Serine protease
Serine protease | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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Serine proteases (or serine endopeptidases) are
They are found ubiquitously in bothClassification
The
For superfamilies, P: superfamily, containing a mixture of nucleophile class families, S: purely serine proteases. superfamily. Within each superfamily, families are designated by their catalytic nucleophile, (S: serine proteases).
Super- family |
Families | Examples |
---|---|---|
SB | S8, S53 | Subtilisin (Bacillus licheniformis) |
SC | S9, S10, S15, S28, S33, S37 | Sus scrofa )
|
SE | S11, S12, S13 | D-Ala-D-Ala peptidase C (Escherichia coli) |
SF | S24, S26 | Signal peptidase I (Escherichia coli) |
SH | S21, S73, S77, S78, S80 | Cytomegalovirus herpesvirus 5)
|
SJ | S16, S50, S69 | Lon-A peptidase (Escherichia coli )
|
SK | S14, S41, S49 | Clp protease (Escherichia coli) |
SO | S74 | Phage K1F endosialidase CIMCD self-cleaving protein (Enterobacteria phage K1F) |
SP | S59 | Homo sapiens )
|
SR | S60 | Homo sapiens )
|
SS | S66 | Murein tetrapeptidase LD-carboxypeptidase (Pseudomonas aeruginosa) |
ST | S54 | Rhomboid-1 (Drosophila melanogaster) |
PA |
S1, S3, S6, S7, S29, S30, S31, S32, S39, S46, S55, S64, S65, S75 |
Bos taurus )
|
PB | S45, S63 | Penicillin G acylase precursor (Escherichia coli )
|
PC | S51 | Dipeptidase E (Escherichia coli) |
PE | P1 | DmpA aminopeptidase (Brucella anthropi) |
None | S48, S62, S68, S71, S72, S79, S81 |
Substrate specificity
Serine proteases are characterised by a distinctive structure, consisting of two beta-barrel domains that converge at the catalytic active site. These enzymes can be further categorised based on their substrate specificity as either trypsin-like, chymotrypsin-like or elastase-like.[5]
Trypsin-like
Trypsin-like proteases cleave peptide bonds following a positively charged amino acid (lysine or arginine).[6] This specificity is driven by the residue which lies at the base of the enzyme's S1 pocket (generally a negatively charged aspartic acid or glutamic acid).
Chymotrypsin-like
The S1 pocket of chymotrypsin-like enzymes is more hydrophobic than in trypsin-like proteases. This results in a specificity for medium to large sized hydrophobic residues, such as tyrosine, phenylalanine and tryptophan.
Thrombin-like
These include thrombin, tissue activating plasminogen and plasmin. They have been found to have roles in coagulation and digestion as well as in the pathophysiology of neurodegenerative disorders such as Alzheimer's and Parkinson's induced dementia. Many highly-toxic thrombin-like serine protease isoforms are found in snake venoms.[7]
Elastase-like
Elastase-like proteases have a much smaller S1 cleft than either trypsin- or chymotrypsin-like proteases. Consequently, residues such as alanine, glycine and valine tend to be preferred.
Subtilisin-like
Catalytic mechanism
The main player in the catalytic mechanism in the serine proteases is the catalytic triad. The triad is located in the active site of the enzyme, where catalysis occurs, and is preserved in all
In the event of catalysis, an ordered mechanism occurs in which several intermediates are generated. The catalysis of the peptide cleavage can be seen as a
Each amino acid in the triad performs a specific task in this process:
- The carbonyl carbon of the scissilepeptide bond of the substrate.
- A pair of electrons on the histidine nitrogen has the ability to accept the hydrogen from the serine -OH group, thus coordinating the attack of the peptide bond.
- The electronegative.
The whole reaction can be summarized as follows:
- The nucleophilic serine.
- The carbonyloxygen moves to the oxygen. As a result, a tetrahedral intermediate is generated.
- The bond joining the nitrogen and the carbon in the peptide bond is now broken. The covalent electrons creating this bond move to attack the hydrogen of the carbonyloxygen double bond move back from the negative oxygen to recreate the bond, generating an acyl-enzyme intermediate.
- Now, water comes into the reaction. Water replaces the carbonyl carbon. Once again, the electrons from the double bond move to the oxygen making it negative, as the bond between the oxygen of the water and the carbon is formed. This is coordinated by the nitrogen of the histidine, which accepts a proton from the water. Overall, this generates another tetrahedral intermediate.
- In a final reaction, the bond formed in the first step between the carbonyl carbon re-forms the double bond with the oxygen. As a result, the C-terminusof the peptide is now ejected.
Additional stabilizing effects
It was discovered that additional amino acids of the protease, Gly 193 and Ser 195, are involved in creating what is called an oxyanion hole. Both Gly 193 and Ser 195 can donate backbone hydrogens for hydrogen bonding. When the
Regulation of serine protease activity
Host organisms must ensure that the activity of serine proteases is adequately regulated. This is achieved by a requirement for initial protease activation, and the secretion of inhibitors.
Zymogen activation
Zymogens are large, inactive structures, which have the ability to break apart or change into the smaller activated enzymes. The difference between zymogens and the activated enzymes lies in the fact that the active site for catalysis of the zymogens is distorted. As a result, the substrate polypeptide cannot bind effectively, and proteolysis does not occur. Only after activation, during which the conformation and structure of the zymogen change and the active site is opened, can proteolysis occur.
Zymogen | Enzyme | Notes |
---|---|---|
Trypsinogen | trypsin | When trypsinogen enters the autocatalytic .
|
Chymotrypsinogen | chymotrypsin | After the Arg 15 - Ile 16 bond in the chymotrypsinogen zymogen is cleaved by trypsin, the newly generated structure called a pi-chymotrypsin undergoes autolysis (self digestion), yielding active chymotrypsin. |
Proelastase | elastase | It is activated by cleavage through trypsin. |
As can be seen, trypsinogen activation to trypsin is essential, because it activates its own reaction, as well as the reaction of both chymotrypsin and elastase. Therefore, it is essential that this activation does not occur prematurely. There are several protective measures taken by the organism to prevent self-digestion:
- The activation of trypsinogen by trypsin is relatively slow
- The zymogens are stored in zymogen granules, capsules that have walls that are thought to be resistant to proteolysis.
Inhibition
There are certain inhibitors that resemble the tetrahedral intermediate, and thus fill up the active site, preventing the enzyme from working properly. Trypsin, a powerful digestive enzyme, is generated in the pancreas. Inhibitors prevent self-digestion of the pancreas itself.
Serine proteases are paired with serine protease inhibitors, which turn off their activity when they are no longer needed.[9][self-published source?]
Serine proteases are inhibited by a diverse group of
A family of arthropod serine peptidase inhibitors, called pacifastin, has been identified in locusts and crayfish, and may function in the arthropod immune system.[10]
Role in disease
Mutations may lead to decreased or increased activity of enzymes. This may have different consequences, depending on the normal function of the serine protease. For example, mutations in
Diagnostic use
Determination of serine protease levels may be useful in the context of particular diseases.
- Coagulation factorlevels may be required in the diagnosis of hemorrhagic or thrombotic conditions.
- Fecal elastase is employed to determine the exocrine activity of the pancreas, e.g., in cystic fibrosis or chronic pancreatitis.
- Serum prostate-specific antigen is used in prostate cancer screening, risk stratification, and post-treatment monitoring.
- Serine protease, as released by type 1 hypersensitivity reactions e.g., anaphylaxis. More useful than histamine due to the longer half-life, meaning it remains in the system for a clinically useful length of time.
Antimicrobial effect
Due to their catalytic activity, some serine proteases possess potent antimicrobial properties. Several in vitro studies have demonstrated the efficacy of some proteases in reducing virulence by cleaving viral surface proteins. Viral entry into host cells is mediated by the interaction of these surface proteins with the host cell. When these proteins are fragmented or inactivated on the viral surface, the viral entry is impaired, leading to a reduction in infectivity of a broad spectrum of pathologically relevant microorganisms like
See also
- Serine hydrolase
- Protease
- cysteine-
- threonine-
- aspartic-
- metallo-
- PA clan
- Convergent evolution
- Proteolysis
- Catalytic triad
- The Proteolysis Map
- Proteases in angiogenesis
- Intramembrane proteases
- Protease inhibitor (pharmacology)
- Protease inhibitor (biology)
- TopFIND - database of protease specificity, substrates, products and inhibitors
- MEROPS - Database of protease evolutionary groups
References
- ^
Hedstrom L (December 2002). "Serine protease mechanism and specificity". Chemical Reviews. 102 (12): 4501–4524. PMID 12475199.
- ^
Madala PK, Tyndall JD, Nall T, Fairlie DP (June 2010). "Update 1 of: Proteases universally recognize beta strands in their active sites". Chemical Reviews. 110 (6): PR1–P31. PMID 20377171.
- PMID 31786268.
- PMID 34687719.
- ^
Ovaere P, Lippens S, Vandenabeele P, Declercq W (September 2009). "The emerging roles of serine protease cascades in the epidermis". Trends in Biochemical Sciences. 34 (9): 453–463. PMID 19726197.
- ^
Evnin LB, Vásquez JR, Craik CS (September 1990). "Substrate specificity of trypsin investigated by using a genetic selection". Proceedings of the National Academy of Sciences of the United States of America. 87 (17): 6659–6663. PMID 2204062.
- ^ PMID 35702592.
- ^
Iván G, Szabadka Z, Ordög R, Grolmusz V, Náray-Szabó G (June 2009). "Four spatial points that define enzyme families". Biochemical and Biophysical Research Communications. 383 (4): 417–420. PMID 19364497.
- ^ "Kimball's Biology Pages, Serine Proteases". Archived from the original on 2005-12-13. Retrieved 2008-06-02.
- S2CID 8797134.
- PMID 35183035.
- PMID 24600012.
External links
- The MEROPS online database for peptidases and their inhibitors: Serine Peptidase
- Serine Proteases site at Saint Louis University (SLU)
- Serine+proteases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)