Enteropeptidase

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enteropeptidase
Crystal structure of Enteropeptidase with an
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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PMCarticles
PubMedarticles
NCBIproteins
protease, serine, 7 (enteropeptidase)
Identifiers
SymbolTMPRSS15
Chr. 21 q21
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StructuresSwiss-model
DomainsInterPro

Enteropeptidase (also called enterokinase) is an enzyme produced by cells of the duodenum and is involved in digestion in humans and other animals. Enteropeptidase converts trypsinogen (a zymogen) into its active form trypsin, resulting in the subsequent activation of pancreatic digestive enzymes.[1][2] Absence of enteropeptidase results in intestinal digestion impairment.[3]

Enteropeptidase is a serine protease (EC 3.4.21.9) consisting of a disulfide-linked heavy-chain of 82-140 kDa that anchors enterokinase in the intestinal brush border membrane and a light-chain of 35–62 kDa that contains the catalytic subunit.[4] Enteropeptidase is a part of the chymotrypsin-clan of serine proteases, and is structurally similar to these proteins.[5]

Historical significance

Enteropeptidase was discovered by

IUBMB name enteropeptidase has been in existence since 1970. However, the original name ‘enterokinase’ has a long history and remains in common use.[8]

Enzyme structure

Enteropeptidase is a type II transmembrane serine

propeptide sequences of different lengths. These enzymes are activated by cleavage at the carboxyl side of lysine or arginine residues present in a highly conserved activation motif. Once activated, TTSPs are predicted to remain membrane-bound through a conserved disulfide bond linking the pro- and catalytic domains.[10]

In the case of cattle enteropeptidase the primary translation product comprises 1035 residues with an expected mass of 114.9 kDa.[11] The detected apparent mass of about 160 kDa is consistent with the specified carbohydrate content of 30 - 40%, with equal amounts of neutral and amino sugars.[12][13] The activation cleavage site after Lys800 splits the heavy and light chains of mature cattle enteropeptidase. There are 17 potential N-linked glycosylation sites in the heavy chain and three in the light chain; most of these are conserved in other species. The heavy chain has a hydrophobic section near the N-terminus that supports the transmembrane anchor.[14][15] The heavy chain influences the specificity of enteropeptidase. Native enteropeptidase is resistant to soybean trypsin inhibitor. However, the isolated light chain is subtle whether prepared by limited reduction of the natural protein[16] or by mutagenesis and expression in COS cells.[17] Native enteropeptidase and the isolated light chain have similar activity toward Gly-(Asp)4-Lys-NHNap, but the secluded light chain has distinctly decreased activity toward trypsinogen . An analogous selective defect in the recognition of trypsinogen can be produced in two-chain enteropeptidase by heating or by acetylation.[18] This behavior implies that the catalytic center and one or more secondary substrate-binding sites are essential for optimal recognition of trypsinogen.

Human enteropeptidase - light chain

Activity

Despite its alternative name (enterokinase), enteropeptidase is a serine protease that catalyses the hydrolysis of peptide bonds in proteins and, unlike other

Asp-Asp-Asp-Asp-Lys).[19] This cleavage results in trypsindependent activation of other pancreatic zymogens, such as chymotrypsinogen, proelastase, procarboxypeptidase and prolipase in the lumen of the gut.[20] As the pro-region of trypsinogen contains this sequence, enteropeptidase catalyses
its activation in vivo:

trypsinogen → trypsin + pro-region (Val-Asp-Asp-Asp-Asp-Lys)

Genetics and disease relevance

In humans, enteropeptidase is encoded by the TMPRSS15

recessive disorder characterised by severe failure to thrive in affected infants, due to enteropeptidase deficiency.[21] Enteropeptidase mRNA expression is limited to the proximal small intestine, and the protein is found in enterocytes of duodenum and proximal jejunum. Upon secretion from the pancreas into the duodenum, trypsinogen encounters enteropeptidase and is activated. Trypsin then cleaves and activates other pancreatic serine protease zymogens (chymotrypsinogen and proelastases), metalloprotease zymogens (procarboxypeptidases) and prolipases. By means of this simple two-step cascade, the destructive activity of these digestive hydrolases is confined to the lumen of the intestine. The physiological importance of this pathway is demonstrated by the severe intestinal malabsorption caused by congenital deficiency of enteropeptidase.[22][23]
This condition can be life-threatening, but responds to oral supplementation with pancreatic extract.

Applications

Enteropeptidase's specificity makes it an ideal tool in biochemical applications; a fusion protein containing a

affinity tag (such as poly-His) linked by this sequence can be cleaved by enteropeptidase to obtain the target protein following protein purification.[19] On the converse, the N-terminal pro-sequence of proteases that must be cleaved prior to activation can be mutated to enable activation with enteropeptidase.[24]

References

  1. PMID 19873112
    .
  2. ISBN 978-0-12-122703-6
    .
  3. PMID 2658218
    .
  4. S2CID 25387669
    .
  5. PMID 8439290
    .
  6. PMID 10493881
    .
  7. PMID 13328891
    .
  8. ISBN 978-0-12-382219-2
    . Retrieved February 20, 2014.
  9. S2CID 254189
    .
  10. PMID 11060317
    .
  11. PMID 8052624
    .
  12. PMID 889800
    .
  13. PMID 762166
    .
  14. PMID 6338012
    .
  15. PMID 9395456
    .
  16. PMID 6386810
    .
  17. PMID 8226855
    .
  18. PMID 12810
    .
  19. ^
    S2CID 206934268
    .
  20. PMID 19872978
    .
  21. PMID 11719902
    .
  22. PMID 4180366
    .
  23. PMID 4322674
    .
  24. PMID 8962677
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Enteropeptidase&oldid=1216165176"