Synthesis, secretion, and deacylation of Ghrelin (Homo sapiens)

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4, 114, 11, 191, 4, 7, 9, 11...4, 11, 12, 19, 202-6, 8, 10...4, 114, 11, 13, 174, 11, 12, 19, 20secretory granulenucleoplasmcytosolendoplasmic reticulum lumenDecS-GHRL-1(24-51) GHRL-1(24-117) O-octanoyl-L-serine-GHRL-1(24-51) GlucagonO-octanoyl-L-serine-GHRL-1(24-117) Acyl GhrelinFAsDecS-GHRL-1(24-50) InsulinPro-des-Gln14-ghrelin GHRL-1 GlcPrepro-des-Gln14-ghrelin Acyl ProghrelinDecS-GHRL-1(24-50) Acyl GhrelinDes-acyl GhrelinGHRL-1(52-117)SPCS2 ButyrylcholinesteraseSEC11C PLA2G7GHRL-1(24-50) Octanoic acidO-octanoyl-L-serine-GHRL-1(24-50) KLF4PCSK1 Preproghrelinandprepro-des-Gln14-ghrelinBCHE LEPSPCS1 ProghrelinandPro-des-Gln14-ghrelinO-octanoyl-L-serine-GHRL-1(24-51) 4xHC-INS(90-110) SPCS3 GHRL-1(24-51) SEC11A DecS-GHRL-1(24-117)IGF1MBOAT4DecS-GHRL-1(24-51) DECAACHE GHRL geneGH1O-octanoyl-L-serine-GHRL-1(24-117)Ca2+ GHRL-1(24-117)DecS-GHRL-1(24-117) O-octanoyl-L-serine-GHRL-1(24-50) 2xHC-INS(25-54) Signal PeptidasePC1:calcium cofactorGHRL-1(52-117)


Description

Ghrelin is a peptide hormone of 28 amino acid residues which is acylated at the serine-3 of the mature peptide. Ghrelin is synthesized in several tissues: X/A-like cells of the gastric mucosa (the major source of ghrelin), hypothalamus, pituitary, adrenal gland, thyroid, breast, ovary, placenta, fallopian tube, testis, prostate, liver, gall bladder, pancreas, fat tissue, human lymphocytes, spleen, kidney, lung, skeletal muscle, myocardium, vein and skin. Ghrelin binds the GHS-R1a receptor present in hypothalamus pituitary, and other tissues. Binding causes appetite stimulation and release of growth hormone. Levels of circulating ghrelin rise during fasting, peak before a meal, and fall according to the calories ingested.
Preproghrelin is cleaved to yield proghrelin which is then acylated by ghrelin O-acyltransferase to yield octanoyl ghrelin and decanoyl ghrelin. Only octanoyl ghrelin is able to bind and activate the GHS-R1a receptor. Unacylated ghrelin (des-acyl ghrelin) is also present in plasma but its function is controversial.
Acyl proghrelin is cleaved by prohormone convertase 1/3 to yield the mature acyl ghrelin and C-ghrelin. Secretion of ghrelin is inhibited by insulin, growth hormone (somatotropin), leptin, glucose, glucagon, and fatty acids. Secretion is stimulated by insulin-like growth factor-1 and muscarinic agonists.
In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase. Other enzymes may also deacylate acyl ghrelin. View original pathway at:Reactome.

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Bibliography

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  1. Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K.; ''Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing.''; PubMed Europe PMC Scholia
  2. Nørrelund H, Hansen TK, Ørskov H, Hosoda H, Kojima M, Kangawa K, Weeke J, Møller N, Christiansen JS, Jørgensen JO.; ''Ghrelin immunoreactivity in human plasma is suppressed by somatostatin.''; PubMed Europe PMC Scholia
  3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K.; ''Ghrelin is a growth-hormone-releasing acylated peptide from stomach.''; PubMed Europe PMC Scholia
  4. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M.; ''The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans.''; PubMed Europe PMC Scholia
  5. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K.; ''Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans.''; PubMed Europe PMC Scholia
  6. De Vriese C, Gregoire F, Lema-Kisoka R, Waelbroeck M, Robberecht P, Delporte C.; ''Ghrelin degradation by serum and tissue homogenates: identification of the cleavage sites.''; PubMed Europe PMC Scholia
  7. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M.; ''Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans.''; PubMed Europe PMC Scholia
  8. Broglio F, Gottero C, Van Koetsveld P, Prodam F, Destefanis S, Benso A, Gauna C, Hofland L, Arvat E, van der Lely AJ, Ghigo E.; ''Acetylcholine regulates ghrelin secretion in humans.''; PubMed Europe PMC Scholia
  9. Wei W, Wang G, Qi X, Englander EW, Greeley GH.; ''Characterization and regulation of the rat and human ghrelin promoters.''; PubMed Europe PMC Scholia
  10. Erdmann J, Lippl F, Schusdziarra V.; ''Differential effect of protein and fat on plasma ghrelin levels in man.''; PubMed Europe PMC Scholia
  11. Soares JB, Leite-Moreira AF.; ''Ghrelin, des-acyl ghrelin and obestatin: three pieces of the same puzzle.''; PubMed Europe PMC Scholia
  12. Yin X, Li Y, Xu G, An W, Zhang W.; ''Ghrelin fluctuation, what determines its production?''; PubMed Europe PMC Scholia
  13. Kanamoto N, Akamizu T, Tagami T, Hataya Y, Moriyama K, Takaya K, Hosoda H, Kojima M, Kangawa K, Nakao K.; ''Genomic structure and characterization of the 5'-flanking region of the human ghrelin gene.''; PubMed Europe PMC Scholia
  14. Lee HJ, Kang YM, Moon CS, Joe MK, Lim JH, Suh YH, Song J, Jung MH.; ''KLF4 positively regulates human ghrelin expression.''; PubMed Europe PMC Scholia
  15. De Vriese C, Hacquebard M, Gregoire F, Carpentier Y, Delporte C.; ''Ghrelin interacts with human plasma lipoproteins.''; PubMed Europe PMC Scholia
  16. Takahashi T, Ida T, Sato T, Nakashima Y, Nakamura Y, Tsuji A, Kojima M.; ''Production of n-octanoyl-modified ghrelin in cultured cells requires prohormone processing protease and ghrelin O-acyltransferase, as well as n-octanoic acid.''; PubMed Europe PMC Scholia
  17. Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H, Yada T, Matsukura S.; ''Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion.''; PubMed Europe PMC Scholia
  18. Möhlig M, Spranger J, Otto B, Ristow M, Tschöp M, Pfeiffer AF.; ''Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans.''; PubMed Europe PMC Scholia
  19. Wierup N, Björkqvist M, Weström B, Pierzynowski S, Sundler F, Sjölund K.; ''Ghrelin and motilin are cosecreted from a prominent endocrine cell population in the small intestine.''; PubMed Europe PMC Scholia
  20. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, Witcher DR, Luo S, Onyia JE, Hale JE.; ''Ghrelin octanoylation mediated by an orphan lipid transferase.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114942view16:46, 25 January 2021ReactomeTeamReactome version 75
113387view11:46, 2 November 2020ReactomeTeamReactome version 74
112592view15:56, 9 October 2020ReactomeTeamReactome version 73
101508view11:37, 1 November 2018ReactomeTeamreactome version 66
101044view21:18, 31 October 2018ReactomeTeamreactome version 65
100575view19:51, 31 October 2018ReactomeTeamreactome version 64
100124view16:37, 31 October 2018ReactomeTeamreactome version 63
99674view15:07, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93787view13:36, 16 August 2017ReactomeTeamreactome version 61
93320view11:20, 9 August 2017ReactomeTeamreactome version 61
88409view11:46, 5 August 2016FehrhartOntology Term : 'ghrelin system pathway' added !
86405view09:17, 11 July 2016ReactomeTeamreactome version 56
83094view09:58, 18 November 2015ReactomeTeamVersion54
82373view13:08, 29 September 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xHC-INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
ACHE ProteinP22303 (Uniprot-TrEMBL)
Acyl GhrelinComplexR-HSA-422059 (Reactome)
Acyl GhrelinComplexR-HSA-422096 (Reactome)
Acyl ProghrelinComplexR-HSA-422078 (Reactome)
BCHE ProteinP06276 (Uniprot-TrEMBL)
ButyrylcholinesteraseComplexR-HSA-2990868 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
DECAMetaboliteCHEBI:30813 (ChEBI)
DecS-GHRL-1(24-117) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
DecS-GHRL-1(24-117)ProteinQ9UBU3-1 (Uniprot-TrEMBL)
DecS-GHRL-1(24-50) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
DecS-GHRL-1(24-51) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
Des-acyl GhrelinComplexR-HSA-422045 (Reactome)
FAsMetaboliteCHEBI:35366 (ChEBI)
GH1ProteinP01241 (Uniprot-TrEMBL) Growth hormone is typically used to refer to the endogenous hormone - somatotropin is reserved for synthetic hormone produced by recombinant technology.
GHRL geneGeneProductENSG00000157017 (Ensembl)
GHRL-1 ProteinQ9UBU3-1 (Uniprot-TrEMBL)
GHRL-1(24-117) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
GHRL-1(24-117)ProteinQ9UBU3-1 (Uniprot-TrEMBL)
GHRL-1(24-50) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
GHRL-1(24-51) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
GHRL-1(52-117)ProteinQ9UBU3-1 (Uniprot-TrEMBL)
GlcMetaboliteCHEBI:17925 (ChEBI)
GlucagonProteinP01275 (Uniprot-TrEMBL)
IGF1ProteinP05019 (Uniprot-TrEMBL)
InsulinComplexR-HSA-74674 (Reactome)
KLF4ProteinO43474 (Uniprot-TrEMBL)
LEPProteinP41159 (Uniprot-TrEMBL)
MBOAT4ProteinQ96T53 (Uniprot-TrEMBL)
O-octanoyl-L-serine-GHRL-1(24-117) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
O-octanoyl-L-serine-GHRL-1(24-117)ProteinQ9UBU3-1 (Uniprot-TrEMBL)
O-octanoyl-L-serine-GHRL-1(24-50) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
O-octanoyl-L-serine-GHRL-1(24-51) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
Octanoic acidMetaboliteCHEBI:28837 (ChEBI)
PC1:calcium cofactorComplexR-HSA-378974 (Reactome)
PCSK1 ProteinP29120 (Uniprot-TrEMBL)
PLA2G7ProteinQ13093 (Uniprot-TrEMBL)
Prepro-des-Gln14-ghrelin ProteinQ9UBU3-2 (Uniprot-TrEMBL) Due to alternative splicing, prepro-des-Gln14-ghrelin is missing Gln37 of the prepropeptide (Gln14 of the mature peptide).
Preproghrelin

and

prepro-des-Gln14-ghrelin		ComplexR-HSA-422026 (Reactome)
Pro-des-Gln14-ghrelin ProteinQ9UBU3-2 (Uniprot-TrEMBL)
Proghrelin

and

Pro-des-Gln14-ghrelin		ComplexR-HSA-422091 (Reactome)
SEC11A ProteinP67812 (Uniprot-TrEMBL)
SEC11C ProteinQ9BY50 (Uniprot-TrEMBL)
SPCS1 ProteinQ9Y6A9 (Uniprot-TrEMBL)
SPCS2 ProteinQ15005 (Uniprot-TrEMBL)
SPCS3 ProteinP61009 (Uniprot-TrEMBL)
Signal PeptidaseComplexR-HSA-264960 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
Acyl GhrelinArrowR-HSA-422021 (Reactome)
Acyl GhrelinArrowR-HSA-422048 (Reactome)
Acyl GhrelinR-HSA-422048 (Reactome)
Acyl GhrelinR-HSA-422058 (Reactome)
Acyl ProghrelinR-HSA-422021 (Reactome)
Butyrylcholinesterasemim-catalysisR-HSA-422058 (Reactome)
DECAR-HSA-422017 (Reactome)
DecS-GHRL-1(24-117)ArrowR-HSA-422017 (Reactome)
Des-acyl GhrelinArrowR-HSA-422058 (Reactome)
FAsTBarR-HSA-422048 (Reactome)
GH1TBarR-HSA-422048 (Reactome)
GHRL geneR-HSA-422088 (Reactome)
GHRL-1(24-117)R-HSA-422017 (Reactome)
GHRL-1(24-117)R-HSA-422104 (Reactome)
GHRL-1(52-117)ArrowR-HSA-422021 (Reactome)
GHRL-1(52-117)ArrowR-HSA-422048 (Reactome)
GHRL-1(52-117)R-HSA-422048 (Reactome)
GlcTBarR-HSA-422048 (Reactome)
GlucagonTBarR-HSA-422048 (Reactome)
IGF1ArrowR-HSA-422048 (Reactome)
InsulinTBarR-HSA-422048 (Reactome)
KLF4ArrowR-HSA-422088 (Reactome)
LEPTBarR-HSA-422048 (Reactome)
MBOAT4mim-catalysisR-HSA-422017 (Reactome)
MBOAT4mim-catalysisR-HSA-422104 (Reactome)
O-octanoyl-L-serine-GHRL-1(24-117)ArrowR-HSA-422104 (Reactome)
Octanoic acidR-HSA-422104 (Reactome)
PC1:calcium cofactormim-catalysisR-HSA-422021 (Reactome)
PLA2G7mim-catalysisR-HSA-422058 (Reactome)
Preproghrelin

and

prepro-des-Gln14-ghrelin		ArrowR-HSA-422088 (Reactome)
Preproghrelin

and

prepro-des-Gln14-ghrelin		R-HSA-422051 (Reactome)
Proghrelin

and

Pro-des-Gln14-ghrelin		ArrowR-HSA-422051 (Reactome)
R-HSA-422017 (Reactome) Proghrelin is decanoylated by ghrelin O-acyltransferase (GOAT/MBOAT4), an enzyme present in the endoplasmic reticulum membrane which both transports the decanoic acid substrate and condenses it on the hydroxyl group of serine-3 of the mature protein. The most common acylated form of ghrelin is octanoyl ghrelin but decanoyl ghrelin is also detected in plasma. GOAT is able to use substrates up to tetradecanoic acid. Ghrelin is the only protein known to undergo such a modification.
R-HSA-422021 (Reactome) Acyl proghrelin is cleaved by prohormone convertase 1/3 (PC1/3) to yield acyl ghrelin (the N-terminal fragment) and C-ghrelin (the C-terminal fragment). Transfection experiments show that PC1/3 is sufficient to generate acyl ghrelin of 28 amino acid residues (acyl ghrelin-28). Acyl ghrelin of 27 amino acid residues (acyl ghrelin-27) can also be detected in plasma. How acyl ghrelin-27 is generated remains undetermined but it is speculated to derive from the cleavage of arginine-28 from the C-terminus of ghrelin by a carboxypeptidase B-like enzyme.
R-HSA-422048 (Reactome) Acyl ghrelin and C-ghrelin are secreted from secretory granules into the bloodstream. Five forms of acyl ghrelin have been detected: octanoyl ghrelin-28, decanoyl ghrelin-28, octanoyl ghrelin-27, decanoyl ghrelin-27, and decenoyl ghrelin-28. Unacylated ghrelin (des-acyl ghrelin) occurs at higher levels than acyl ghrelin however its function and mechanism of generation are controversial. The function, if any, of C-ghrelin is also unknown.
Secretion of ghrelin is stimulated by insulin-like growth factor-1 and muscarinic agonists; Secretion is inhibited by insulin, somatotropin, leptin, glucose, glucagon, and fatty acids. Carbohydrates have more inhibitory effect than fat does. The mechanisms by which the regulation is effected are unknown.
R-HSA-422051 (Reactome) The N-terminal 23 amino acid residues are cleaved from preproghrelin by the signal peptidase complex. The products are proghrelin (94 amino acid residues) or des-acyl-Gln14 proghrelin (93 amino acid residues), depending on the variant of the mRNA that was translated.
R-HSA-422058 (Reactome) The majority of circulating ghrelin is not acylated (des-acyl ghrelin). Acyl ghrelin can be deacylated in the bloodstream by butyrylcholinesterase and platelet-activating factor acetylhydrolase, which are associated with circulating lipids. Other enzymes may also have this capability. It is unknown if a portion of des-acyl ghrelin in the bloodstream is generated by direct synthesis and secretion.
R-HSA-422088 (Reactome) The ghrelin gene is transcribed and spliced to yield two variants: isoform 1 encodes full-length preproghrelin and isoform 2 encodes des-acyl-Gln14 preproghrelin, which is missing glutamine at position 14 of the mature peptide. Des-acyl-Gln14 ghrelin is found in rodents but is present in negligible quantities in humans. Somatostatin and leptin inhibit ghrelin mRNA levels. Estrogen increases ghrelin mRNA levels. The KLF4 transcription factor binds the ghrelin promoter and activates transcription. Putative binding sites for other transcription factors have been identified but their functions have not been demonstrated.
R-HSA-422104 (Reactome) Proghrelin is octanoylated by ghrelin O-acyltransferase (GOAT/MBOAT4), an enzyme present in the endoplasmic reticulum membrane which both transports the octanoic acid substrate and condenses it on the hydroxyl group of serine-3 of the mature protein. The most common acylated form of ghrelin is octanoyl ghrelin but decanoyl ghrelin is also detected. Ghrelin is the only protein known to undergo such a modification.
Signal Peptidasemim-catalysisR-HSA-422051 (Reactome)
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