Pepsinogen is an inactive protein molecule, also known as a zymogen, produced by specialized cells lining the stomach walls. It performs an initial, yet indirect, function in the digestion of food. Pepsinogen exists in an inactive form as a protective measure, preventing the powerful digestive enzyme it becomes from damaging the cells that create it. Once secreted, this molecule initiates the breakdown of dietary proteins.
From Precursor to Protease: The Activation of Pepsinogen
The transformation of pepsinogen into its active form, pepsin, is entirely dependent on the highly acidic environment of the stomach. Pepsinogen is stored and released by gastric chief cells located deep within the stomach lining. Upon the ingestion of food, the stomach’s parietal cells secrete hydrochloric acid (HCl), which rapidly lowers the internal pH to between 1.5 and 2.5.
This low pH triggers a conformational change in the pepsinogen molecule. The acidic conditions disrupt electrostatic interactions that hold a small segment, called the prosegment, in place, which blocks the enzyme’s active site. The prosegment is then cleaved off, unveiling the active enzyme, pepsin. This initial activation can occur spontaneously at a pH below 5, but the newly formed pepsin can also activate other pepsinogen molecules in a process called autocatalysis.
The resulting active enzyme, pepsin, is an aspartic protease, meaning it uses two aspartic acid residues in its active site to break chemical bonds. Pepsin’s primary digestive function is to cleave large, complex dietary proteins into smaller fragments known as peptides. This action begins the chemical digestion of proteins, preparing them for final breakdown and absorption later in the small intestine. The enzyme functions optimally in the stomach’s acidic conditions and becomes inactive once the partially digested contents move into the higher pH of the small intestine.
The Two Forms: Pepsinogen I and Pepsinogen II
Pepsinogen exists as two immunochemically distinct groups: Pepsinogen I (PGI) and Pepsinogen II (PGII). These two groups are encoded by different genes and exhibit distinct production locations within the gastrointestinal tract. This difference in origin allows scientists to use their levels to map the health of different regions of the stomach.
PGI is primarily secreted by the chief cells and mucous neck cells located in the mucosa of the gastric body and fundus, which are the upper and central parts of the stomach. PGII, however, has a wider distribution across the upper digestive system. It is secreted by cells in the gastric body and fundus, but also by cells in the pyloric glands of the antrum (the lower part of the stomach) and even in the upper part of the duodenum.
Although the majority of both forms are secreted into the gastric lumen, about one percent of both PGI and PGII diffuses into the bloodstream. These circulating levels of both forms allow them to be measured non-invasively and used as indicators of health.
Pepsinogen as a Health Biomarker
The levels of PGI and PGII in the blood serum, and especially their ratio, offer a non-invasive way to assess the status of the stomach lining. This serological testing is widely used as a screening tool for certain gastric pathologies, providing insight without the need for an immediate endoscopy. A key application is the assessment of atrophic gastritis, a condition where the stomach lining becomes inflamed and loses the glands that produce acid and enzymes.
As atrophic gastritis progresses, the chief cells in the gastric body that produce PGI are lost, causing serum PGI levels to decrease. Because PGII is produced across a wider area, its level remains relatively stable or decreases less dramatically. Consequently, a significantly low PGI/PGII ratio is a strong indicator of moderate to severe atrophic gastritis. This low ratio is considered a robust biomarker because atrophic gastritis is a known precursor condition for more serious issues, including gastric cancer.
Another important clinical use involves detecting the presence of pepsin outside of the stomach. Pepsin is normally confined to the stomach, but its detection in samples taken from the throat or saliva is a definitive diagnostic tool for Laryngopharyngeal Reflux (LPR), often called “silent reflux”. In LPR, stomach contents, including pepsin, travel up the esophagus and into the upper airways, causing damage. Pepsin remains active even at the higher pH levels found in the throat, and its presence confirms that the symptoms are caused by gastric reflux.