A novel proteolytic activity in serum processes rat prohaptoglobin.

The heterotetrameric plasma glycoprotein rat haptoglobin previously was shown to be synthesized by hepatocytes in a precursor form, prohaptoglobin, which contains one alpha-subunit region and one beta-subunit region. Two of these molecules, each with a molecular weight of 45,000, are joined by a disulfide bond and subsequently the subunit regions of each polypeptide are separated by site-specific proteolysis, yielding the tetrameric native protein. Although some of this processing occurs intracellularly, a substantial proportion of the prohaptoglobin is secreted [J. M. Hanley, T. H. Haugen, and E. C. Heath (1983) J. Biol. Chem. 258, 7858-7869]. However, a proteolytic activity was found in rat plasma and serum which also is capable of site-specific cleavage of prohaptoglobin. Further investigation of this novel activity has demonstrated that it cleaves prohaptoglobin accurately, in the same site-specific manner as the intracellular protease, and that it most likely is not a serine protease or a metalloenzyme but can be inhibited by sulfhydryl-reactive compounds. Furthermore, it appears to be synthesized and secreted by hepatocytes, and thus may be identical to the intracellular processing protease.