Protein digestion is the breakdown of large, complex molecules into their fundamental building blocks: amino acids. Proteins are long chains of amino acids linked by peptide bonds. Since these large molecules cannot pass through the intestinal lining whole, they must be chemically dismantled into individual amino acids or very short chains of two or three amino acids. This complex process provides the components necessary for building and repairing tissues and synthesizing hormones.
Initial Breakdown in the Stomach
The chemical breakdown of proteins begins in the highly acidic stomach. Specialized cells secrete hydrochloric acid (HCl), which initiates digestion. The acidity (pH 1.5 to 3.5) causes denaturation, unfolding the protein’s complex structure.
This unfolding exposes the polypeptide chains, making the internal peptide bonds accessible to digestive enzymes. The acid also activates pepsinogen, converting it into the active enzyme, pepsin. Pepsin is an endopeptidase that breaks peptide bonds in the middle of the protein chain.
Pepsin cleaves the large polypeptide into smaller fragments, referred to as oligopeptides. This stage is responsible for only 10 to 20% of the total protein breakdown. The resulting mixture, called chyme, then moves into the small intestine for the main phase of digestion.
The Main Enzymatic Phase in the Small Intestine
The bulk of protein digestion occurs in the duodenum and jejunum of the small intestine, utilizing a different set of enzymes. As acidic chyme enters, the pancreas releases a neutralizing bicarbonate solution along with inactive protein-digesting enzymes, known as zymogens (including trypsinogen, chymotrypsinogen, and procarboxypeptidases).
To prevent the pancreas from digesting itself, these enzymes are activated only upon reaching the intestinal lumen. Activation begins with enteropeptidase, an enzyme embedded in the brush border, which converts trypsinogen into active trypsin. Trypsin then acts as the master activator, triggering the conversion of the remaining zymogens into active forms like chymotrypsin and carboxypeptidases.
These activated pancreatic proteases dismantle the shorter polypeptides from the stomach. Endopeptidases (trypsin and chymotrypsin) cleave internal peptide bonds, while exopeptidases (carboxypeptidases) remove amino acids sequentially from the C-terminus. Their combined action rapidly breaks down polypeptides into a mix of small peptides—predominantly dipeptides and tripeptides—and individual free amino acids.
The final step of chemical digestion occurs at the brush border surface of the intestinal cells. Here, membrane-bound peptidases complete the process by cleaving any remaining small peptides into their final, absorbable components. These enzymes ensure the protein is fully prepared for transport across the intestinal wall.
Absorption of Amino Acids and Peptides
Once proteins are reduced to their smallest components, enterocytes (intestinal absorptive cells) move them from the gut lumen into the body. Free amino acids are primarily absorbed through secondary active transport mechanisms. These transporters are specific to different classes of amino acids, such as acidic, basic, or neutral.
The transport of individual amino acids across the apical membrane (the side facing the lumen) is coupled with the inward movement of sodium ions (Na+), known as sodium co-transport. The low sodium concentration inside the cell, maintained by a sodium-potassium pump, provides the electrochemical gradient necessary to drive the amino acid into the enterocyte.
Dipeptides and tripeptides are absorbed whole via a separate and highly efficient mechanism. This is mediated by the Peptide Transporter 1 (PEPT1), which uses a proton (H+) gradient to power the uptake of these small peptides. This proton-coupled transport is often a faster route for protein absorption than the transport of single amino acids.
Once inside the enterocyte, absorbed di- and tripeptides are immediately hydrolyzed into individual amino acids by cytoplasmic peptidases. Virtually all protein fragments are converted into single amino acids before exiting the cell. These free amino acids then exit the enterocyte across the basolateral membrane (the side facing the blood) through various non-sodium-dependent carrier proteins. They are released into the portal vein, which carries them directly to the liver for distribution and metabolic processing throughout the body.