Proteins are a major source of dietary nitrogen, with Americans typically consuming 70-100 g/day (Fig. 19.2). However, proteins are too large to be absorbed by the intestine. Exceptions to this rule include newborns who can absorb maternal antibodies from breast milk. Therefore, proteins need to be broken down into di-and tripeptides, as well as individual amino acids, which can be absorbed. The stomach, pancreas, and small intestine all produce proteolytic enzymes responsible for degrading proteins (Fig. 19.4).

In the stomach, proteins are initially digested by gastric juice, which contains hydrochloric acid (HCl) and the proenzyme pepsinogen. The HCl in the stomach, although dilute (pH 2-3), helps denature proteins and make them more susceptible to hydrolysis by proteases. Pepsinogen, secreted by the chief cells of the stomach, is an acid-stable endopeptidase that undergoes a conformational change in the presence of HCl. This change activates pepsin, which then releases polypeptides and a few free amino acids from dietary proteins.

Upon entering the small intestine, the polypeptides produced by pepsin in the stomach are further cleaved into oligopeptides and amino acids by pancreatic proteases. These pancreatic proteases consist of both endopeptidases, which cleave within peptide bonds, and exopeptidases, which cut at the ends of peptide chains. The specificity of each enzyme depends on the adjacent amino acid R-groups (Fig. 19.5). For example, trypsin specifically cleaves peptide bonds when arginine or lysine contribute to the carbonyl group. Like pepsin, these pancreatic proteases are initially synthesized and secreted as inactive zymogens.

The release and activation of pancreatic zymogens are mediated by the hormone cholecystokinin, which is produced in the small intestine. Enteropeptidase (also known as enterokinase) is a serine protease located on the luminal surface of intestinal mucosal cells. It converts the pancreatic zymogen trypsinogen to trypsin by removing a hexapeptide from the N-terminus. Trypsin then activates other trypsinogen molecules by cleaving specific peptide bonds. This cascade of proteolytic activity is initiated by enteropeptidase, as trypsin serves as the common activator for all pancreatic zymogens (Fig. 19.5).
Most of the nitrogen in the diet is consumed in the form of protein, typically amounting to 70–100 g/day in the American diet (see Fig. 19.2). Proteins are generally too large to be absorbed by the intestine. [Note: An example of an exception to this rule is that newborns can take up maternal antibodies in breast milk.] Therefore, proteins must be hydrolyzed to yield di-and tripeptides as well as individual amino acids, which can be absorbed. Proteolytic enzymes responsible for degrading proteins are produced by three different organs: the stomach, the pancreas, and the small intestine (Fig. 19.4).
A. Digestion by gastric secretion
The digestion of proteins begins in the stomach, which secretes gastric juice, a unique solution containing hydrochloric acid (HCl) and the proenzyme pepsinogen.
1.
Hydrochloric acid: Stomach HCl is too dilute (pH 2–3) to hydrolyze proteins. The acid, secreted by the parietal cells of the stomach, functions instead to kill some bacteria and to denature proteins, thereby making them more susceptible to subsequent hydrolysis by proteases.
2.
Pepsin: This acid-stable endopeptidase is secreted by the chief cells of the stomach as an inactive zymogen (or proenzyme), pepsinogen. [Note: In general, zymogens contain extra amino acids in their sequences that prevent them from being catalytically active. Removal of these amino acids permits the proper folding required for an active enzyme.] In the presence of HCl, pepsinogen undergoes a conformational change that allows it to cleave itself (autocatalysis) to the active form, pepsin, which releases polypeptides and a few free amino acids from dietary proteins.
B. Digestion by pancreatic enzymes
On entering the small intestine, the polypeptides produced in the stomach by the action of pepsin are further cleaved to oligopeptides and amino acids by a group of pancreatic proteases that include both endopeptidases (that cleave within) and exopeptidases (that cut at an end). [Note: Bicarbonate (HCO3−), secreted by the pancreas in response to the intestinal hormone secretin, raises the intestinal pH.] 1.
Specificity: Each of these enzymes has a different specificity for the amino acid R-groups adjacent to the susceptible peptide bond (Fig. 19.5). For example, trypsin cleaves only when the carbonyl group of the peptide bond is contributed by arginine or lysine. These enzymes, like pepsin described above, are synthesized and secreted as inactive zymogens.
2.
Zymogen release: The release and activation of the pancreatic zymogens are mediated by the secretion of cholecystokinin, a polypeptide hormone of the small intestine (see p. 176).
3.
Zymogen activation: Enteropeptidase (also called enterokinase), a serine protease synthesized by and present on the luminal (apical) surface of intestinal mucosal cells (enterocytes) of the brush border, converts the pancreatic zymogen trypsinogen to trypsin by removal of a hexapeptide from the N-terminus of trypsinogen. Trypsin subsequently converts other trypsinogen molecules to trypsin by cleaving a limited number of specific peptide bonds in the zymogen. Thus, enteropeptidase unleashes a cascade of proteolytic activity because trypsin is the common activator of all the pancreatic zymogens (see Fig. 19.5).
4.