Procesamiento de La Insulina

Report for Pathway Review
Introduction
This report is intended for reviewers of the pathway "Insulin processing". It has been
automatically generated.
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1 Insulin processing (Pathway)
Authors
May, B, Gopinathrao, G, 2008-11-19 19:22:37.
Editors
Reviewers
D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.
The generation of insulin-containing secretory granules from proinsulin in the lumen of the
endoplasmic reticulum (ER) can be described in 4 steps: formation of intramolecular disulfide
bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yield
insulin, translocation of the granules across the cytosol to the plasma membrane.
Transcription of the human insulin gene INS is activated by 4 important transcription factors:
Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the
promoters of the insulin gene and act synergistically to promote transcription. Expression of the
transcription factors is upregulated in response to glucose.
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
cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is
stabilized by glucose.
In the process annotated in detail here, within the ER, three intramolecular disulfide bonds form
between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of
the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by
Ero1-like alpha
The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High
concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7
and the proinsulin 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 the
endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites
of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the
cystine-bonded A and B chains of mature insulin and the C peptide, which will also 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 10000 insulin granules of which about 1000 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.
References
Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J,
Schermerhorn T, Straub SG, Yajima H, Sharp GW, "Triggering and augmentation mechanisms,
granule pools, and biphasic insulin secretion", Diabetes, 51, 2002, S83-90.
Dodson G, Steiner D, "The role of assembly in insulin's biosynthesis", Curr Opin Struct Biol, 8,
1998, 189-94.
Gerber SH, Sdhof TC, "Molecular determinants of regulated exocytosis", Diabetes, 51, 2002,
S3-11.
Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS, "Regulation of the insulin
gene by glucose and fatty acids", J Nutr, 136, 2006, 873-6.
Rutter GA, Hill EV, "Insulin vesicle release: walk, kiss, pause ... then run", Physiology
(Bethesda), 21, 2006, 189-96.
1.1 Oxidation of cysteine to cystine in Proinsulin (Reaction)
Authors
Editors
Reviewers
Cystine bonds are formed in Proinsulin-1 between cysteine residues 31 and 96, cysteine
residues 43 and 109, and cysteine residues 95 and 100. Ero1-like alpha does not directly
catalyze the oxidation of cysteines to cystine. Instead it maintains a suitably oxidizing
environment for the reactions to occur . Though Ero1-like alpha can act via specific isomerases
such as P4HB/PDI, there is currently no evidence that formation of cystine bonds in insulin
requires a specific isomerase. Interestingly, even in beta cells of wild type animals, trace
amounts of incorrectly bonded proinsulin can be detected. Thus, the formation of correct cystine
bonds may involve a period of bond shuffling.
References
Chang SG, Choi KD, Jang SH, Shin HC, "Role of disulfide bonds in the structure and activity of
human insulin", Mol Cells, 16, 2003, 323-30.
1998, 189-94.
Liu M, Li Y, Cavener D, Arvan P, "Proinsulin disulfide maturation and misfolding in the
endoplasmic reticulum", J Biol Chem, 280, 2005, 13209-12.
Liu M, Ramos-Castaeda J, Arvan P, "Role of the connecting peptide in insulin biosynthesis",
J Biol Chem, 278, 2003, 14798-805.
Min CY, Qiao ZS, Feng YM, "Unfolding of human proinsulin. Intermediates and possible role of
its C-peptide in folding/unfolding", Eur J Biochem, 271, 2004, 1737-47.
Qiao ZS, Min CY, Hua QX, Weiss MA, Feng YM, "In vitro refolding of human proinsulin. Kinetic
intermediates, putative disulfide-forming pathway folding initiation site, and potential role of
C-peptide in folding process", J Biol Chem, 278, 2003, 17800-9.
1.2 Cystine-bonded Proinsulin translocates from the endoplasmic

reticulum to the Golgi (BlackBoxEvent)
Authors
Editors
Reviewers
Proinsulin in the endoplasmic reticulum moves to the Golgi apparatus via vesicles that bud from
the endoplasmic reticulum.
References
1998, 189-94.
Orci L, Ravazzola M, Amherdt M, Madsen O, Vassalli JD, Perrelet A, "Direct identification of
prohormone conversion site in insulin-secreting cells", Cell, 42, 1985, 671-81.
1.3 ZnT6 transports zinc into the golgi apparatus (Reaction)
Authors
Jassal, Bijay, 2009-09-11.
Editors
Reviewers
He, Lei, 2009-11-12.
Two human genes mediate the transport of zinc into the TGN and they are both localized to the
TGN. The human gene SLC30A6 encodes the zinc transporter ZnT6. By Western blot studies,
ZnT6 is only found in the brain and lung in human (Huang L et al, 2002).
References
Huang L, Kirschke CP, Gitschier J, "Functional characterization of a novel mammalian zinc
transporter, ZnT6", J Biol Chem, 277, 2002, 26389-95.
1.4 ZnT7 transports zinc into the golgi apparatus (Reaction)
Authors
Editors
Reviewers
He, Lei, 2009-11-12.
The human gene SLC30A7 encodes the zinc transporter ZnT7. It is thought to be present in the
small intestine and lung in humans (Kirschke CP and Huang L, 2003). Functional properties
assigned to ZnT7 are based on studies conducted with mouse experiments.
References
Kirschke CP, Huang L, "ZnT7, a novel mammalian zinc transporter, accumulates zinc in the
Golgi apparatus", J Biol Chem, 278, 2003, 4096-102.
Source reaction
This reaction was inferred from the corresponding reaction "Znt7 transports zinc into the golgi
apparatus" in species Mus musculus.
The mouse SLC30A7 gene encodes Znt7 and is detected in many tissues such as liver, kidney,
heart and brain by Northern blot analysis. Stable expression of Znt7 in CHO cells results in zinc
accumulation in the golgi apparatus (Kirschke CP, Huang L, 2003).
The following literature references support the source reaction:
1.5 Proinsulin binds zinc and calcium forming

Proinsulin:zinc:calcium (Reaction)
Authors
Editors
Reviewers
In the presence of high concentrations of zinc and calcium, proinsulin spontaneously forms
soluble complexes containing 6 molecules of proinsulin, 2 zinc ions, and 1 calcium ion. Zinc
Transporters ZnT5, ZnT6, and ZnT7 are found in the membrane of the Golgi in pancreatic cells
(and also in many other cell types). They play a role in maintaining the high zinc concentration in
the Golgi lumen and thus catalyze the formation of the proinsulin-zinc-calcium complex. Other
transporters, such as the newly identified ZnT9 and ZnT10, may also be involved but this is
presently unknown.
References
1998, 189-94.
Dunn MF, "Zinc-ligand interactions modulate assembly and stability of the insulin hexamer -- a
review", Biometals, 18, 2005, 295-303.
Kaarsholm NC, Ko HC, Dunn MF, "Comparison of solution structural flexibility and zinc binding
domains for insulin, proinsulin, and miniproinsulin", Biochemistry, 28, 1989, 4427-35.
Kadima W, "Role of metal ions in the T- to R-allosteric transition in the insulin hexamer",
Biochemistry, 38, 1999, 13443-52.
Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M, "Overview of mammalian zinc transporters",
Cell Mol Life Sci, 61, 2004, 49-68.
1.6 Proinsulin:Zinc:Calcium complex translocates to immature

secretory granule (BlackBoxEvent)
Authors
Editors
Reviewers
Immature, clathrin-coated vesicles containing proinsulin-zinc-calcium complexes bud from the
trans-golgi network.
References
1998, 189-94.
1.7 Processing of Proinsulin to Insulin (BlackBoxEvent)
Authors
May, B, 2008-05-13 13:18:27.
Editors
Reviewers
Proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases Convertase 1/3
and Convertase 2. The exopeptidase Carboxypeptidase E then removes 2 amino acids from the
carboxyl termini. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is
not soluble and forms crystals inside the secretory granules.
References
Aldibbiat A, Marriott CE, Scougall KT, Campbell SC, Huang GC, MacFarlane WM, Shaw JA,
"Inability to process and store proinsulin in transdifferentiated pancreatic acinar cells lacking the
regulated secretory pathway", J Endocrinol, 196, 2008, 33-43.
Bailyes EM, Shennan KI, Usac EF, Arden SD, Guest PC, Docherty K, Hutton JC, "Differences
between the catalytic properties of recombinant human PC2 and endogenous rat PC2",
Biochem J, 309, 1995, 587-94.
Chen H, Jawahar S, Qian Y, Duong Q, Chan G, Parker A, Meyer JM, Moore KJ, Chayen S,
Gross DJ, Glaser B, Permutt MA, Fricker LD, "Missense polymorphism in the human
carboxypeptidase E gene alters enzymatic activity", Hum Mutat, 18, 2001, 120-31.
Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, Kerr-Conte J,
Van Lommel L, Grunwald D, Favier A, Seve M, "In vivo expression and functional
characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion", J Cell Sci,
119, 2006, 4199-206.
1998, 189-94.

Irminger JC, Meyer K, Halban P, "Proinsulin processing in the rat insulinoma cell line INS after
overexpression of the endoproteases PC2 or PC3 by recombinant adenovirus", Biochem J, 320,
1996, 11-5.
Itoh Y, Tanaka S, Takekoshi S, Itoh J, Osamura RY, "Prohormone convertases (PC1/3 and
PC2) in rat and human pancreas and islet cell tumors: subcellular immunohistochemical
analysis", Pathol Int, 46, 1996, 726-37.
Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ,
Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A,
Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S,
"Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein
convertase 1 deficiency", J Clin Invest, 112, 2003, 1550-60.
Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC,
O'Rahilly S, "Obesity and impaired prohormone processing associated with mutations in the
human prohormone convertase 1 gene", Nat Genet, 16, 1997, 303-6.
Biochemistry, 38, 1999, 13443-52.
Kaufmann JE, Irminger JC, Mungall J, Halban PA, "Proinsulin conversion in GH3 cells after
coexpression of human proinsulin with the endoproteases PC2 and/or PC3", Diabetes, 46, 1997,
978-82.
Malide D, Seidah NG, Chretien M, Bendayan M, "Electron microscopic immunocytochemical
evidence for the involvement of the convertases PC1 and PC2 in the processing of proinsulin in
pancreatic beta-cells", J Histochem Cytochem, 43, 1995, 11-9.
Smeekens SP, Montag AG, Thomas G, Albiges-Rizo C, Carroll R, Benig M, Phillips LA, Martin
S, Ohagi S, Gardner P, "Proinsulin processing by the subtilisin-related proprotein convertases
furin, PC2, and PC3", Proc Natl Acad Sci U S A, 89, 1992, 8822-6.
Smith GD, Pangborn WA, Blessing RH, "The structure of T6 human insulin at 1.0 A resolution",
Acta Crystallogr D Biol Crystallogr, 59, 2003, 474-82.
Steiner DF, "The proprotein convertases", Curr Opin Chem Biol, 2, 1998, 31-9.
Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner DF, "Severe block in processing of
proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of
mice lacking prohormone convertase 1/3", Proc Natl Acad Sci U S A, 99, 2002, 10299-304.
1.8 ZnT5 transports zinc into secretory granules in pancreatic beta

cells (Reaction)
Authors
Editors
Reviewers
He, Lei, 2009-11-12.
The human gene SLC30A5 encodes the zinc transporter ZnT5. This protein is widely expressed
but is most abundant in pancreatic beta cells (Kambe T et al, 2002). In these cells, ZnT5
mediates the transport of zinc into secretory granules that contain insulin.
References
Kambe T, Narita H, Yamaguchi-Iwai Y, Hirose J, Amano T, Sugiura N, Sasaki R, Mori K,
Iwanaga T, Nagao M, "Cloning and characterization of a novel mammalian zinc transporter, zinc
transporter 5, abundantly expressed in pancreatic beta cells", J Biol Chem, 277, 2002,
19049-55.
1.9 SLC30A8 transports Zn2+ from cytosol to secretory granule

(Reaction)
Authors
Editors
Reviewers
He, Lei, 2009-11-12.
The human SLC30A8 gene encodes the zinc transporter ZnT8 which is specifically expressed in
pancreatic beta cells (Chimienti et al. 2005). Zinc is required for zinc-insulin crystallization within
secretory vesicles of these cells. After glucose stimulation, large amounts of zinc are secreted
locally in the extracellular matrix together with insulin. It has been suggested that this
co-secreted zinc plays a role in islet cell paracrine and/or autocrine communication (Chimienti F
et al, 2006). Loss of function mutations in SLC30A8 are strongly protective against type 2
diabetes, suggesting SLC20A8 inhibition as a therapeutic target in T2D prevention. (Flannick et
al. 2014).
References
119, 2006, 4199-206.
Chimienti F, Favier A, Seve M, "ZnT-8, a pancreatic beta-cell-specific zinc transporter",
Biometals, 18, 2005, 313-7.
1.10 Insulin secretory granule translocates to cell cortex

(BlackBoxEvent)
Authors
May, B, 2008-05-13 13:18:27.
Editors
Reviewers
Insulin-containing secretory vesicles are translocated along microtubules (polymerized tubulin)
from the trans-golgi to the cellular cortex. Motor activity is provided by Dynamin-1 but the
complex that connects the secretory granule to the Kinesin-1 is not yet fully known. The process
is stimulated by intracellular calcium ions (Ca2+).
References
(Bethesda), 21, 2006, 189-96.
Source reaction
This reaction was inferred from the corresponding reaction "Insulin secretory granule
translocates to cell cortex" in species Mus musculus.
Insulin-containing secretory vesicles are translocated along microtubules (polymerized tubulin)
from the trans-golgi to the cellular cortex. Motor activity is provided by Kinesin-1 but the complex
that connects the secretory granule to the Kinesin-1 is not yet fully known. The process is
stimulated by intracellular calcium ions (Ca2+).
Meng YX, Wilson GW, Avery MC, Varden CH, Balczon R, "Suppression of the expression of a
pancreatic beta-cell form of the kinesin heavy chain by antisense oligonucleotides inhibits insulin
secretion from primary cultures of mouse beta-cells", Endocrinology, 138, 1997, 1979-87.
(Bethesda), 21, 2006, 189-96.

Varadi A, Tsuboi T, Johnson-Cadwell LI, Allan VJ, Rutter GA, "Kinesin I and cytoplasmic dynein
orchestrate glucose-stimulated insulin-containing vesicle movements in clonal MIN6 beta-cells",
Biochem Biophys Res Commun, 311, 2003, 272-82.
1.11 Insulin secretory granules translocate across the cortical

actin network to dock at plasma membrane (BlackBoxEvent)
Authors
May, B, 2008-05-13 13:18:27.
Editors
Reviewers
Insulin-containing secretory granules are bound to Myosin Va via Rab27a in a complex of
uncertain composition. Myosin Va moves along the cortical actin network (actin at the periphery
of the cytoplasm), carrying the granules to the inner surface of the plasma membrane. A beta
cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner
surface of the plasma membrane and a subset of about 100 docked granules form the "readily
releasable" pool (granules which are released within about 5 minutes of glucose stimulation).
Docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory
granule and EXOC4/Sec8 located at the plasma membrane. Additional components (EXOC1,
EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex.
References
Lang J, "Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine
secretion", Eur J Biochem, 259, 1999, 3-17.
(Bethesda), 21, 2006, 189-96.
Tsuboi T, Ravier MA, Xie H, Ewart MA, Gould GW, Baldwin SA, Rutter GA, "Mammalian exocyst
complex is required for the docking step of insulin vesicle exocytosis", J Biol Chem, 280, 2005,
25565-70.
Source reaction
This reaction was inferred from the corresponding reaction "Insulin secretory granules
translocate across the cortical actin network to dock at the plasma membrane" in species Mus
musculus.
Insulin-containing secretory granules are bound to Myosin Va via Rab27a in a complex of
uncertain composition. Mysosin Va moves along the cortical actin network (actin at the periphery
of the cytoplasm), carrying the granules to the inner surface of the plasma membrane.
Goehring AS, Pedroja BS, Hinke SA, Langeberg LK, Scott JD, "MyRIP anchors protein kinase A
to the exocyst complex", J Biol Chem, 282, 2007, 33155-67.
Kasai K, Ohara-Imaizumi M, Takahashi N, Mizutani S, Zhao S, Kikuta T, Kasai H, Nagamatsu S,
Gomi H, Izumi T, "Rab27a mediates the tight docking of insulin granules onto the plasma
membrane during glucose stimulation", J Clin Invest, 115, 2005, 388-96.
Merrins MJ, Stuenkel EL, "Kinetics of Rab27a-dependent actions on vesicle docking and priming
in pancreatic beta-cells", J Physiol, 586, 2008, 5367-81.
(Bethesda), 21, 2006, 189-96.
Varadi A, Tsuboi T, Rutter GA, "Myosin Va transports dense core secretory vesicles in
pancreatic MIN6 beta-cells", Mol Biol Cell, 16, 2005, 2670-80.
Yi Z, Yokota H, Torii S, Aoki T, Hosaka M, Zhao S, Takata K, Takeuchi T, Izumi T, "The
Rab27a/granuphilin complex regulates the exocytosis of insulin-containing dense-core
granules", Mol Cell Biol, 22, 2002, 1858-67.
1.12 Exocyst complex formation (BlackBoxEvent)
Authors
Editors
A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the
inner surface of the plasma membrane and a subset of about 100 docked granules form the
"readily releasable" pool (granules which are released within about 5 minutes of glucose
stimulation). As inferred from rat MIN6 cells, docking occurs by interaction between
EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at
the plasma membrane (Tsuboi et al. 2005). Additional components (EXOC1, EXOC2, EXOC5,
EXOC6, EXOC7, EXOC8) form the Exocyst Complex. EXOC7 binds the plasma membrane
(Matern et al. 2001).
References
Matern HT, Yeaman C, Nelson WJ, Scheller RH, "The Sec6/8 complex in mammalian cells:
characterization of mammalian Sec3, subunit interactions, and expression of subunits in
polarized cells", Proc Natl Acad Sci U S A, 98, 2001, 9648-53.
(Bethesda), 21, 2006, 189-96.
25565-70.
Full List of Literature References for Pathway "Insulin

processing"
Aldibbiat A, Marriott CE, Scougall KT, Campbell SC, Huang GC, MacFarlane WM, Shaw JA,
"Inability to process and store proinsulin in transdifferentiated pancreatic acinar cells lacking the
regulated secretory pathway", J Endocrinol, 196, 2008, 33-43.
Bailyes EM, Shennan KI, Usac EF, Arden SD, Guest PC, Docherty K, Hutton JC, "Differences
between the catalytic properties of recombinant human PC2 and endogenous rat PC2",
Biochem J, 309, 1995, 587-94.
Chang SG, Choi KD, Jang SH, Shin HC, "Role of disulfide bonds in the structure and activity of
human insulin", Mol Cells, 16, 2003, 323-30.
Chen H, Jawahar S, Qian Y, Duong Q, Chan G, Parker A, Meyer JM, Moore KJ, Chayen S,
Gross DJ, Glaser B, Permutt MA, Fricker LD, "Missense polymorphism in the human
carboxypeptidase E gene alters enzymatic activity", Hum Mutat, 18, 2001, 120-31.
119, 2006, 4199-206.
Chimienti F, Favier A, Seve M, "ZnT-8, a pancreatic beta-cell-specific zinc transporter",

Biometals, 18, 2005, 313-7.
1998, 189-94.
Gerber SH, Sdhof TC, "Molecular determinants of regulated exocytosis", Diabetes, 51, 2002,
S3-11.
Huang L, Kirschke CP, Gitschier J, "Functional characterization of a novel mammalian zinc
transporter, ZnT6", J Biol Chem, 277, 2002, 26389-95.
Irminger JC, Meyer K, Halban P, "Proinsulin processing in the rat insulinoma cell line INS after
overexpression of the endoproteases PC2 or PC3 by recombinant adenovirus", Biochem J, 320,
1996, 11-5.
Itoh Y, Tanaka S, Takekoshi S, Itoh J, Osamura RY, "Prohormone convertases (PC1/3 and
PC2) in rat and human pancreas and islet cell tumors: subcellular immunohistochemical
analysis", Pathol Int, 46, 1996, 726-37.
Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ,
Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A,
Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S,
"Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein
convertase 1 deficiency", J Clin Invest, 112, 2003, 1550-60.
Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC,
O'Rahilly S, "Obesity and impaired prohormone processing associated with mutations in the
human prohormone convertase 1 gene", Nat Genet, 16, 1997, 303-6.
Kaarsholm NC, Ko HC, Dunn MF, "Comparison of solution structural flexibility and zinc binding
domains for insulin, proinsulin, and miniproinsulin", Biochemistry, 28, 1989, 4427-35.
Biochemistry, 38, 1999, 13443-52.
Kambe T, Narita H, Yamaguchi-Iwai Y, Hirose J, Amano T, Sugiura N, Sasaki R, Mori K,
Iwanaga T, Nagao M, "Cloning and characterization of a novel mammalian zinc transporter, zinc
transporter 5, abundantly expressed in pancreatic beta cells", J Biol Chem, 277, 2002,
19049-55.
Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M, "Overview of mammalian zinc transporters",
Cell Mol Life Sci, 61, 2004, 49-68.

Kaufmann JE, Irminger JC, Mungall J, Halban PA, "Proinsulin conversion in GH3 cells after
coexpression of human proinsulin with the endoproteases PC2 and/or PC3", Diabetes, 46, 1997,
978-82.
Lang J, "Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine
secretion", Eur J Biochem, 259, 1999, 3-17.
Liu M, Li Y, Cavener D, Arvan P, "Proinsulin disulfide maturation and misfolding in the
endoplasmic reticulum", J Biol Chem, 280, 2005, 13209-12.
Liu M, Ramos-Castaeda J, Arvan P, "Role of the connecting peptide in insulin biosynthesis",
J Biol Chem, 278, 2003, 14798-805.
Malide D, Seidah NG, Chretien M, Bendayan M, "Electron microscopic immunocytochemical
evidence for the involvement of the convertases PC1 and PC2 in the processing of proinsulin in
pancreatic beta-cells", J Histochem Cytochem, 43, 1995, 11-9.
Matern HT, Yeaman C, Nelson WJ, Scheller RH, "The Sec6/8 complex in mammalian cells:
characterization of mammalian Sec3, subunit interactions, and expression of subunits in
polarized cells", Proc Natl Acad Sci U S A, 98, 2001, 9648-53.
Min CY, Qiao ZS, Feng YM, "Unfolding of human proinsulin. Intermediates and possible role of
its C-peptide in folding/unfolding", Eur J Biochem, 271, 2004, 1737-47.
Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS, "Regulation of the insulin
gene by glucose and fatty acids", J Nutr, 136, 2006, 873-6.
Qiao ZS, Min CY, Hua QX, Weiss MA, Feng YM, "In vitro refolding of human proinsulin. Kinetic
intermediates, putative disulfide-forming pathway folding initiation site, and potential role of
C-peptide in folding process", J Biol Chem, 278, 2003, 17800-9.
(Bethesda), 21, 2006, 189-96.
Smeekens SP, Montag AG, Thomas G, Albiges-Rizo C, Carroll R, Benig M, Phillips LA, Martin
S, Ohagi S, Gardner P, "Proinsulin processing by the subtilisin-related proprotein convertases
furin, PC2, and PC3", Proc Natl Acad Sci U S A, 89, 1992, 8822-6.
Smith GD, Pangborn WA, Blessing RH, "The structure of T6 human insulin at 1.0 A resolution",
Acta Crystallogr D Biol Crystallogr, 59, 2003, 474-82.
Steiner DF, "The proprotein convertases", Curr Opin Chem Biol, 2, 1998, 31-9.
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Procesamiento de La Insulina

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Procesamiento de La Insulina

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Reaction Diagram Key

1 Insulin processing (Pathway)

Proinsulin-zinc-calcium complexes bud in vesicles from the trans-Golgi to form immature

1.1 Oxidation of cysteine to cystine in Proinsulin (Reaction)

C-peptide in folding process", J Biol Chem, 278, 2003, 17800-9.

1.2 Cystine-bonded Proinsulin translocates from the endoplasmic

1.3 ZnT6 transports zinc into the golgi apparatus (Reaction)

1.4 ZnT7 transports zinc into the golgi apparatus (Reaction)

1.5 Proinsulin binds zinc and calcium forming

1.6 Proinsulin:Zinc:Calcium complex translocates to immature

1.7 Processing of Proinsulin to Insulin (BlackBoxEvent)

review", Biometals, 18, 2005, 295-303.

1.8 ZnT5 transports zinc into secretory granules in pancreatic beta

1.9 SLC30A8 transports Zn2+ from cytosol to secretory granule

1.10 Insulin secretory granule translocates to cell cortex

(Bethesda), 21, 2006, 189-96.

1.11 Insulin secretory granules translocate across the cortical

1.12 Exocyst complex formation (BlackBoxEvent)

Full List of Literature References for Pathway "Insulin

Chimienti F, Favier A, Seve M, "ZnT-8, a pancreatic beta-cell-specific zinc transporter",

Cell Mol Life Sci, 61, 2004, 49-68.

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