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Proprotein convertase 1

Proprotein convertase 1

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Proprotein convertase 1, also known as prohormone convertase, prohormone convertase 3, or neuroendocrine convertase 1 and often abbreviated as PC1/3 is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that in humans is encoded by the PCSK1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

. PCSK1 and PCSK2
Proprotein convertase 2
Proprotein convertase 2 also known as prohormone convertase 2 or neuroendocrine convertase 2 is a serine protease and proprotein convertase PC2, like proprotein convertase 1 , is an enzyme responsible for the first step in the maturation of many neuroendocrine peptides from their precursors, such...

 differentially cleave proopiomelanocortin
Proopiomelanocortin
Pro-opiomelanocortin is a precursor polypeptide with 241 amino acid residues. POMC is synthesized from the 285-amino acid long polypeptide precursor, pre-pro-opiomelanocortin , by the removal of a 44-amino acid long signal peptide sequence during translation.The POMC gene is located on chromosome...

 and they act together to process proinsulin
Proinsulin
Proinsulin is the prohormone precursor to insulin made in the beta cells of the islets of Langerhans, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene.- Synthesis and post-translational modification :...

 and proglucagon
Proglucagon
Proglucagon is a protein that in humans is encoded by the GCG gene.Proglucagon is a precursor of glucagon, and several other components. It is generated in the alpha cells of the pancreas and in the intestinal L cells in the distal ileum and colon...

 in pancreatic islets
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...

.

Function


PC1/3 is an enzyme that performs the proteolytic cleavage
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...

 of prohormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

s to their intermediate (or sometimes completely cleaved) forms. It is present only in neuroendocrine cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

s such as brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

, pituitary and adrenal, and most often cleaves after a pair of basic residue
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....

s within prohormones but can occasionally cleave after a single arginine. It binds to a protein known as proSAAS, which also represents its endogenous inhibitor. PC1 is synthesized as a 99 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

 proform quickly converted to an 87 kDa major active form, which itself is nearly completely cleaved to a 66 kDa active form within neuroendocrine cells.

Proprotein convertase 1 is the enzyme largely responsible for the first step in the biosynthesis of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

. Following the action of proprotein convertase 1, a carboxypeptidase is required to remove the basic residues from the processing intermediate and generate the bioactive form of insulin. Another prohormone convertase, proprotein convertase 2
Proprotein convertase 2
Proprotein convertase 2 also known as prohormone convertase 2 or neuroendocrine convertase 2 is a serine protease and proprotein convertase PC2, like proprotein convertase 1 , is an enzyme responsible for the first step in the maturation of many neuroendocrine peptides from their precursors, such...

 plays a more minor role in the first step of insulin biosynthesis, but a greater role in the first step of glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...

 biosynthesis. The knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...

 of proprotein convertase 1 is not lethal in mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

 or humans, most likely due to the presence of the second convertase, although mice lacking proprotein convertase 1 activity show a number of defects including slow growth.

Proprotein convertase 1 is a calcium (Ca2+) activated serine endoprotease (meaning that a serine residue is part of the active site that hydrolyzes the peptide bond within the substrate). It is related to the bacterial enzyme known as subtilisin
Subtilisin
Subtilisin is a non-specific protease initially obtained from Bacillus subtilis.Subtilisins belong to subtilases, a group of serine proteases that initiate the nucleophilic attack on the peptide bond through a serine residue at the active site. They are physically and chemically...

. There are nine subtilisin homologs in mammals; in addition to proprotein convertase 1 and 2, other members of this enzyme family include furin
Furin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...

, PACE4
PCSK6
Proprotein convertase subtilisin/kexin type 6 is an enzyme that in humans is encoded by the PCSK6 gene.-Further reading:...

, PC4
PCSK4
Proprotein convertase subtilisin/kexin type 4 is an enzyme that in humans is encoded by the PCSK4 gene.-Further reading:...

, PC5/6
PCSK5
Proprotein convertase subtilisin/kexin type 5 is an enzyme that in humans is encoded by the PCSK5 gene.-Further reading:...

, PC7/8
PCSK7
Proprotein convertase subtilisin/kexin type 7 is an enzyme that in humans is encoded by the PCSK7 gene.-Further reading:...

, PCSK9
PCSK9
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme which in humans is encoded by the PCSK9 gene with orthologs found across many species.- Function :...

, and SKI1/S1P.