Digestive enzyme

Digestive enzymes are enzymes that break down polymeric macromolecules into their smaller building blocks, in order to facilitate their absorption by the body. Digestive enzymes are found in the digestive tracts of animals (including humans) and in the traps 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 are diverse and are found in the saliva secreted by the salivary glands, in the stomach secreted by cells lining the stomach, in the pancreatic juice secreted by pancreatic exocrine cells, and in the intestinal (small and large) secretions, or as part of the lining of the gastrointestinal tract.

Digestive enzymes are classified based on their target substrates:

• proteases and peptidases split proteins into small peptides and amino acids.
• lipases split fat into three fatty acids and a glycerol molecule.
• amylases split carbohydrates such as starch and sugars into simple sugars such as glucose.
• nucleases split nucleic acids into nucleotides.

In the human digestive system, the main sites of digestion are the oral cavity, the stomach, and the small intestine. Digestive enzymes are secreted by different exocrine glands including:

• Salivary glands
• Secretory cells in the stomach
• Secretory cells in the pancreas
• Secretory glands in the small intestine

Mouth

Complex food substances that are taken by animals and humans must be broken down into simple, soluble, and diffusible substances before they can be absorbed. In the oral cavity, salivary glands secrete an array of enzymes and substances that aid in digestion and also disinfection. They include the following:^[1]

• lingual lipase: Lipid digestion initiates in the mouth. Lingual lipase starts the digestion of the lipids/fats.
• Salivary amylase: Carbohydrate digestion also initiates in the mouth. Amylase, produced by the salivary glands, breaks complex carbohydrates to smaller chains, or even simple sugars. It is sometimes referred to as ptyalin.
• lysozyme: Considering that food contains more than just essential nutrients, e.g. bacteria or viruses, the lysozome offers a limited and non-specific, yet beneficial antiseptic function in digestion.
• Haptocorrin (also known as R-factor): Helps with the absorption of Vitamin B12. After Vitamin B12 is released from its original carrier protein in the stomach, it gets bound to Haptocorrin. Haptocorrin protects it from acidic conditions of the stomach but is cleaved in the duodenum by pancreatic proteases. Vitamin B12 can then bind to intrinsic factor (IF) that has been produced by parietal cells. Finally, the IF-Vitamin B12 complex is taken up by in ileum via the cubam receptor.

Of note is the diversity of the salivary glands. There are two types of salivary glands:

• serous glands: These glands produce a secretion rich in water, electrolytes, and enzymes. A great example of a serous oral gland is the parotid gland.
• Mixed glands: These glands have both serous cells and mucous cells, and include sublingual and submandibular glands. Their secretion is mucinous and high in viscosity.

Stomach

The enzymes that are secreted in the stomach are called gastric enzymes. The stomach plays a major role in digestion, both in a mechanical sense by mixing and crushing the food, and also in an enzymatic sense, by digesting it. The following are enzymes, hormones or compounds produced by the stomach and their respective function:

• Pepsin is the main gastric enzyme. It is produced by the stomach cells called "chief cells" in its inactive form pepsinogen, which is a zymogen. Pepsinogen is then activated by the stomach acid into its active form, pepsin. Pepsin breaks down the protein in the food into smaller particles, such as peptide fragments and amino acids. Protein digestion, therefore, first starts in the stomach, unlike carbohydrate and lipids, which start their digestion in the mouth.
• Hydrochloric acid (HCl): This is in essence positively charged hydrogen atoms (H+), or in lay-terms stomach acid, and is produced by the cells of the stomach called parietal cells. HCl mainly functions to denature the proteins ingested, to destroy any bacteria or virus that remains in the food, and also to activate pepsinogen into pepsin.
• Intrinsic factor (IF): Intrinsic factor is produced by the parietal cells of the stomach. Vitamin B12 (Vit. B12) is an important vitamin that requires assistance for absorption in terminal ileum. Initially in the saliva, haptocorrin secreted by salivary glands binds Vit. B, creating a Vit. B12-Haptocorrin complex. The purpose of this complex is to protect Vitamin B12 from hydrochloric acid produced in the stomach. Once the stomach content exits the stomach into the duodenum, haptocorrin is cleaved with pancreatic enzymes, releasing the intact vitamin B12. Intrinsic factor (IF) produced by the parietal cells then binds Vitamin B12, creating a Vit. B12-IF complex. This complex is then absorbed at the terminal portion of the ileum.
• Mucin: The stomach has a priority to destroy the bacteria and viruses using its highly acidic environment but also has a duty to protect its own lining from its acid. The way that the stomach achieves this is by secreting mucin and bicarbonate via its mucous cells, and also by having a rapid cell turn-over.
• Gastrin: This is an important hormone produced by the "G cells" of the stomach. G cells produce gastrin in response to stomach stretching occurring after food enters it, and also after stomach exposure to protein. Gastrin is an endocrine hormone and therefore enters the bloodstream and eventually returns to the stomach where it stimulates parietal cells to produce hydrochloric acid (HCl) and Intrinsic factor (IF).
• Gastric Lipase: Gastric lipase is an acidic lipase secreted by the gastric chief cells in the fundic mucosa in the stomach. It has a pH optimum of 3-6. Gastric lipase, together with lingual lipase, comprise the two acidic lipases. These lipases, unlike alkaline lipases (such as pancreatic lipase), do not require bile acid or colipase for optimal enzymatic activity. Acidic lipases make up 30% of lipid hydrolysis occurring during digestion in the human adult, with gastric lipase contributing the most of the two acidic lipases. In neonates, acidic lipases are much more important, providing up to 50% of total lipolytic activity.

Of note is the division of function between the cells covering the stomach. There are four types of cells in the stomach:

• Parietal cells: Produce hydrochloric acid and intrinsic factor.
• Gastric chief cells: Produce pepsinogen. Chief cells are mainly found in the body of stomach, which is the middle or superior anatomic portion of the stomach.
• Mucous neck and pit cells: Produce mucin and bicarbonate to create a "neutral zone" to protect the stomach lining from the acid or irritants in the stomach chyme.
• G cells: Produce the hormone gastrin in response to distention of the stomach mucosa or protein, and stimulate parietal cells production of their secretion. G cells are located in the antrum of the stomach, which is the most inferior region of the stomach.

Secretion by the previous cells is controlled by the enteric nervous system. Distention in the stomach or innervation by the vagus nerve (via the parasympathetic division of the autonomic nervous system) activates the ENS, in turn leading to the release of acetylcholine. Once present, acetylcholine activates G cells and parietal cells.

Pancreas

Pancreas is both an endocrine and an exocrine gland, in that it functions to produce endocrinic hormones released into the circulatory system (such as insulin, and glucagon), to control glucose metabolism, and also to secrete digestive/exocrinic pancreatic juice, which is secreted eventually via the pancreatic duct into duodenum. Digestive or exocrine function of pancreas is as significant to the maintenance of health as its endocrine function.

Two of the population of cells in the pancreatic parenchyma make up its digestive enzymes:

• Ductal cells: Mainly responsible for production of bicarbonate (HCO3), which acts to neutralize the acidity of the stomach chyme entering duodenum through the pylorus. Ductal cells of the pancreas are stimulated by the hormone secretin to produce their bicarbonate-rich secretions, in what is in essence a bio-feedback mechanism; highly acidic stomach chyme entering the duodenum stimulates duodenal cells called "S cells" to produce the hormone secretin and release to the bloodstream. Secretin having entered the blood eventually comes into contact with the pancreatic ductal cells, stimulating them to produce their bicarbonate-rich juice. It is interesting to note that secretin also inhibits production of gastrin by "G cells", and also stimulates acinar cells of the pancreas to produce their pancreatic enzyme.
• Acinar cells: Mainly responsible for production of the inactive pancreatic enzymes (zymogens) that, once present in the small bowel, become activated and perform their major digestive functions by breaking down proteins, fat, and DNA/RNA. Acinar cells are stimulated by cholecystokinin (CCK), which is a hormone/neurotransmitter produced by the intestinal cells (I cells) in the duodenum. CCK stimulates production of the pancreatic zymogens.

Pancreatic juice, composed of the secretions of both ductal and acinar cells, is made up of the following digestive enzymes:^[2]

• Trypsinogen, which is an inactive(zymogenic) protease that, once activated in the duodenum into trypsin, breaks down proteins at the basic amino acids. Trypsinogen is activated via the duodenal enzyme enterokinase into its active form trypsin.
• Chymotrypsinogen, which is an inactive (zymogenic) protease that, once activated by duodenal enterokinase, breaks down proteins at their aromatic amino acids. Chymotrypsinogen can also be activated by trypsin.
• Carboxypeptidase, which is a protease that takes off the terminal amino acid group from a protein
• Several elastases that degrade the protein elastin and some other proteins.
• Pancreatic lipase that degrades triglycerides into fatty acids and glycerol.
• Sterol esterase
• Phospholipase
• Several nucleases that degrade nucleic acids, like DNAase and RNAase
• Pancreatic amylase that breaks down starch and glycogen which are alpha-linked glucose polymers. Humans lack the cellulases to digest the carbohydrate cellulose which is a beta-linked glucose polymer.

Pancreas's exocrine function owes part of its immaculate function to bio-feedback mechanisms controlling secretion of its juice. The following significant pancreatic bio-feedback mechanisms are essential to the maintenance of pancreatic juice balance/production:^[3]

• Secretin, a hormone produced by the duodenal "S cells" in response to the stomach chyme containing high hydrogen atom concentration (high acidicity), is released into the blood stream; upon return to the digestive tract, secretion decreases gastric emptying, increases secretion of the pancreatic ductal cells, as well as stimulating pancreatic acinar cells to release their zymogenic juice.
• Cholecystokinin (CCK) is a unique peptide released by the duodenal "I cells" in response to chyme containing high fat or protein content. Unlike secretin, which is an endocrine hormone, CCK actually works via stimulation of a neuronal circuit, the end-result of which is stimulation of the acinar cells to release their content. CCK also increases gallbladder contraction, resulting in bile squeezed into the cystic duct, common bile duct and eventually the duodenum. Bile of course helps absorption of the fat by emulsifying it, increasing its absorptive surface. Bile is made by the liver, but is stored in the gallbladder.
• Gastric inhibitory peptide (GIP) is produced by the mucosal duodenal cells in response to chyme containing high amounts of carbohydrate, proteins, and fatty acids. Main function of GIP is to decrease gastric emptying.
• Somatostatin is a hormone produced by the mucosal cells of the duodenum and also the "delta cells" of the pancreas. Somatostatin has a major inhibitory effect, including on pancreatic production.

Small intestine

The following enzymes/hormones are produced in the duodenum:

• secretin: This is an endocrine hormone produced by the duodenal "S cells" in response to the acidity of the gastric chyme.
• Cholecystokinin (CCK): This is not by definition a hormone; there is new evidence suggesting that CCK works by a very complex neuronal bi-directional pathway.^[4] Regardless of its pathway, its eventual role is to increase secretion of acinar cells and increased production of pancreatic juice. CCK also increases gallbladder contraction, causing release of pre-stored bile into the cystic duct, and eventually into the common bile duct and via the ampulla of Vater into the second anatomic position of the duodenum. CCK also decreases the tone of the sphincter of Oddi, which is the sphincter that regulates flow through the ampulla of Vater. CCK also decreases gastric activity and decreases gastric emptying, thereby giving more time to the pancreatic juices to neutralize the acidity of the gastric chyme.
• Gastric inhibitory peptide (GIP): This peptide decreases gastric motility and is produced by duodenal mucosal cells.
• motilin: This substance increases gastro-intestinal motility via specialized receptors called "motilin receptors."
• somatostatin: This hormone is produced by duodenal mucosa and also by the delta cells of the pancreas. Its main function is to inhibit a variety of secretory mechanisms.

Throughout the lining of the small intestine there are numerous brush border enzymes whose function is to further break down the chyme released from the stomach into absorbable particles. Some of these enzymes include:

• Erepsin: It converts peptones and polypeptides into amino acids.
• Maltase: It converts maltose into glucose.
• Lactase: This is a significant brush border enzyme that converts lactose into glucose and galactose. A majority of Middle-Eastern and Asian population lack this enzyme. This enzyme also decreases with age. As such lactose intolerance is often a common abdominal complaint in the Middle-Eastern, Asian, and older population, manifesting with bloating, abdominal pain, and osmotic diarrhea.
• Sucrase: It converts sucrose into glucose and fructose.
• Other disaccharidases

References

1. Brown, Thomas A. "Rapid Review Physiology." Mosby Elsevier, 1st Ed. p. 235
2. Bowen, R. "Exocrine Secretion of the Pancreas"
3. Brown, Thomas A. "Rapid Review Physiology." Mosby Elsevier, 1st Ed. p. 244
4. Morino, P; Mascagni, F; McDonald, A; Hökfelt, T (1994). "Cholecystokinin corticostriatal pathway in the rat: Evidence for bilateral origin from medial prefrontal cortical areas". Neuroscience 59 (4): 939–52. doi:10.1016/0306-4522(94)90297-6. PMID 7520138.