Enteropeptidase is an enzyme of the duodenal mucosa whose function is to activate pancreatic enzymes. It is at the beginning of an entire activation cascade of digestive enzymes. Dysfunction of enteropeptidase leads to maldigestion and malabsorption of food in the small intestine.
What is an enteropeptidase?
Enteropeptidase represents an enzyme of the duodenal mucosa that initiates activation of pancreatic digestive enzymes by activation of trypsinogen to trypsin. The secretion of enteropeptidase occurs in the brush border of the duodenal mucosa. Specifically, lieberkühn’s glands are responsible for secretion. The lieberkühn’s glands are tubular depressions in the small and large intestinal epithelium. In the small intestine, they are located between the villi of the small intestine. Also known as Lieberkühn’s crypts, the glands secrete a variety of enzymes in addition to enteropeptidase. The stimulation for secretion of enteropeptidase occurs when the gastric predigested food pulp enters the duodenum. The enzyme alone does not act on the food components. Only activation of the enzyme trypsin sets in motion the whole activation cascade of digestive enzymes. Enteropeptidase, like trypsin and the other pancreatic proteases, is a serine protease. The active site contains the catalytic triad of aspartic acid, histidine, and serine. As an endopeptidase, enteropeptidase cleaves proteins only at certain characteristic sites with specific recognition motifs in the amino acid sequence. Thus, the enzyme always cleaves at the recognition motif Asp-Asp-Asp-Lys. In trypsinogen, the hexapeptide Val-(Asp)4-Lys is cleaved, yielding trypsin.
Function, action, and roles
The function of enteropeptidase is to activate the digestive enzymes of the pancreas. In doing so, it initiates only the first step of activation with the conversion of trypsinogen to trypsin. For its part, trypsin is a serine protease that cleaves proteins at the same characteristic recognition motif. It itself now continues the activation of trypsinogen. At the same time, it activates other pancreatic enzymes from their respective precursors, such as chymotrypsinogen, pro-elastase, pro-carboxypeptidase, pro-phospholipase and proenteropeptidase. Enteropeptidase is also initially present in the inactive proform. Upon entry of the food pulp into the duodenum, duodenase is secreted in addition to proenteropeptidase, which activates the proform of enteropeptidase. Thus, after the onset of the activation cascade, trypsin takes over the activations of all pancreatic enzymes including proenteropeptidase and trypsinogen. The activation of proenteropeptidase to enteropeptidase occurs even more effectively by the action of trypsin than by duodenase. The primary presence of the digestive enzymes in their inactive form is extremely important. The action of the proteases in particular is nonspecific. All proteins containing the characteristic recognition motif within the molecule are hydrolytically cleaved. If the enzymes were immediately catalytically active, digestion of endogenous proteins would already occur in the pancreas and pancreatic duct. As a result, the pancreas would dissolve itself. Thus, activation takes place only in the duodenum outside the exocrine glands. Here, the enzymes can begin to break down the food components without attacking the body’s own tissues. To prevent premature activation of the enzymes, an additional trypsin inhibitor acts in the excretory duct of the pancreas. However, trypsin plays the key role in the digestive cascade. Once this enzyme is activated, the activation of all the digestive enzymes, including enteropeptidase, cannot be stopped.
Formation, occurrence, properties, and optimal levels
Enteropeptidase, like all serine proteases, also acts nonspecifically, cleaving proteins at a characteristic recognition motif. Enteropeptidase consists of a light chain and a heavy chain linked by disulfide bridges. The serine protease domain is located on the light chain. The heavy chain has a molecular mass of 82 to 140 kilodaltons, with the molecular mass of the light chain being 35 to 62 kilodaltons. The structure of enteropeptidase in the light chain is similar to the other serine proteases trypsin and chymotrypsin. The heavy chain is membrane-bound and affects the specificity of the enzyme.The isolated light chain was found to have similar activity against the characteristic recognition motif -(Asp)4-Lys- but much less activity against trypsinogen.
Diseases and disorders
Human enteropeptidase is encoded by the ENTK gene on chromosome 21. Mutation of this gene results in severe disease in affected children. The enzyme can no longer activate the other digestive enzymes. The food components are no longer broken down and consequently can no longer be absorbed by the small intestine. The primary cause is maldigestion (insufficient breakdown), which leads to malabsorption of the food components. The body is no longer supplied with sufficient nutrients. This leads to failure to thrive, growth disorders and typical protein deficiency symptoms with the formation of edema. At the same time, carbohydrates and fats are poorly absorbed in addition to proteins. Since the undigested food components reach the large intestine and are decomposed there by fermenting and putrefactive bacteria, flatulence, diarrhea and abdominal pain also occur. To date, 15 cases of congenital enteropeptidase deficiency have been described worldwide. However, the symptoms of the disease occur much more frequently. Enteropeptidase deficiency does not always have to be present. Since trypsin plays a key role in the activation of digestive enzymes, a defect or deficiency of trypsin also leads to similar symptoms. Treatment of these disorders is the same in both cases. The enzymes are administered in activated form. Certainly, there are many more undiagnosed cases of enteropeptidase deficiency. If the diagnosis is certain, enteropeptidase could also be substituted causally. Enteropeptidase deficiency is also secondary to severe intestinal diseases. Differential diagnosis should clarify such diseases as celiac disease, shortened small intestine, lactase deficiency, or others.
