Summary: Trypsin and protease inhibitor
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This is the Wikipedia entry entitled "Kunitz STI protease inhibitor". More...
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Kunitz STI protease inhibitor Edit Wikipedia article
|Trypsin and protease inhibitor|
|Structure of a Kunitz-type trypsin inhibitor.|
Kunitz soybean trypsin inhibitor is a type of protein contained in legume seeds which functions as a protease inhibitor. Kunitz-type Soybean Trypsin Inhibitors are usually specific for either trypsin or chymotrypsin. They are thought to protect seeds against consumption by animal predators.
Two types of trypsin inhibitors are found in soy: the Kunitz trypsin inhibitor (KTI) and the Bowman-Birk inhibitor (BBI). KTI is a large (20,100 daltons), strong inhibitor of trypsin, while BBI is much smaller (8,000 daltons) and inhibits both trypsin and chymotrypsin. Both inhibitors have significant anti-nutritive effects in the body, affecting digestion by hindering protein hydrolysis and activation of other enzymes in the gut. In soy, KTI is found in much larger concentrations than BBI is soy, however, to achieve the highest nutritional value from this ingredient, both of these inhibitors must be denatured in some way. Whole soybeans have been reported to contain 17â27 mg of trypsin inhibitor per gram.
Proteins from the Kunitz family contain from 170 to 200 amino acid residues and one or two intra-chain disulfide bonds. The best conserved region is found in their N-terminal section. The crystal structures of soybean trypsin inhibitor (STI), trypsin inhibitor DE-3 from the Kaffir tree Erythrina caffra (ETI) and the bifunctional proteinase K/alpha-amylase inhibitor from wheat (PK13) have been solved, showing them to share the same 12-stranded beta sheet structure as those of interleukin 1 and heparin-binding growth factors. The beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel beta barrel. Despite the structural similarity, STI shows no interleukin-1 bioactivity, presumably as a result of their primary sequence disparities. The active inhibitory site containing the scissile bond is located in the loop between beta-strands 4 and 5 in STI and ETI.
The STIs belong to a superfamily that also contains the interleukin-1 proteins, heparin binding growth factors (HBGF) and histactophilin, all of which have very similar structures, but share no sequence similarity with the STI family.
 Action and Consequences of Trypsin Inhibitors
Trypsin inhibitors require a specific three-dimensional structure in order to follow through with inactivation of trypsin in the body. They bind strongly to trypsin, blocking its active site and instantly forming an irreversible compound and halting digestion of certain proteins. Trypsin, a serine protease, is responsible for cleaving peptide bonds containing carbonyl groups from arginine or lysine. After a meal, trypsin is stimulated by cholecystokinin and undergoes specific proteolysis for activation. Free trypsin is then able to activate other serine proteases, such as chymotrypsin, elastase, and more trypsin (by autocatalysis), or continue breaking down proteins. However, if trypsin inhibitors (specifically KTI) are present, the majority of trypsin in the cycle of digestion is inactivated and ingested proteins remain whole. Effects of this occurrence include gastric distress, and pancreatic hyperplasia (proliferation of cells) or hypertrophy (enlargement of cells). The amount of soy inhibitors is directly related to the amount of trypsin it will inhibit, therefore a product with high concentration of soy is suspect to produce large values of inhibition. In a rat model, animals were fed either soy protein concentrate or direct concentrate of the Kunitz trypsin inhibitor. In both instances, after a week the rats showed a dose-related increase in pancreas weight due to both hyperplasia and hypertrophy. This indicates that long-term consumption of a diet high in soy with strong trypsin inhibitor activity may produce unwanted effects in humans as well.
 Inactivation of Trypsin Inhibitors
A significant amount of research is being done to determine the best method of inhibitor inactivation. The most successful methods found so far include:
- Addition of Sulfites
 Cancer Research
While trypsin inhibitors have been widely regarded as anti-nutritive factors in soy, research is currently being done on the inhibitorsâ possible anti-carcinogenic characteristics. Some research has shown that protease inhibitors can cause irreversible suppressive effect on carcinogenic cell growth. However, the mechanism is still unknown. The cancers showing positive results for this new development are colon, oral, lung, liver, and esophageal cancers. Further research is still necessary to determine things such as the method of delivery for this natural anti-carcinogen, as well as performing extensive clinical trials in this area.
- PDB 1tie; Onesti S, Brick P, Blow DM (January 1991). "Crystal structure of a Kunitz-type trypsin inhibitor from Erythrina caffra seeds". J. Mol. Biol. 217 (1): 153â76. doi:10.1016/0022-2836(91)90618-G. PMID 1988676.
- Rawlings ND, Tolle DP, Barrett AJ (March 2004). "Evolutionary families of peptidase inhibitors". Biochem. J. 378 (Pt 3): 705â16. doi:10.1042/BJ20031825. PMC 1224039. PMID 14705960. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1224039/.
- [Soybean Protease Inhibitors in Foods], DiPietro CM, Liener IE, 1989. J Food Sci.
- Murzin AG, Lesk AM, Chothia C (January 1992). "beta-Trefoil fold. Patterns of structure and sequence in the Kunitz inhibitors interleukins-1 beta and 1 alpha and fibroblast growth factors". J. Mol. Biol. 223 (2): 531â43. doi:10.1016/0022-2836(92)90668-A. PMID 1738162.
- [Principles of Biochemistry], Horton HR, Moran, LA, Scrimgeour KG, Perry MD, Rawn JD, 2006.
- [Hypertrophy and hyperplasia of the rat pancreas produced by short-term dietary administration of soya-derived protein and soybean trypsin inhibitor], Smith JC, Wilson Fd, Allen PV, Berry DL, 1989. J Appl Toxic.
- [The Role of Soy Products in Reducing Risk of Cancer], Messina M, Barnes S, 1991. J Natl Cancer Institute.
- Trypsin+Inhibitor,+Kunitz+Soybean at the US National Library of Medicine Medical Subject Headings (MeSH)
- Rawlings ND, Morton FR, Kok CY, Kong J, Barrett AJ. "Inhibitor family I3 (Kunitz-P family)". MEROPS - the Protease Database. http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=i03. Retrieved 2008-12-19.
- Bassaneze V, Gozzo AJ, Nunes VA, Paiva PB, Araujo MS, Sampaio CAM. "Kunitz STI inhibitors". A web/HMMer based tool to study Kunitz protease inhibitors. Federal University of SÃ£o Paulo. http://compbio.epm.br/kunitz/index.html. Retrieved 2008-12-19.
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External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002160
Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger precursor protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. This domain prevents access of the substrate to the active site. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Other inhibitors interact direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties.
The Kunitz-type soybean trypsin inhibitor (STI) family consists mainly of proteinase inhibitors from Leguminosae seeds [PUBMED:14705960]. They belong to MEROPS inhibitor family I3, clan IC. They exhibit proteinase inhibitory activity against serine proteinases; trypsin (MEROPS peptidase family S1, INTERPRO) and subtilisin (MEROPS peptidase family S8, INTERPRO), thiol proteinases (MEROPS peptidase family C1, INTERPRO) and aspartic proteinases (MEROPS peptidase family A1, INTERPRO) [PUBMED:14705960].
Inhibitors from cereals are active against subtilisin and endogenous alpha-amylases, while some also inhibit tissue plasminogen activator. The inhibitors are usually specific for either trypsin or chymotrypsin, and some are effective against both. They are thought to protect the seeds against consumption by animal predators, while at the same time existing as seed storage proteins themselves - all the actively inhibitory members contain 2 disulphide bridges. The existence of a member with no inhibitory activity, winged bean albumin 1, suggests that the inhibitors may have evolved from seed storage proteins.
Proteins from the Kunitz family contain from 170 to 200 amino acid residues and one or two intra-chain disulphide bonds. The best conserved region is found in their N-terminal section. The crystal structures of soybean trypsin inhibitor (STI), trypsin inhibitor DE-3 from the Kaffir tree Erythrina caffra (ETI) [PUBMED:1988676] and the bifunctional proteinase K/alpha-amylase inhibitor from wheat (PK13) have been solved, showing them to share the same 12-stranded beta-sheet structure as those of interleukin-1 and heparin-binding growth factors [PUBMED:1738162]. The beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel beta-barrel. Despite the structural similarity, STI shows no interleukin-1 bioactivity, presumably as a result of their primary sequence disparities. The active inhibitory site containing the scissile bond is located in the loop between beta-strands 4 and 5 in STI and ETI.
The STIs belong to a superfamily that also contains the interleukin-1 proteins, heparin binding growth factors (HBGF) and histactophilin, all of which have very similar structures, but share no sequence similarity with the STI family.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||endopeptidase inhibitor activity (GO:0004866)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
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- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
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You can see the alignments as HTML or in three different sequence viewers:
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You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||17|
|Number in full:||766|
|Average length of the domain:||164.40 aa|
|Average identity of full alignment:||31 %|
|Average coverage of the sequence by the domain:||83.53 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Kunitz_legume domain has been found. There are 55 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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