Medical Physiology, 3rd Edition

Protein Digestion

Proteins require hydrolysis to oligopeptides or amino acids before absorption in the small intestine

With the exception of antigenic amounts of dietary protein that are absorbed intact, proteins must first be digested into their constituent oligopeptides and amino acids before being taken up by the enterocytes. Digestion-absorption occurs through four major pathways. First, several luminal enzymes (i.e., proteases) from the stomach and pancreas may hydrolyze proteins to peptides and then to amino acids, which are then absorbed (Fig. 45-6). Second, luminal enzymes may digest proteins to peptides, but enzymes present at the brush border digest the peptides to amino acids, which are then absorbed. Third, luminal enzymes may digest proteins to peptides, which are themselves taken up as oligopeptides by the enterocytes. Further digestion of the oligopeptides by cytosolic enzymes yields intracellular amino acids, which are moved by transporters across the basolateral membrane into the blood. Fourth, luminal enzymes may digest dietary proteins to oligopeptides, which are taken up by enterocytes via an endocytotic process (Fig. 45-7) and moved directly into the blood. Overall, protein digestion-absorption is very efficient; <4% of ingested nitrogen is excreted in the stool.

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FIGURE 45-6 Action of luminal, brush-border, and cytosolic peptidases. Pepsin from the stomach and the five pancreatic proteases hydrolyze proteins—both dietary and endogenous—to single amino acids, AA, or to oligopeptides, (AA)n. These reactions occur in the lumen of the stomach or small intestine. A variety of peptidases at the brush borders of enterocytes then progressively hydrolyze oligopeptides to amino acids. The enterocyte directly absorbs some of the small oligopeptides via the action of the H/oligopeptide cotransporter PepT1. These small peptides are digested to amino acids by peptidases in the cytoplasm of the enterocyte.

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FIGURE 45-7 Absorption of whole proteins. Both enterocytes and specialized M cells can take up intact proteins. The more abundant enterocytes can endocytose far more total protein than can the M cells. However, the lysosomal proteases in the enterocytes degrade ~90% of this endocytosed protein. The less abundant M cells take up relatively little intact protein, but about half of this emerges intact at the basolateral membrane. There, immunocompetent cells process the target antigens and then transfer them to lymphocytes, initiating an immune response.

The protein that is digested and absorbed in the small intestine comes from both dietary and endogenous sources. Dietary protein in developed countries amounts to 70 to 100 g/day. This amount is far in excess of minimum daily requirements and represents 10% to 15% of energy intake. In contrast, dietary protein content in developing countries in Africa is often 50 g/day. Deficiency states are rare unless intake is markedly reduced.

Proteins are encoded by messenger RNA (mRNA) and consist of 20 different amino acids. Nine of these amino acids are essential (see Table 58-2); that is, they are not synthesized in adequate amounts by the body and thus must be derived from either animal or plant protein sources. In addition, cells synthesize some other amino acids by post-translational modifications: γ-carboxyglutamic acid, hydroxylysine, 4-hydroxyproline, and 3-hydroxyproline. Protein digestion is influenced by the amino-acid composition of the protein, by the source of protein, and by food processing. Thus, proteins rich in proline and hydroxyproline are digested relatively less completely. Cooking, storage, and dehydration also reduce the completeness of digestion. In general, protein derived from animal sources is digested more completely than plant protein.

In addition to protein from dietary sources, significant amounts of endogenous protein are secreted into the gastrointestinal tract, then conserved by protein digestion and absorption. Such endogenous sources represent ~50% of the total protein entering the small intestine and include enzymes, hormones, and immunoglobulins present in salivary, gastric, pancreatic, biliary, and jejunal secretions. A second large source of endogenous protein is desquamated intestinal epithelial cells as well as plasma proteins that the small intestine secretes.

Neonates can absorb substantial amounts of intact protein from colostrum (see p. 1146) through the process of endocytosis. This mechanism is developmentally regulated and in humans remains active only until ~6 months of age. In adults, proteins are almost exclusively digested to their constituent amino acids and dipeptides, tripeptides, or tetrapeptides before absorption. However, even adults absorb small amounts of intact proteins. These absorbed proteins can be important in inducing immune responses to dietary proteins.

Luminal digestion of protein involves both gastric and pancreatic proteases, and yields amino acids and oligopeptides

Both gastric and pancreatic proteases, unlike the digestive enzymes for carbohydrates and lipids, are secreted as proenzymes that require conversion to their active form for protein hydrolysis to occur. The gastric chief cells secrete pepsinogen. We discuss the pH-dependent activation of pepsinogen on pages 873–874Pepsin has a maximal hydrolytic activity between pH 1.8 and 3.5, and becomes irreversibly inactivated at above pH 7.2. Pepsin is an endopeptidase with primary specificity for peptide linkages of aromatic and larger neutral amino acids. Although pepsin in the stomach partially digests 10% to 15% of dietary protein, pepsin hydrolysis is not absolutely necessary; patients with either total gastrectomies or pernicious anemia imageN45-6 (who do not secrete acid and thus whose intragastric pH is always >7) do not have increased fecal nitrogen excretion.

N45-6

Pernicious Anemia

Contributed by Henry Binder

The close relationship between acid and gastrin release is clearly manifested in individuals with impaired acid secretion. In pernicious anemia, atrophy of the gastric mucosa in the corpus and an absence of parietal cells result in a lack in the secretion of both gastric acid and intrinsic factor (IF). Many patients with pernicious anemia exhibit antibody-mediated immunity against their parietal cells, and many of these patients also produce anti-IF autoantibodies.

Because IF is required for cobalamin absorption in the ileum, the result is impaired cobalamin absorption. In contrast, the antrum is normal. Moreover, plasma gastrin levels are markedly elevated as a result of the absence of intraluminal acid, which normally triggers gastric D cells to release somatostatin (see pp. 868–870); this, in turn, inhibits antral gastrin release (see Box 42-1). Because parietal cells are absent, the elevated plasma gastrin levels are not associated with enhanced gastric acid secretion.

The clinical complications of cobalamin deficiency evolve over a period of years. Patients develop megaloblastic anemia (in which the circulating red blood cells are enlarged), a distinctive form of glossitis, and a neuropathy. The earliest neurological findings are those of peripheral neuropathy, as manifested by paresthesias and slow reflexes, as well as impaired senses of touch, vibration, and temperature. If untreated, the disease will ultimately involve the spinal cord, particularly the dorsal columns, thus producing weakness and ataxia. Memory impairment, depression, and dementia can also result. Parenteral administration of cobalamin reverses and prevents the manifestations of pernicious anemia, but it does not influence parietal cells or restore gastric secretion of either IF or intraluminal acid.

Five pancreatic enzymes (Table 45-2) participate in protein digestion and are secreted as inactive proenzymes. Trypsinogen is initially activated by a jejunal brush-border enzyme, enterokinase (enteropeptidase), by the cleavage of a hexapeptide, thereby yielding trypsin. Trypsin not only autoactivates trypsinogen but also activates the other pancreatic proteolytic proenzymes. The secretion of proteolytic enzymes as proenzymes, with subsequent luminal activation, prevents pancreatic autodigestion before enzyme secretion into the intestine.

TABLE 45-2

Pancreatic Peptidases

PROENZYME

ACTIVATING AGENT

ACTIVE ENZYME

ACTION

PRODUCTS

Trypsinogen

Enteropeptidase (i.e., enterokinase from jejunum) and trypsin

Trypsin

Endopeptidase

Oligopeptides (2–6 amino acids)

Chymotrypsinogen

Trypsin

Chymotrypsin

Endopeptidase

Oligopeptides (2–6 amino acids)

Proelastase

Trypsin

Elastase

Endopeptidase

Oligopeptides (2–6 amino acids)

Procarboxypeptidase A

Trypsin

Carboxypeptidase A

Exopeptidase

Single amino acids

Procarboxypeptidase B

Trypsin

Carboxypeptidase B

Exopeptidase

Single amino acids

Pancreatic proteolytic enzymes are either exopeptidases or endopeptidases and function in an integrated manner. Trypsin, chymotrypsin, and elastase are endopeptidases with affinity for peptide bonds adjacent to specific amino acids, so that their action results in the production of oligopeptides with two to six amino acids. In contrast, the exopeptidases—carboxypeptidase A and carboxypeptidase B—hydrolyze peptide bonds adjacent to the carboxyl (C) terminus, which results in the release of individual amino acids. The coordinated action of these pancreatic proteases converts ~70% of luminal amino nitrogen to oligopeptides and ~30% to free amino acids.

Brush-border peptidases fully digest some oligopeptides to amino acids, whereas cytosolic peptidases digest oligopeptides that directly enter the enterocyte

Small peptides present in the small-intestinal lumen after digestion by gastric and pancreatic proteases undergo further hydrolysis by peptidases at the brush border (see Fig. 45-6). Multiple peptidases are present both on the brush border and in the cytoplasm of villous epithelial cells. This distribution of cell-associated peptidases stands in contrast to that of the oligosaccharidases, which are found only at the brush border. Because each peptidase recognizes only a limited repertoire of peptide bonds, and because the oligopeptides to be digested contain 24 different amino acids, large numbers of peptidases are required to ensure the hydrolysis of peptides.

As we discuss below, a transporter on the apical membrane of enterocytes can take up small oligopeptides, primarily dipeptides and tripeptides. Once inside the cell, these oligopeptides may be further digested by cytoplasmic peptidases. The brush-border and cytoplasmic peptidases have substantially different characteristics. For example, the brush-border peptidases have affinity for relatively larger oligopeptides (three to eight amino acids), whereas the cytoplasmic peptidases primarily hydrolyze dipeptides and tripeptides. Because the brush-border and cytoplasmic enzymes often have different biochemical properties (e.g., heat lability and electrophoretic mobility), it is evident that the peptidases in the brush border and cytoplasm are distinct, independently regulated molecules.

Like the pancreatic proteases, each of the several brush-border peptidases is an endopeptidase, an exopeptidase, or a dipeptidase with affinity for specific peptide bonds. The exopeptidases are either carboxypeptidases, which release C-terminal amino acids, or aminopeptidases, which hydrolyze the amino acids at the amino (N)–terminal end. Cytoplasmic peptidases are relatively less numerous.

 

SMALL INTESTINE

LARGE INTESTINE

Length (m)

6

2.4

Area of apical plasma membrane (m2)

~200

~25

Folds

Yes

Yes

Villi

Yes

No

Crypts or glands

Yes

Yes

Microvilli

Yes

Yes

Nutrient absorption

Yes

No

Active Na+ absorption

Yes

Yes

Active K+ secretion

No

Yes