Intramolecular activation of pepsinogen

Abstract

Two pathways for pepsinogen activation have been demonstrated. Intramolecular activation, which is kinetically first-order, predominates over the autocatalytic pathway if the pH is below 3 and the protein concentration is less than 1 mg/ml during activation. Intramolecular pepsinogen activation is inhibited either by pepstatin, a potent pepsin inhibitor, or by purified globin from hemoglobin, a good pepsin substrate. Also, pepsinogen at pH 2 can be bound to a pepstatin-Sepharose column and recovered as native zymogen upon elution in pH 8 buffer. Kinetic studies of the globin inhibition of pepsinogen activation show that globin binds to a pepsinogen intermediate. This interaction gives rise to competitive inhibition of intramolecular pepsinogen activation. The evidence presented in this paper suggests that pepsinogen is converted rapidly upon acidification to the pepsinogen intermediate delta.