Converting tissue plasminogen activator to a zymogen: a regulatory triad of Asp-His-Ser.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print Cited Medium: Print ISSN: 0036-8075 (Print) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE

Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-

Enzyme Precursors/*metabolism ; Tissue Plasminogen Activator/*metabolism; Amino Acid Sequence ; Aspartic Acid/chemistry ; Base Sequence ; Catalysis ; Chymotrypsin/chemistry ; Chymotrypsin/metabolism ; Enzyme Precursors/chemistry ; Histidine/chemistry ; Hydrogen Bonding ; Kinetics ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutation ; Plasminogen/metabolism ; Plasminogen Activator Inhibitor 1/metabolism ; Serine/chemistry ; Tissue Plasminogen Activator/chemistry ; Tissue Plasminogen Activator/genetics

Unlike most serine proteases of the chymotrypsin family, tissue-type plasminogen activator (tPA) is secreted from cells as an active, single-chain enzyme with a catalytic efficiency only slightly lower than that of the proteolytically cleaved form. A zymogenic mutant of tPA has been engineered that displays a reduction in catalytic efficiency by a factor of 141 in the single-chain form while retaining full activity in the cleaved form. The residues introduced in the mutant, serine 292 and histidine 305, are proposed to form a hydrogen-bonded network with aspartate 477, similar to the aspartate 194-histidine 40-serine 32 network found to stabilize the zymogen chymotrypsinogen.

0 (Enzyme Precursors)
0 (Plasminogen Activator Inhibitor 1)
30KYC7MIAI (Aspartic Acid)
452VLY9402 (Serine)
4QD397987E (Histidine)
9001-91-6 (Plasminogen)
EC 3.4.21.1 (Chymotrypsin)
EC 3.4.21.68 (Tissue Plasminogen Activator)

Date Created: 19931015 Date Completed: 19931115 Latest Revision: 20190618

20221213

10.1126/science.8211162

8211162