Trypsinogen (/ˌtrɪpˈsɪnədʒən,-ˌdʒɛn/[1][2]) is theprecursor form (orzymogen) oftrypsin, adigestive enzyme. It is produced by thepancreas and found inpancreatic juice, along withamylase,lipase, andchymotrypsinogen. It is cleaved to its active form,trypsin, byenteropeptidase, which is found in theintestinal mucosa. Once activated, the trypsin can cleave more trypsinogen intotrypsin, a process called autoactivation.Trypsin cleaves thepeptide bond on the carboxyl side of basicamino acids such asarginine andlysine.
Trypsinogen is theproenzyme precursor oftrypsin. Trypsinogen (the inactive form) is stored in thepancreas so that it may be released when required for proteindigestion. Thepancreas stores the inactive form trypsinogen because the activetrypsin would cause severe damage to the tissue of thepancreas. Trypsinogen is released by the pancreas into the second part of theduodenum, via thepancreatic duct, along with other digestive enzymes.[3]
Trypsinogen is activated by enteropeptidase (also known as enterokinase). Enteropeptidase is produced by themucosa of duodenum and it cleaves the peptide bond of trypsinogen after residue 15, which is alysine. The N-terminal peptide is discarded, and a slight rearrangement of the folded protein occurs. The newly formed N-terminal residue (residue 16) inserts into a cleft, where its α-amino group forms an ion pair with the aspartate near the active site serine, and results in the conformational rearrangement of other residues. The amino group of Gly 193 orientates itself into the correct position, which completes theoxyanion hole in active site, thereby activating the protein.[4] Since trypsin also cleaves the peptide bond after an arginine or a lysine, it can cleave other trypsinogen, and the activation process therefore becomes autocatalytic.
Trypsin is produced, stored and released as the inactive trypsinogen to ensure that the protein is only activated in the appropriate location. Premature trypsin activation can be destructive and may trigger a series of events that lead to pancreatic self-digestion. In normal pancreas, around 5% of trypsinogens are thought to get activated[citation needed], therefore there are a number of defenses against such inappropriate activation. Trypsinogen is stored in intracellular vesicles in the pancreas called zymogen granules whose membranous walls are thought to be resistant to enzymatic degradation. A further safeguard against inappropriate trypsin activation is the presence of inhibitors such asbovine pancreatic trypsin inhibitor (BPTI) and serine protease inhibitor Kazal-type 1 (SPINK1), which binds to any trypsin formed. Trypsin autocatalytic activation of trypsinogen is also a slow process due to the presence of a large negative charge on the conserved N-terminal hexapeptide of trypsinogen, which repels theaspartate on the back of trypsin's specificity pocket.[5] Trypsin may also inactivate other trypsin by cleavage.
Serum trypsinogen is measured using ablood test. High levels are seen in acutepancreatitis[6] andcystic fibrosis.[7]
Threeisoforms of trypsinogens may be found in human pancreatic juice. These are the cationic, anionic, and meso trypsinogen, and they account for 23.1%, 16%, and 0.5% of total pancreatic secretory proteins, respectively.[8] Other forms of trypsinogen have been found in other organisms.
The inappropriate activation of trypsinogen in the pancreas can lead topancreatitis. Some type of pancreatitis may be associated with mutant forms of trypsinogen. A mutation at Arg 117, a trypsin-sensitive site, incationic trypsinogen has been implicated in hereditary pancreatitis, a rare form of early-onset genetic disorder. Arg 117 may be a fail-safe mechanism by which trypsin, when activated within the pancreas, may become inactivated, and loss of this cleavage site would result in a loss of control and permit autodigestion resulting in pancreatitis.[9] Other mutations have also been found that are linked to pancreatitis.[10]
