Pancreatic ribonuclease family (, ''RNase'', ''RNase I'', ''RNase A'', ''pancreatic RNase'', ''ribonuclease I'', ''endoribonuclease I'', ''ribonucleic phosphatase'', ''alkaline ribonuclease'', ''ribonuclease'', ''gene S glycoproteins'', ''Ceratitis capitata alkaline ribonuclease'', ''SLSG glycoproteins'', ''gene S locus-specific glycoproteins'', ''S-genotype-assocd. glycoproteins'', ''ribonucleate 3'-pyrimidino-oligonucleotidohydrolase'') is a superfamily of

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...

-specific

endonucleases Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (without regard to sequence), while many, typically called restriction endonucleases ...

found in high quantity in the

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...

of certain

mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

and of some

reptiles Reptiles, as most commonly defined are the animals in the Class (biology), class Reptilia ( ), a paraphyletic grouping comprising all sauropsid, sauropsids except birds. Living reptiles comprise turtles, crocodilians, Squamata, squamates (lizar ...

. Specifically, the enzymes are involved in endonucleolytic cleavage of 3'-phosphomono

nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules w ...

and 3'-phosphooligonucleotides ending in C-P or U-P with 2',3'-cyclic phosphate intermediates. Ribonuclease can unwind the

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

helix by complexing with single-stranded RNA; the complex arises by an extended multi-site cation-anion interaction between

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

and

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

residues of the enzyme and phosphate groups of the nucleotides.

Notable family members

Bovine pancreatic ribonuclease is the best-studied member of the family and has served as a model system in work related to

protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduci ...

disulfide bond In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

formation, protein

crystallography Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids. Crystallography is a fundamental subject in the fields of materials science and solid-state physics (condensed matter physics). The wor ...

and

spectroscopy Spectroscopy is the field of study that measures and interprets the electromagnetic spectra that result from the interaction between electromagnetic radiation and matter as a function of the wavelength or frequency of the radiation. Matter wa ...

, and

protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...

. Human genome contains 8 genes that share the structure and function with bovine pancreatic ribonuclease, with 5 additional pseudo-genes. These structure and dynamics of these enzymes are related to their diverse biological functions. Other proteins belonging to the pancreatic ribonuclease superfamily include: bovine seminal vesicle and brain ribonucleases; kidney non-secretory ribonucleases; liver-type ribonucleases;

angiogenin Angiogenin (ANG) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ''ANG'' gene. Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular ...

, which induces vascularisation of normal and malignant tissues;

eosinophil cationic protein Eosinophil cationic protein (ECP) also known as ribonuclease 3 is a basic protein located in the eosinophil primary matrix. In humans, the eosinophil cationic protein is encoded by the ''RNASE3'' gene. ECP is released during degranulation of eosi ...

, a cytotoxin and helminthotoxin with ribonuclease activity; and frog liver ribonuclease and frog sialic acid-binding lectin. The sequence of pancreatic ribonucleases contains four conserved

s and three amino acid residues involved in the catalytic activity.

Human genes

Human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

encoding proteins containing this

domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...

include: * ANG, * RNASE1, RNASE10, RNASE12,

RNASE2 Eosinophil-derived neurotoxin is an enzyme that in humans is encoded by the ''RNASE2'' gene. The protein encoded by this gene is found in eosinophil granulocytes. It is closely related to the eosinophil cationic protein (''RNASE3'') from which it ...

RNASE3 Eosinophil cationic protein (ECP) also known as ribonuclease 3 is a basic protein located in the eosinophil primary matrix. In humans, the eosinophil cationic protein is encoded by the ''RNASE3'' gene. ECP is released during degranulation of eosi ...

, RNASE4,

RNASE6 Ribonuclease A family member k6 is a protein that in humans is encoded by the RNASE6 gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation' ...

, RNASE7, and RNASE8.

Cytotoxicity

Some members of the pancreatic ribonuclease family have

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

effects. Mammalian cells are protected from these effects due to their extremely high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

for

ribonuclease inhibitor Ribonuclease inhibitor (RI) is a large (~450 residues, ~49 kDa), acidic (pI ~4.7), leucine-rich repeat protein that forms extremely tight complexes with certain ribonucleases. It is a major cellular protein, comprising ~0.1% of all cellular prot ...

(RI), which protects cellular RNA from degradation by pancreatic ribonucleases. Pancreatic ribonucleases that are not inhibited by RI are approximately as toxic as

alpha-sarcin rRNA endonuclease (, ''alpha-sarcin'') is an enzyme that catalyses the hydrolysis of the phosphodiester linkage between guanosine and adenosine residues at one specific position in the 28S rRNA of rat ribosomes. This enzyme also acts on bacteri ...

diphtheria toxin Diphtheria toxin is an exotoxin secreted by '' Corynebacterium diphtheriae'', the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophageA prophage is a virus that has inserted itself into the genome of the host ...

, or

ricin Ricin ( ) is a lectin (a carbohydrate-binding protein) and a highly potent toxin produced in the seeds of the castor oil plant, ''Ricinus communis''. The median lethal dose (LD50) of ricin for mice is around 22 micrograms per kilogram of body ...

. Two pancreatic ribonucleases isolated from the

oocytes An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ge ...

of the

Northern leopard frog ''Lithobates pipiens''Integrated Taxonomic Information System nternet2012''Lithobates pipiens'' pdated 2012 Sept; cited 2012 Dec 26Available from: www.itis.gov/ or ''Rana pipiens'', commonly known as the northern leopard frog, is a species of le ...

amphinase Amphinase is a ribonuclease enzyme found in the oocytes of the Northern leopard frog ''(Rana pipiens)''. Amphinase is a member of the pancreatic ribonuclease protein superfamily and degrades long RNA substrates. Along with ranpirnase, another leo ...

and

ranpirnase Ranpirnase is a ribonuclease enzyme found in the oocytes of the Northern Leopard Frog (''Rana pipiens''). Ranpirnase is a member of the pancreatic ribonuclease (RNase A) protein superfamily and degrades RNA substrates with a sequence preference fo ...

- are not inhibited by RI and show differential cytotoxicity against

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

cells. Ranpirnase was studied in a Phase III

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

as a treatment candidate for

mesothelioma Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The most common area affected is the lining of the lungs and chest wall. Less commonly the lining ...

, but the trial did not demonstrate statistical significance against primary endpoints.

References

{{Portal bar, Biology, border=no Ribonucleases EC 3.1.27 Protein domains