title: Autoactivation of prolegumain is accelerated by glycosaminoglycans.
abstract: The cysteine protease legumain participates in several biological and pathological processes including tumour invasion and metastasis. Legumain is synthesized as a zymogen and undergoes pH-dependent autoactivation of the proform in order to reach an enzymatically active form. Here we demonstrate that the naturally occurring polyanionic glycosaminoglycans (GAGs) chondroitin 4-sulphate (C4S), chondroitin 6-sulphate (C6S), chondroitin 4,6-sulphate (C4,6S), heparin, heparan sulphate (HS) as well as chondroitin sulphate (CS)-derived decasaccharides accelerated the autocatalytic activation of prolegumain through ionic interactions in a concentration-, size- and time-dependent manner at pH 4.0. In contrast, at pH 5.0 only C4S and C4,6S were able to promote prolegumain activation, while CS-derived decasaccharides, C6S, heparin and HS lost their effect at this pH.
authors.affiliation: School of Pharmacy, University of Oslo, Norway.
authors.forename: Lise
authors.initials: L
authors.lastname: Berven
authors.forename: Harald Thidemann
authors.initials: HT
authors.lastname: Johansen
authors.forename: Rigmor
authors.initials: R
authors.lastname: Solberg
authors.forename: Svein Olav
authors.initials: SO
authors.lastname: Kolset
authors.forename: Anne Berit C
authors.initials: AB
authors.lastname: Samuelsen
mesh_terms: D055332:Cystatin M / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008970:Molecular Weight; D009994:Osmolar Concentration; D013997:Time Factors; D000099240:Asparaginyl Endopeptidase
chemical_list: D055332:Cystatin M; D003546:Cysteine Endopeptidases; D004792:Enzyme Precursors; D006025:Glycosaminoglycans; D000099240:Asparaginyl Endopeptidase