Human Biochemistry Volume 2 - Murray R. 1993

Special Topics
Nutrition, Digestion, and Absorption
Pancreatic and Intestinal Digestion

Gastric contents, or chyme, periodically enter the duodenum through the pyloric sphincter during Digestion. The pancreatic and common Bile ducts open into the duodenum in close proximity to the pylorus. The alkaline secretions of the Pancreas and bile neutralize the chyme, shifting its pH toward the alkaline side. This pH shift is essential for the enzymatic activity of pancreatic and intestinal juices, while inhibiting the further action of Pepsin.

Bile

In addition to its numerous roles in intermediate METABOLISM, the Liver plays a vital role in digestion due to its ability to produce bile. The Gallbladder, a saclike organ adjacent to the hepatic duct, stores a portion of the bile produced by the liver between meals. During digestion, the gallbladder contracts and rapidly releases bile into the Small Intestine via the common bile duct. Pancreatic secretions mix with the bile as they enter the common bile duct just upstream of its opening into the duodenum.

A. Composition of bile. Hepatic bile differs in composition from gallbladder bile. The latter, as shown in Table 53.10, is more concentrated.

B. Functions of bile.

1. Emulsification. Bile salts have the remarkable ability to significantly lower surface tension. This allows them to emulsify fats in the intestine, solubilizing Fatty acids and Water-insoluble soaps. The presence of bile in the intestine facilitates the completion of fat DIGESTION AND ABSORPTION, as well as the absorption of Fat-soluble Vitamins A, D, E, and K. When fat digestion is impaired, other nutrients are also poorly digested because the fat coats food particles and prevents Enzymes from acting upon them. Under these conditions, The activity of intestinal Bacteria leads to increased putrefaction and gas formation.

2. Acid neutralization. Aside from its digestive functions, bile—having a pH slightly above 7—neutralizes the acidic chyme coming from The Stomach, preparing it for intestinal digestion.

Class="center">Table 53.10. Composition of hepatic and gallbladder bile

3. Excretion. Bile is an important vehicle for excreting bile acids and cholesterol, but it also clears various drugs, toxins, bile pigments, and inorganic substances such as copper, zinc, and mercury from the body.

4. Cholesterol solubility in bile; gallstone formation. Free cholesterol is insoluble in water and is therefore incorporated into micelles formed by phosphatidylcholine and bile salts. Furthermore, phosphatidylcholine—the predominant phospholipid in bile—is itself insoluble in aqueous systems, but it can be rendered soluble by bile salts within mixed micelles. Large amounts of cholesterol present in human bile are solubilized in these water-soluble mixed micelles, facilitating The transport of cholesterol into the intestine via the bile duct. However, the actual solubility of cholesterol in bile depends on The ratio of bile salts, phosphatidylcholine, and cholesterol. It also depends on the water content of the bile, which is particularly critical in the case of dilute hepatic bile.

Using a triangular coordinate system (Fig. 53.2), Admirand and Small (Redinger and Small) successfully determined the maximum solubility of cholesterol in human gallbladder bile. The diagram shows that any point within this system located above the curve ABC represents a bile composition in which cholesterol is either supersaturated or precipitates out of solution.

It is believed that patients with cholelithiasis produce abnormal bile supersaturated with cholesterol at some point in their lives. Over time, various factors, such as infection, may act as triggers promoting the precipitation of excess cholesterol from the supersaturated bile in the form of crystals. If these newly formed crystals are not immediately flushed out with the bile into the intestine, they continue to grow, eventually forming stones. Determining the activity of Key Enzymes involved in bile acid synthesis in the livers of patients with gallstones has shown that their cholesterol synthesis is elevated while bile acid synthesis is reduced, resulting in an increased concentration of cholesterol in the liver. A decrease in 7α-hydroxylase activity can lead to a depletion of the enterohepatic pool of bile acids, which signals the liver to produce even greater amounts of cholesterol. Consequently, the bile becomes overloaded with cholesterol, failing to dissolve completely in mixed micelles.

Based on the data on cholesterol solubility outlined above, attempts have been made to develop Methods for dissolving gallstones or preventing their further formation. The Use of chenodeoxycholic acid offers the possibility of targeted Treatment for patients with radiopaque stones in a functioning gallbladder, as this compound has The ability to inhibit hepatic hydroxymethylglutaryl (HMG)-CoA reductase, thereby reducing cholesterol synthesis.

Fig. 53.2. Representation of the three major bile components (bile acids, phosphatidylcholine, and cholesterol) on triangular coordinates. Each component is expressed as a percentage of the total molar amount of bile salts, phosphatidylcholine, and cholesterol. The curve indicates the maximum solubility of cholesterol in various mixtures of bile salts and phosphatidylcholine. The intersection of the dashed lines corresponds to normal bile (5% cholesterol, 15% phosphatidylcholine, and 80% bile salts) and lies within the single-phase micellar liquid zone. Bile with a composition falling above this line must contain excess cholesterol as a supersaturated solution or precipitate (crystals or liquid crystals). (Reproduced, with permission, from Redinger R. N. Small D. M. Bile composition, bile salt metabolism, and gallstones. Arch. Intern. Med., 1972, 130, 620. Copyright © 1972. American Medical Association.)

5. Bile pigment metabolism. The derivation of bile pigments from Hemoglobin is discussed in Chapter 33.

Digestion by Pancreatic Secretions

Pancreatic juice is a clear, watery fluid, similar in water content to saliva, containing protein along with organic and inorganic ions (predominantly Na⁺, К⁺, НСО^-₃, and Сl^-), as well as small amounts of Са²⁺, Zn²⁺, НРO^2-₄, and SO²⁺₄. The pH of pancreatic secretion is distinctly alkaline, ranging from 7.5 to 8.0 or higher.

The secretion contains numerous enzymes, some of which are secreted as zymogens.

A. Trypsin, Chymotrypsin, and Elastase. The proteolytic activity of pancreatic juice is driven by three Endopeptidases—trypsin, chymotrypsin, and elastase—which break down Proteins and Polypeptides arriving from the stomach into polypeptides, Peptides, or both. Trypsin specifically cleaves peptide bonds formed by basic Amino Acids, chymotrypsin targets bonds between uncharged amino acid residues (such as aromatics), whereas elastase, contrary to its name, has a fairly broad Specificity, cleaving bonds adjacent to small amino acid residues like Glycine, Alanine, and Serine. All three enzymes are secreted as zymogens. Trypsinogen activation is carried out by another proteolytic enzyme, enterokinase, secreted by the intestinal mucosa. It hydrolyzes a Lysine peptide bond in the zymogen, releasing a small polypeptide, which prompts the molecule to unfold into active trypsin. The resulting trypsin acts not only on new trypsinogen molecules but also on other pancreatic zymogens—chymotrypsinogen, proelastase, and procarboxypeptidase—yielding chymotrypsin, elastase, and carboxypeptidase, respectively.

B. Carboxypeptidase. The further breakdown of polypeptides generated by endopeptidase action is carried out by an exopeptidase, carboxypeptidase, which attacks the C-terminal peptide bond, releasing single amino acids.

C. Amylase. The starch-digesting activity of pancreatic juice is attributed to pancreatic a-amylase. It acts similarly to salivary amylase, hydrolyzing starch and Glycogen to form maltose, maltotriose [three a-glucose residues linked by a(1→4) bonds], as well as a mixture of branched (1→6) Oligosaccharides (a-dextrins), linear oligosaccharides, and a small amount of glucose.

D. Lipase. Pancreatic lipase acts at the oil-water interface of finely emulsified lipid droplets formed in the intestine through mechanical agitation in the presence of the products of lingual lipase, bile salts, colipase (a protein present in pancreatic juice), Phospholipids, and phospholipase A₂ (also a component of pancreatic juice). Phospholipase A₂ and colipase are secreted as pro-forms, and their activation requires tryptic Hydrolysis of specific peptide bonds. Ca²⁺ is essential for phospholipase A₂ activity. Following limited hydrolysis of the phospholipid ester bond at position 2 by phospholipase A₂ (see Fig. 25.5), lipase binds to the substrate interface, and rapid hydrolysis of triacylglycerols ensues. Colipase binds to the bile salt–triacylglycerol/water interface, providing a high-affinity anchor for lipase. Complete hydrolysis of triacylglycerols yields glycerol and fatty acids. Note, however, that the Cleavage of the second and third fatty acids from triacylglycerols becomes progressively more difficult. Pancreatic lipase is essentially specific for the hydrolysis of primary ester bonds, i.e., the bonds at positions 1 and 3 of triacylglycerols. During fat digestion, the aqueous or "micellar" phase contains mixed disc-shaped micelles and Liposomes composed of bile salts saturated with lipolysis products (see Fig. 15.34). Because the hydrolysis of the secondary ester bond in triacylglycerol is hindered, it can be assumed that triacylglycerol digestion is preceded by the removal of terminal fatty acids to yield 2-monoacylglycerol. Since the remaining fatty acid is linked by a secondary ester bond, its removal requires isomerization to a primary ester bond. This is a relatively slow process; consequently, the primary End products of triacylglycerol digestion are indeed 2-monoacylglycerols, with less than one-quarter of the digested triacylglycerol breaking down completely into glycerol and fatty acids (Fig. 53.3).

E. Cholesteryl ester hydrolase (cholesterol esterase). Under conditions typical of the intestinal lumen, this enzyme catalyzes the hydrolysis of cholesterol esters, which are subsequently absorbed from the intestine in an unesterified, free form.

E. Ribonuclease (RNase) and deoxyribonuclease (DNase) are derived from pancreatic tissue (see Chapters 38 and 39).

F. Phospholipase A₂. Phospholipase A₂ hydrolyzes the ester bond at the C-2 position of Glycerophospholipids from both biliary and dietary sources, yielding lysophospholipids.

Digestion by Intestinal Secretions

Intestinal juice, secreted by Brunner's and Lieberkühn's glands, also contains digestive enzymes, which include:

Fig. 53.3. Digestion and absorption of triacylglycerols. FA — long-chain fatty acids. (Modified from Mattson F. H., Volpenheim R. A. The digestion and absorption of triglycerides. J. Biol. Chem., 1964, 239, 2772.)

1) aminopeptidase, an exopeptidase that hydrolyzes peptide bonds adjacent to the N-terminal amino acids of polypeptides and oligopeptides; dipeptidases of varying specificity, some of which may be located within the intestinal epithelium, completing The breakdown of dipeptides into free amino acids;

2) specific disaccharidases and oligosaccharidases, such as α-glucosidase (maltase), which removes single glucose residues from α(1→4)-linked oligosaccharides and Disaccharides starting from the non-reducing ends; isomaltase (α-dextrinase), which hydrolyzes the (1→6)-bonds of α-dextrins; β-galactosidase (lactase), which removes galactose from lactose; sucrase, which hydrolyzes sucrose; and trehalase, which splits trehalose;

3) phosphatase, which removes phosphate groups from various organic phosphates (hexose phosphates and glycerophosphate) and from dietary NUCLEOTIDES or those generated from Nucleic Acids via nuclease digestion;

4) polynucleotidases, which break down nucleic acids into nucleotides;

5) nucleosidases (nucleoside phosphorylases), which catalyze the phosphorolysis of nucleosides to yield free nitrogenous bases and pentose phosphates;

6) intestinal secretions also appear to contain a phospholipase that acts on phospholipids to produce glycerol, fatty acids, phosphoric acid, and nitrogenous bases such as Choline.

Major Digestion Products

The ultimate outcome of the action of these digestive enzymes is the breakdown of dietary components into forms capable of being absorbed and assimilated. These end products of digestion are Monosaccharides (primarily glucose) for CARBOHYDRATES, amino acids for proteins, fatty acids, glycerol, and monoacylglycerols for triacylglycerols, and bases, nucleosides, and pentoses for nucleic acids.

Plant Cell wall Polysaccharides and Lignin, which resist digestion by mammalian enzymes, comprise dietary fiber and constitute the bulk remaining after digestion. Fiber serves the vital function of adding dietary bulk, as discussed earlier in this chapter. The principal digestive processes are summarized in Table 53.11.