Pathway: Insulin processing
Reactions in pathway: Insulin processing :
Insulin processing
Generation of insulin containing secretory granules from newly synthesized proinsulin in the lumen of the endoplasmic reticulum (ER) involves formation of proinsulin intramolecular disulfide bonds, formation of proinsulin zinc calcium complexes, proteolytic cleavage of proinsulin to yield insulin and C peptide, and translocation of the granules across the cytosol to the plasma membrane (Dodson & Steiner 1998).
Transcription of the human insulin gene INS is annotated as part of the pathway “Regulation of gene expression in beta cells” (see reaction R-HSA-211289). The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is co-translationally cleaved to yield proinsulin.
In the process annotated here, within the ER, three intramolecular disulfide bonds form in proinsulin, mediated by P4HD (PDI1A) and ERO1B proteins. Correctly folded, disulfide-bonded proinsulin then moves via vesicles from the ER to the Golgi Complex where it forms complexes with zinc and calcium.
Proinsulin zinc calcium complexes bud in vesicles from the trans Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules, endoproteases PCKS1 and PCKS2 (Prohormone Convertases 1 and 2) cleave proinsulin at two sites and CPE (Carboxypeptidase E) removes additional amino acid residues to yield the cystine bonded A and B chains of mature insulin and the C peptide, which will be secreted with the insulin. The insulin zinc calcium complexes form insoluble crystals within the granule.
The insulin containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin 1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.
A pancreatic beta cell contains about 10,000 insulin granules of which about 1,000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin 2/VAMP2 on the granule membrane. Exocytosis is a calcium dependent process due to interaction of the calcium binding membrane protein Synaptotagmin V/IX with the SNARE type proteins.
Transcription of the human insulin gene INS is annotated as part of the pathway “Regulation of gene expression in beta cells” (see reaction R-HSA-211289). The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is co-translationally cleaved to yield proinsulin.
In the process annotated here, within the ER, three intramolecular disulfide bonds form in proinsulin, mediated by P4HD (PDI1A) and ERO1B proteins. Correctly folded, disulfide-bonded proinsulin then moves via vesicles from the ER to the Golgi Complex where it forms complexes with zinc and calcium.
Proinsulin zinc calcium complexes bud in vesicles from the trans Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules, endoproteases PCKS1 and PCKS2 (Prohormone Convertases 1 and 2) cleave proinsulin at two sites and CPE (Carboxypeptidase E) removes additional amino acid residues to yield the cystine bonded A and B chains of mature insulin and the C peptide, which will be secreted with the insulin. The insulin zinc calcium complexes form insoluble crystals within the granule.
The insulin containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin 1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.
A pancreatic beta cell contains about 10,000 insulin granules of which about 1,000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin 2/VAMP2 on the granule membrane. Exocytosis is a calcium dependent process due to interaction of the calcium binding membrane protein Synaptotagmin V/IX with the SNARE type proteins.
Peptide hormones are cleaved from larger precursors in the secretory system (endoplasmic reticulum, Golgi apparatus, secretory granules) of the cell. After secretion peptide hormones are modified and degraded by extracellular proteases.
Insulin processing occurs in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin by PCSK1 (PC1/3) and PCSK2 to yield insulin, translocation of the granules across the cytosol to the plasma membrane.
During Synthesis, secretion, and deacetylation of Ghrelin, proghrelin is acylated by ghrelin O-acyltransferase and cleaved by PCSK1 to yield the mature acyl ghrelin and C-ghrelin. In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase.
During Metabolism of Angiotensinogen to Angiotensin, Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Two C-terminal amino acid residues of angiotensin I are then removed by angiotensin-converting enzyme (ACE), located on the surface of endothelial cells, to yield angiotensin II (angiotensin-2, angiotensin-(1-8)), the active peptide that causes vasoconstriction, resorption of sodium and chloride, excretion of potassium, water retention, and aldosterone secretion. More recently other, more tissue-localized pathways leading to angiotensin II and alternative derivatives of angiotensinogen have been identified and described.
Incretin synthesis, secretion, and inactivation occurs through processing of incretin precursors (preproGLP-1 and preproGIP) by PCSK1. After secretion both incretins (GLP-1 and GIP) can be inactivated by cleavage by DPP4.
Peptide hormone biosynthesis describes processing of glycoprotein hormones (those which include carbohydrate side-chains) and corticotropin.
Insulin processing occurs in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin by PCSK1 (PC1/3) and PCSK2 to yield insulin, translocation of the granules across the cytosol to the plasma membrane.
During Synthesis, secretion, and deacetylation of Ghrelin, proghrelin is acylated by ghrelin O-acyltransferase and cleaved by PCSK1 to yield the mature acyl ghrelin and C-ghrelin. In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase.
During Metabolism of Angiotensinogen to Angiotensin, Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Two C-terminal amino acid residues of angiotensin I are then removed by angiotensin-converting enzyme (ACE), located on the surface of endothelial cells, to yield angiotensin II (angiotensin-2, angiotensin-(1-8)), the active peptide that causes vasoconstriction, resorption of sodium and chloride, excretion of potassium, water retention, and aldosterone secretion. More recently other, more tissue-localized pathways leading to angiotensin II and alternative derivatives of angiotensinogen have been identified and described.
Incretin synthesis, secretion, and inactivation occurs through processing of incretin precursors (preproGLP-1 and preproGIP) by PCSK1. After secretion both incretins (GLP-1 and GIP) can be inactivated by cleavage by DPP4.
Peptide hormone biosynthesis describes processing of glycoprotein hormones (those which include carbohydrate side-chains) and corticotropin.
Metabolism of proteins, as annotated here, covers the full life cycle of a protein from its synthesis to its posttranslational modification and degradation, at various levels of specificity. Protein synthesis is accomplished through the process of Translation of an mRNA sequence into a polypeptide chain. Protein folding is achieved through the function of molecular chaperones which recognize and associate with proteins in their non-native state and facilitate their folding by stabilizing the conformation of productive folding intermediates (Young et al. 2004). Following translation, many newly formed proteins undergo Post-translational protein modification, essentially irreversible covalent modifications critical for their mature locations and functions (Knorre et al. 2009), including gamma carboxylation, synthesis of GPI-anchored proteins, asparagine N-linked glycosylation, O-glycosylation, SUMOylation, ubiquitination, deubiquitination, RAB geranylgeranylation, methylation, carboxyterminal post-translational modifications, neddylation, and phosphorylation. Peptide hormones are synthesized as parts of larger precursor proteins whose cleavage in the secretory system (endoplasmic reticulum, Golgi apparatus, secretory granules) is annotated in Peptide hormone metabolism. After secretion, peptide hormones are modified and degraded by extracellular proteases (Chertow, 1981 PMID:6117463). Protein repair enables the reversal of damage to some amino acid side chains caused by reactive oxygen species. Pulmonary surfactants are lipids and proteins that are secreted by the alveolar cells of the lung that decrease surface tension at the air/liquid interface within the alveoli to maintain the stability of pulmonary tissue (Agassandian and Mallampalli 2013). Nuclear regulation, transport, metabolism, reutilization, and degradation of surfactant are described in the Surfactant metabolism pathway. Amyloid fiber formation, the accumulation of mostly extracellular deposits of fibrillar proteins, is associated with tissue damage observed in numerous diseases including late phase heart failure (cardiomyopathy) and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's.