BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 6. AMINO ACID METABOLISM AND FUNCTIONS. PROTEIN BIOSYNTHESIS

6.3. Protein Digestion

6.3.1. Protein Digestion in the Stomach

Gastric juice is a product of several Cell types. Parietal (oxyntic) Cells in the gastric mucosa produce Hydrochloric acid, whereas chief cells secrete pepsinogen. Accessory and other gastric epithelial cells produce mucin-containing mucus. Parietal cells also secrete a glycoprotein known as the "intrinsic factor" (Castle's factor) into the gastric lumen. This protein binds to the "extrinsic factor"—Vitamin B12—protecting it from degradation and facilitating its absorption.

Production and Role of Hydrochloric Acid. The primary digestive function of The Stomach is to initiate Protein Digestion, a process in which hydrochloric acid plays a crucial role. Dietary Proteins entering the stomach stimulate the release of histamine and a group of Peptide Hormones called gastrins, which in turn regulate the secretion of HCl and the proenzyme pepsinogen. HCl is produced in the parietal Cells of the gastric glands through a series of reactions schematically illustrated in Fig. 6.2.

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Fig. 6.2. Hydrochloric acid secretion in the stomach:

1 - Carbonic anhydrase; 2 - H⁺/K⁺-ATPase; 3 - anion exchanger proteins; 4 - chloride channel

The source of H⁺ is H₂CO₃, which is formed within the gastric parietal cells from H₂O and CO₂ (diffusing from the Blood) via the catalytic action of carbonic anhydrase (carbonate dehydratase):

The dissociation of H2CO3 yields bicarbonate, which is exported into the plasma via specialized transport proteins in exchange for Cl^-, and H⁺ ions, which are actively transported into the gastric lumen driven by membrane-bound H⁺/K⁺-ATPase. Consequently, the proton concentration in the gastric lumen increases $10^6$-fold. Cl^- ions enter the lumen through chloride channels.

The concentration of HCl in gastric juice can reach 0.16 mol/L, causing the pH to drop to 1.0–2.0. The consumption of protein-rich meals is frequently followed by alkaline tide in urine due to the secretion of large amounts of bicarbonate during HCl production.

HCl induces the Denaturation of raw dietary proteins, increasing the accessibility of peptide bonds to proteases. Furthermore, HCl exerts a bactericidal effect, preventing pathogenic Bacteria from entering the intestines. In addition, hydrochloric acid activates pepsinogen and establishes the optimal pH for Pepsin activity.

Mechanism of Pepsin Activation. Stimulated by gastrins, chief cells in the gastric glands synthesize and secrete pepsinogen, the inactive precursor of pepsin. Pepsinogen is a single-polypeptide protein with a molecular mass of 40 kDa. Upon exposure to HCl, it is converted into active pepsin (molecular mass 32.7 kDa) with an optimal pH of 1.0–2.5. During activation, partial proteolysis cleaves a 42-amino-acid peptide from the N-terminus of the pepsinogen molecule. This fragment contains virtually all positively charged Amino Acids present in pepsinogen. As a result, active pepsin is enriched in negatively charged amino acids, which drive the conformational rearrangements required to form the Active Site. Active pepsin molecules are initially generated by HCl and subsequently propagate their own formation through autocatalysis by activating other pepsin molecules. Pepsin preferentially hydrolyzes peptide bonds formed by aromatic amino acids (phenylalanine, Tryptophan, Tyrosine), and at a slower rate, those involving leucine and dicarboxylic amino acids. Because pepsin is an endopeptidase, its action in the stomach yields shorter Peptides rather than free amino acids.

Age-Related Features of protein DIGESTION IN THE Stomach. In infants, the stomach contains rennin (chymosin), an enzyme that coagulates milk. Casein, the principal milk protein, is a mixture of proteins that differ in Amino Acid Composition and electrophoretic mobility. Rennin catalyzes the Cleavage of a glycopeptide from casein, yielding paracasein. Paracasein then binds Ca²⁺ ions to form an insoluble clot, preventing milk from leaving the stomach too rapidly. Adult stomachs lack rennin; instead, milk coagulation is driven by HCl and pepsin.

Another protease, gastrinixin, has been identified in the human gastric mucosa. All three Enzymes (pepsin, rennin, and gastrinixin) share Structure/154.html">Sequence Homology, indicating they evolved from a common ancestral Gene.

Impaired Protein Digestion in the Stomach. Various gastrointestinal disorders can impair the secretion of HCl and pepsinogen, leading to a marked decrease in protein digestion. Pathological alterations in Gastric Acidity are the most frequent finding. Impaired pepsin synthesis occurs less commonly and is typically associated with severe gastric damage.

Gastric acidity measurements are used in the Diagnosis of various gastric disorders (Table 6.2). Elevated gastric acidity is usually accompanied by heartburn and diarrhea, and can serve as a symptom of gastric and duodenal ulcers, as well as hyperacid gastritis. Decreased acidity is observed in certain forms of gastritis. A complete absence of HCl and pepsin (gastric achylia) occurs in atrophic gastritis and is frequently complicated by pernicious anemia resulting from inadequate intrinsic factor production and impaired vitamin B₁₂ absorption. Anacidity (gastric juice pH > 6.0) indicates a substantial loss of parietal cells within the gastric mucosa and is frequently associated with Gastric Cancer.

Table 6.2

Components of Gastric Juice under Normal and Pathological Conditions

Note: P - pepsin, IF - intrinsic factor, LA - lactic acid; B - blood.

Gastric acidity is expressed in titration units (TU), defined as the volume (in mL) of 0.1 mol NaOH solution required to titrate 100 mL of gastric juice using a specific indicator. Total acidity, bound HCl, and free HCl are distinguished when determining gastric acidity.

Total gastric acidity represents the aggregate of all acid-reacting substances in gastric juice collected over a 1-hour period. The normal range for total acidity is 40-60 TU.

Bound hydrochloric acid is HCl bound to proteins and their digestion products. The normal range of bound HCl in healthy individuals is 20-30 CU.

Free HCl is hydrochloric acid that is not bound to the components of gastric juice. The normal range for free HCl is 20-40 CU.

The normal pH of gastric juice ranges from 1.5 to 2.0.

Lactic acid is normally absent in gastric juice. It appears when free hydrochloric acid is reduced or absent due to the proliferation of lactic acid bacteria, or in the presence of gastric malignancies, where tumor cells metabolize glucose via anaerobic pathways.

In the diagnosis of gastric diseases, biochemical analyses are routinely complemented by radiological and endoscopic examinations, as well as biopsy.