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 othe ...
-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 ...
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 o ...
and of some
reptiles
Reptiles, as most commonly defined are the animals in the class Reptilia ( ), a paraphyletic grouping comprising all sauropsids except birds. Living reptiles comprise turtles, crocodilians, squamates ( lizards and snakes) and rhynchoceph ...
.
Specifically, the enzymes are involved in endonucleolytic cleavage of 3'-phosphomono
nucleotides and 3'-phosphooligonucleotides ending in C-P or U-P with 2',3'-cyclic phosphate intermediates. Ribonuclease can unwind the
RNA 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 − ...
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 reproduc ...
,
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 ...
, 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, 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
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 ...
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, cultu ...
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
* ...
include:
*
ANG,
*
RNASE1
Ribonuclease pancreatic is an enzyme that in humans is encoded by the ''RNASE1'' gene.
Function
This gene encodes a member of the pancreatic-type of secretory ribonucleases, a subset of the ribonuclease A super-family. The encoded endonuclease ...
, RNASE10, RNASE12,
RNASE2,
RNASE3,
RNASE4,
RNASE6, 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 c ...
effects. Mammalian cells are protected from these effects due to their extremely high
affinity 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,
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 h ...
, 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 bo ...
.
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 g ...
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 and
ranpirnase - 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, diet ...
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
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Ribonucleases
EC 3.1.27
Protein domains