Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site

Structural studies on a hereditarily abnormal plasminogen, plasminogen Tochigi, have been performed to identify the difference responsible for its lack of proteolytic activity. The plasminogen sample used was from a heterozygote and thus consisted of apparently equal amounts of normal and defective plasminogen molecules. Amino acid sequence analysis of a tryptic peptide isolated from the abnormal plasminogen indicated that Ala-600 (equivalent to Ala-55 in the chymotrypsin numbering system) had been replaced by Thr. No other substitutions in the active-site residues--namely, His-57, Asp-102, and Ser-195--were found. Molecular models for chymotrypsin and the bovine trypsin-pancreatic trypsin inhibitor complex indicate that Ala-55 is very near the active-site His. The Thr at position 55 in plasminogen (plasmin) Tochigi may perturb His-57 such that the proton transfers associated with the normal catalytic process cannot occur in the abnormal plasmin.