Trypsin inhibitor

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A trypsin inhibitor (TI) is a protein and a type of serine protease inhibitor (serpin) that reduces the biological activity of trypsin by controlling the activation and catalytic reactions of proteins. [1] Trypsin is an enzyme involved in the breakdown of many different proteins, primarily as part of digestion in humans and other animals such as monogastrics and young ruminants. Serpins – including trypsin inhibitors – are irreversible and suicide substrate-like inhibitors. [2] [3]

Contents

It destructively alters trypsin thereby rendering it unavailable to bind with proteins for the digestion process. [4] As a result, protease inhibitors that interfere with digestion activity have an antinutritional effect. Therefore, trypsin inhibitors are considered an anti-nutritional factor or ANF. [5] Additionally, trypsin inhibitor partially interferes with chymotrypsin function.

Trypsinogen is an inactive form of trypsin, its inactive form ensures protein aspects of the body, such as the pancreas and muscles, are not broken down. It is formed in the pancreas and activated to trypsin with enteropeptidase [6] Chymotrypsinogen is the inactive form of chymotrypsin and has similar functions as trypsin.

The presence of trypsin inhibitor has been found to result in delayed growth as well as metabolic and digestive diseases. [7] Additionally, pancreatic hypertrophy is a common occurrence with trypsin inhibitor consumption [8] The presence of trypsin inhibitor in a product reduces the protein efficiency and therefore results in the consumers body not being able to efficiently and fully utilize the protein. [9]

Function

Trypsin inhibitor is present in various foods such as soybeans, grains, cereals and various additional legumes. [10] The main function of trypsin inhibitors in these foods is to act as a defense mechanism. By having this harmful component wild animals learn that any food that contains trypsin inhibitor is a food to avoid. Trypsin inhibitor can also be essential for biological processes within the plant.

Trypsin inhibitor can also naturally occur in the pancreas of species such as bovines. The function of this is to protect the animal from any accidental activation of trypsinogen and/or chymotrypsinogen [11]

Inactivation

Trypsin inhibitor is heat labile, therefore by exposing these foods to heat, the trypsin inhibitor is removed and the food subsequently becomes safe to eat. [12] Boiling soybeans for 14 minutes inactivates about 80% of the inhibitor, and for 30 minutes, about 90%. At higher temperatures, e.g. in pressure cookers, shorter cooking times are needed. [13] ELISA tests can be used to measure the degree of deactivation achieved.

Applications in commercial industries

The most prominent application of trypsin inhibitor is livestock feed. Soybeans are a popular ingredient in livestock feed therefore trypsin inhibitor can be a concern due to the presence of it in soybeans. The majority of soybeans used in livestock feed is converted to soybean meal and through the process the trypsin inhibitor is removed due to the heat treatment. However, experiments have been done concerning animals who consume active trypsin inhibitor and they consistently have decreased weights.

Major commercial sources
SourceInhibitor Molecular weight Inhibitory powerDetails
Blood plasma α1-antitrypsin 52 kDa Also known as serum trypsin inhibitor
Lima beans 8–10 kDa2.2 times weightA mixture of six different inhibitors
Bovine pancreas and lung Aprotinin 6.5 kDa2.5 times weightAlso known as BPTI (basic pancreatic trypsin inhibitor) and Kunitz inhibitor. Best-known pancreatic inhibitor. Inhibits several different serine proteases
Raw avian egg white Ovomucin 8–10 kDa1.2 times weightThe ovomucoids are a mixture of several different glycoprotein protease inhibitors
Soybeans 20.7–22.3 kDa1.2 times weightA mixture of several different inhibitors. All also bind chymotrypsin to a lesser degree.

A study revealing that a protease inhibitor from the eggs of the freshwater snail Pomacea canaliculata , interacting as a trypsin inhibitor with the protease of potential predators, was reported in 2010, the first direct evidence for this mechanism in the animal kingdom. [14]

Clinical significance

The peptide tumor-associated trypsin inhibitor (TATI) has been used as a marker of mucinous ovarian carcinoma, urothelial carcinoma, and renal cell carcinoma. TATI is metabolised by the kidneys and is, thus, elevated in patients with kidney failure. It may be elevated in non-neoplastic processes such as pancreatitis and can be used as a prognostic marker in this setting (levels above 70 micrograms/L are associated with poor prognosis).

Fifty percent of stage I mucinous ovarian carcinomas are associated with elevated TATI, and nearly 100% of stage IV tumors show elevated TATI.

Eighty-five to 95% of pancreatic adenocarcinomas are associated with increased TATI (but elevation in pancreatitis limits the clinical utility of TATI in this setting; see above).

Sixty percent of gastric adenocarcinomas show elevated TATI, in particular tumors of diffusely infiltrative/signet ring type. TATI, thus, complements CEA, which is elevated exclusively in intestinal type adenocarcinoma of the stomach.

In urothelial carcinoma, TATI expression varies with stage, ranging from 20% in low-stage tumors to 80% of high-stage tumors.

TATI sensitivity in the setting of renal cell carcinoma is approximately 70%. Elevated TATI is more likely to be seen in patients with advanced-stage disease.

In nearly all tumor types studied, TATI is a marker of poor prognosis. [15]

Related Research Articles

<span class="mw-page-title-main">Proteolysis</span> Breakdown of proteins into smaller polypeptides or amino acids

Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, but may also occur by intra-molecular digestion.

<span class="mw-page-title-main">Trypsin</span> Family of digestive enzymes

Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the digestive system of many vertebrates, where it hydrolyzes proteins. Trypsin is formed in the small intestine when its proenzyme form, the trypsinogen produced by the pancreas, is activated. Trypsin cuts peptide chains mainly at the carboxyl side of the amino acids lysine or arginine. It is used for numerous biotechnological processes. The process is commonly referred to as trypsin proteolysis or trypsinization, and proteins that have been digested/treated with trypsin are said to have been trypsinized. Trypsin was discovered in 1876 by Wilhelm Kühne and was named from the Ancient Greek word for rubbing since it was first isolated by rubbing the pancreas with glycerin.

<span class="mw-page-title-main">Pancreas</span> Organ of the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin, and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins, and fats in food entering the duodenum from the stomach.

<span class="mw-page-title-main">Protease</span> Enzyme that cleaves other proteins into smaller peptides

A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in many biological functions, including digestion of ingested proteins, protein catabolism, and cell signaling.

<span class="mw-page-title-main">Serpin</span> Superfamily of proteins with similar structures and diverse functions

Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases. They are notable for their unusual mechanism of action, in which they irreversibly inhibit their target protease by undergoing a large conformational change to disrupt the target's active site. This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site.

<span class="mw-page-title-main">Serine protease</span> Class of enzymes

Serine proteases are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like.

<span class="mw-page-title-main">Digestive enzyme</span> Class of enzymes

Digestive enzymes are a group of enzymes that break down polymeric macromolecules into their smaller building blocks, in order to facilitate their absorption into the cells of the body. Digestive enzymes are found in the digestive tracts of animals and in the tracts of carnivorous plants, where they aid in the digestion of food, as well as inside cells, especially in their lysosomes, where they function to maintain cellular survival. Digestive enzymes of diverse specificities are found in the saliva secreted by the salivary glands, in the secretions of cells lining the stomach, in the pancreatic juice secreted by pancreatic exocrine cells, and in the secretions of cells lining the small and large intestines.

Trypsinogen is the precursor form of trypsin, a digestive enzyme. It is produced by the pancreas and found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is cleaved to its active form, trypsin, by enteropeptidase, which is found in the intestinal mucosa. Once activated, the trypsin can cleave more trypsinogen into trypsin, a process called autoactivation. Trypsin cleaves the peptide bond on the carboxyl side of basic amino acids such as arginine and lysine.

<span class="mw-page-title-main">Carcinoembryonic antigen</span> Glycoprotein secreted into the luminal surface of the epithelia in the gastrointestinal tract

Carcinoembryonic antigen (CEA) describes a set of highly related glycoproteins involved in cell adhesion. CEA is normally produced in gastrointestinal tissue during fetal development, but the production stops before birth. Consequently, CEA is usually present at very low levels in the blood of healthy adults. However, the serum levels are raised in some types of cancer, which means that it can be used as a tumor marker in clinical tests. Serum levels can also be elevated in heavy smokers.

<span class="mw-page-title-main">Enteropeptidase</span> Class of enzymes

Enteropeptidase is an enzyme produced by cells of the duodenum and is involved in digestion in humans and other animals. Enteropeptidase converts trypsinogen into its active form trypsin, resulting in the subsequent activation of pancreatic digestive enzymes. Absence of enteropeptidase results in intestinal digestion impairment.

<span class="mw-page-title-main">Aprotinin</span> Antifibrinolytic molecule

The drug aprotinin, is a small protein bovine pancreatic trypsin inhibitor (BPTI), or basic trypsin inhibitor of bovine pancreas, which is an antifibrinolytic molecule that inhibits trypsin and related proteolytic enzymes. Under the trade name Trasylol, aprotinin was used as a medication administered by injection to reduce bleeding during complex surgery, such as heart and liver surgery. Its main effect is the slowing down of fibrinolysis, the process that leads to the breakdown of blood clots. The aim in its use was to decrease the need for blood transfusions during surgery, as well as end-organ damage due to hypotension as a result of marked blood loss. The drug was temporarily withdrawn worldwide in 2007 after studies suggested that its use increased the risk of complications or death; this was confirmed by follow-up studies. Trasylol sales were suspended in May 2008, except for very restricted research use. In February 2012 the European Medicines Agency (EMA) scientific committee reverted its previous standpoint regarding aprotinin, and has recommended that the suspension be lifted. Nordic became distributor of aprotinin in 2012.

<span class="mw-page-title-main">Maspin</span> Protein-coding gene in the species Homo sapiens

Maspin is a protein that in humans is encoded by the SERPINB5 gene. This protein belongs to the serpin superfamily. SERPINB5 was originally reported to function as a tumor suppressor gene in epithelial cells, suppressing the ability of cancer cells to invade and metastasize to other tissues. Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis. However, a subsequent study using viral transduction as a method of gene transfer was not able to reproduce the original findings and found no role for maspin in tumour biology. Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype. These data are consistent with the observation that maspin is not expressed in early embryogenesis. The precise molecular function of maspin is thus currently unknown.

Ulinastatin, as an urinary trypsin inhibitor (UTI), is a glycoprotein that is isolated from healthy human urine or synthetically produced and has molecular weight of 25 - 40kDa. Highly purified ulinastatin has been clinically used for the treatment of acute pancreatitis, chronic pancreatitis, Stevens–Johnson syndrome, burns, septic shock, and toxic epidermal necrolysis (TEN).

<span class="mw-page-title-main">Trypsin 1</span> Protein-coding gene in the species Homo sapiens

Trypsin-1, also known as cationic trypsinogen, is a protein that in humans is encoded by the PRSS1 gene. Trypsin-1 is the main isoform of trypsinogen secreted by pancreas, the others are trypsin-2, and trypsin-3 (meso-trypsinogen).

<span class="mw-page-title-main">SPINK1</span> Protein-coding gene in the species Homo sapiens

Pancreatic secretory trypsin inhibitor (PSTI) also known as serine protease inhibitor Kazal-type 1 (SPINK1) or tumor-associated trypsin inhibitor (TATI) is a protein that in humans is encoded by the SPINK1 gene.

<span class="mw-page-title-main">CELA3B</span> Protein-coding gene in the species Homo sapiens

Chymotrypsin-like elastase family member 3B also known as elastase-3B, protease E, or fecal elastase is an enzyme that in humans is encoded by the CELA3B gene.

<span class="mw-page-title-main">CELA3A</span> Protein-coding gene in the species Homo sapiens

Chymotrypsin-like elastase family member 3A is an enzyme that in humans is encoded by the CELA3A gene.

<span class="mw-page-title-main">Kunitz STI protease inhibitor</span>

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.

<span class="mw-page-title-main">PRSS2</span> Protein-coding gene in the species Homo sapiens

Protease, serine, 2 is a protein that in humans is encoded by the PRSS2 gene.

<span class="mw-page-title-main">PRSS3</span> Protein-coding gene in the species Homo sapiens

Protease, serine, 3 is a protein that in humans is encoded by the PRSS3 gene.

References

  1. ↑ "Trypsin Inhibitors". Sigma-Aldrich.
  2. ↑ Cohen, Maja; Davydov, Olga; Fluhr, Robert (2019-02-05). "Plant serpin protease inhibitors: specificity and duality of function". Journal of Experimental Botany . Society for Experimental Biology (OUP). 70 (7): 2077–2085. doi:10.1093/jxb/ery460. ISSN   0022-0957. PMID   30721992.
  3. ↑ Silverman, Gary A.; Bird, Phillip I.; Carrell, Robin W.; Church, Frank C.; Coughlin, Paul B.; Gettins, Peter G.W.; Irving, James A; Lomas, David A.; Luke, Cliff J.; Moyer, Richard W.; Pemberton, Philip A.; Remold-O'Donnell, Eileen; Salvesen, Guy S.; Travis, James; Whisstock, James C. (2001). "The Serpins Are an Expanding Superfamily of Structurally Similar but Functionally Diverse Proteins". Journal of Biological Chemistry . American Society for Biochemistry and Molecular Biology (Elsevier). 276 (36): 33293–33296. doi: 10.1074/jbc.r100016200 . ISSN   0021-9258. PMID   11435447. S2CID   18684515.
  4. ↑ Farady, Christopher J.; Craik, Charles S. (2010-11-04). "Mechanisms of Macromolecular Protease Inhibitors". ChemBioChem . Chemistry Europe (Wiley). 11 (17): 2341–2346. doi:10.1002/cbic.201000442. ISSN   1439-4227. PMC   4150018 . PMID   21053238. NIHMSID 336639.
  5. ↑ Aviles-Gaxiola, S., Chuck-Hernandez, C., and Serna Saldivar, S.O (2018). "Inactivation methods of trypsin inhibitor in legumes: a review". Journal of Food Science. 83 (1): 17–29. doi: 10.1111/1750-3841.13985 . PMID   29210451.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ↑ Hirota, M., Ohmuraya, M., and Baba, H. (2006). "The role of trypsin, trypsin inhibitor and trypsin receptor in the onset and aggravation of pancreatitis". Journal of Gastroenterology. 41 (9): 832–836. doi:10.1007/s00535-006-1874-2. PMID   17048046. S2CID   19643108.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ↑ Coscueta, Pintado, Pico, Knobel, Boschetti, Malpiede, and Nerli (2017). "Continuous method to determine the trypsin inhibitor activity in soybean flour". Food Chemistry. 214: 156–161. doi:10.1016/j.foodchem.2016.07.056. PMID   27507460.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Hwang, Foard, Wei. "A Soybean Trypsin Inhibitor". The Journal of Biological Chemistry. 252: 1099–1101. doi: 10.1016/S0021-9258(19)75211-9 .{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Klomklao, Benjakul, Kishimura, Chaijan (2011). "Extraction, purification and properties of trypsin inhibitor from Thai mung bean (Vigna radiata (L.) R. Wilczek)". Food Chemistry. 129 (4): 1348–1354. doi:10.1016/j.foodchem.2011.05.029.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Renee, Janet. "Foods containing protease".
  11. ↑ "Trypsin Inhibitors". Worthington Biochemical Corporation.
  12. ↑ Kadam, S.S., and Smithard, R.R. (1987). "Effects of heat treatments on trypsin inhibitor and hemagglutinating activities in winged bean". Plants Foods for Human Nutrition. 37 (2): 151–159. doi:10.1007/BF01092051. S2CID   84193551.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ↑ Liu, KeShun (2012-12-06). Soybeans: Chemistry, Technology, and Utilization. Springer. ISBN   978-1-4615-1763-4.
  14. ↑ Dreon M. S., Ituarte S. & Heras H. (2010). "The Role of the Proteinase Inhibitor Ovorubin in Apple Snail Eggs Resembles Plant Embryo Defense against Predation". PLoS ONE 5(12): e15059. doi : 10.1371/journal.pone.0015059.
  15. ↑ De Mais, Daniel. ASCP Quick Compendium of Clinical Pathology, 2nd Ed. ASCP Press 2009.
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