derived enzyme could elicit an immune response in humans, and (2) the complex is susceptible to dissociation. Here, we have addressed both limitations in the first semisynthesis of an RNase S conjugate derived from human pancreatic ribonuclease and stabilized by a covalent interfragment cross-link. We anticipate that this strategy will enable unprecedented applications of the "RNase-S" system.
Topics: Amino Acid Sequence; Electrophoresis, Polyacrylamide Gel; Humans; Ribonuclease, Pancreatic; Ribonucleases; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 33296182
DOI: 10.1021/acs.bioconjchem.0c00557 -
International Journal of Molecular... Mar 2016The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the... (Review)
Review
The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play an essential role in host defense. Ribonuclease 7 (RNase 7) is an epithelial-derived secreted peptide with potent broad-spectrum antimicrobial activity. This review summarizes the published literature on RNase 7's antimicrobial properties, structure, regulation, and contributions to host defense. In doing so, we conclude by highlighting key knowledge gaps that must be investigated to completely understand the potential of developing RNase 7 as a novel therapeutic for human infectious diseases.
Topics: Animals; Humans; Immunity, Innate; Ribonucleases
PubMed: 27011175
DOI: 10.3390/ijms17030423 -
Cellular and Molecular Life Sciences :... Aug 1998The structural and enzymatic properties of RNase 4 are reviewed. This RNase shows a much higher interspecies similarity (approximately 90%) than the other members of the... (Review)
Review
The structural and enzymatic properties of RNase 4 are reviewed. This RNase shows a much higher interspecies similarity (approximately 90%) than the other members of the RNase A superfamily. The enzyme is ubiquitous, with the highest amounts present in liver and lung. Its unique uridine specificity results from alterations in and around the pyrimidine-binding site. In particular, the shortened C-terminus and the side chains of Phe-42, Asp-80 and Arg-101 appear to be involved. RNase 4 binds tightly to the intracellular RNase inhibitor, with a Kd of 4 x 10(-15) M.
Topics: Amino Acid Sequence; Animals; Conserved Sequence; Evolution, Molecular; Humans; Molecular Sequence Data; Multigene Family; Ribonucleases; Sequence Homology, Amino Acid
PubMed: 9760989
DOI: 10.1007/s000180050209 -
Current Pharmaceutical Biotechnology Jun 2008Onconase (ONC) is an amphibian member of the bovine pancreatic ribonuclease (RNase A) superfamily that exhibits innate antitumoral activity. ONC has been granted both... (Review)
Review
Onconase (ONC) is an amphibian member of the bovine pancreatic ribonuclease (RNase A) superfamily that exhibits innate antitumoral activity. ONC has been granted both orphan-drug and fast-track status by the U.S. Food and Drug Administration for the treatment of malignant mesothelioma, and is poised to become the first chemotherapeutic agent based on a ribonuclease. Investigations into the mechanism of ribonuclease-based cytotoxicity have elucidated several important determinants for cytotoxicity, including efficient deliverance of ribonucleolytic activity to the cytosol and preservation of conformation stability. Nevertheless, the most striking similarity between ONC and bovine seminal ribonuclease, another naturally cytotoxic ribonuclease, is their insensitivity to inhibition by the potent cytosolic ribonuclease inhibitor protein (RI). RI typically binds to its ribonuclease ligands with femtomolar affinity--an extraordinary feat considering the modest sequence identity among the bound ribonucleases. Mammalian ribonucleases such as RNase A or its human homologue, RNase 1, have the potential to be more attractive chemotherapeutic agents than ONC owing to their higher catalytic activity, low potential for immunogenicity, favorable tissue distribution, and high therapeutic index, but are limited by their sensitivity to RI. These non-toxic mammalian ribonucleases can be transformed into potent cytotoxins by engendering them with RI-evasion using protein engineering strategies such as site-directed mutagenesis, multimerization, fusion to a targeting moiety, and chemical modification. In several instances, these engineered ribonucleases exhibit greater cytotoxicity in vitro than does ONC. Herein, we review the biochemical characteristics of RIribonuclease complexes and progress towards the development of mammalian ribonuclease-based chemotherapeutics through the elicitation of RI-evasion.
Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Cytosol; Enzyme Stability; Humans; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Protein Binding; Ribonucleases; Sequence Alignment
PubMed: 18673284
DOI: 10.2174/138920108784567344 -
Progress in Biophysics and Molecular... 1988
Review
Topics: Amino Acid Sequence; Animals; Base Sequence; Biological Evolution; Humans; Molecular Sequence Data; Protein Conformation; Ribonucleases; Sequence Homology, Nucleic Acid
PubMed: 3074337
DOI: 10.1016/0079-6107(88)90001-6 -
Proceedings of the National Academy of... Jun 1976Crystals of solid phase-derived semisynthetic ribonuclease-S' were prepared and compared with those for native ribonuclease-S' and -S. The semisynthetic species used was...
Crystals of solid phase-derived semisynthetic ribonuclease-S' were prepared and compared with those for native ribonuclease-S' and -S. The semisynthetic species used was the noncovalent complex of synthetic fragment-(1-20), corresponding to residues 1 through 20 of bovine pancreatic ribonuclease-A (ribonucleate 3'-pyrimidino-oligonucleotidohydrolase, EC 3.1.4.22), and native ribonuclease-S-(21-124); the fragment containing residues 21 through 124 of ribonuclease-A. This semisynthetic complex was completely active enzymatically, was homogeneous as judged by polyacrylamide gel electrophoresis, and had no greater than trace amounts of excess ribonuclease-s(21-124) as judged by affinity chromatography. Crystallization of both semisynthetic and native ribonuclease-s' at pH 5.3 resulted in well-formed crystallseater than trace amounts of excess ribonuclease-S-T21-124) as judged by affinity chromatography. Crystallization of both semisynthetic and native ribonuclease-S' at pH 5.3 resulted in well-formed crystals with the symmetry of space group P3121 and unit cell dimensions a=b=44.82, c=97.3 A. This crystal form corresponds to the Y form of native ribonuclease-S previously reported [Wyckoff et al. (1967) J. Biol. Chem. 242, 3749-3753]. X-ray diffraction patterns of the crystals were indistinguishable, indicative of the structural identity of semisynthetic and native ribonuclease-S'.
Topics: Crystallography; Protein Conformation; Ribonucleases; X-Ray Diffraction
PubMed: 1064856
DOI: 10.1073/pnas.73.6.1844 -
Current Pharmaceutical Biotechnology Jun 2008After a short introduction with some examples of cytotoxic ribonucleases, the importance of natural or artificial dimerization (oligomerization) as a way for a... (Review)
Review
After a short introduction with some examples of cytotoxic ribonucleases, the importance of natural or artificial dimerization (oligomerization) as a way for a ribonuclease to acquire novel functional properties has been pointed out. In particular, the role of the three dimensional domain swapping mechanism in bovine pancreatic ribonuclease A oligomerization, as well as its impact for the acquisition of novel biological functions (among which a remarkable antitumor action) by the enzyme protein in oligomeric form have been discussed. Finally, the structural and functional features that could explain why oligomeric ribonuclease A becomes able to display a cytotoxic activity, and the possible use and limits of the three dimensional domain-swapped oligomers of ribonuclease A as anticancer therapeutic agents have been described and discussed.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cytosol; Dimerization; Humans; Models, Molecular; Neoplasms; Protein Conformation; Protein Transport; RNA, Neoplasm; Ribonucleases
PubMed: 18673285
DOI: 10.2174/138920108784567308 -
Annual Review of Microbiology Oct 2021Ribonucleases (RNases) are essential for almost every aspect of RNA metabolism. However, despite their important metabolic roles, RNases can also be destructive enzymes.... (Review)
Review
Ribonucleases (RNases) are essential for almost every aspect of RNA metabolism. However, despite their important metabolic roles, RNases can also be destructive enzymes. As a consequence, cells must carefully regulate the amount, the activity, and the localization of RNases to avoid the inappropriate degradation of essential RNA molecules. In addition, bacterial cells often must adjust RNase levels as environmental situations demand, also requiring careful regulation of these critical enzymes. As the need for strict control of RNases has become more evident, multiple mechanisms for this regulation have been identified and studied, and these are described in this review. The major conclusion that emerges is that no common regulatory mechanism applies to all RNases, or even to a family of RNases; rather, a wide variety of processes have evolved that act on these enzymes, and in some cases, multiple regulatory mechanisms can even act on a single RNase.
Topics: Bacteria; Ribonucleases
PubMed: 34081529
DOI: 10.1146/annurev-micro-020121-011201 -
Archives of Biochemistry and Biophysics Nov 1956
Topics: Acids; Biochemical Phenomena; Ribonucleases
PubMed: 13373430
DOI: 10.1016/0003-9861(56)90199-0