title: Selective inactivation of serine proteases by nonheme iron complexes.
abstract: Oxidative inactivation of the serine proteases trypsin and chymotrypsin by nonheme iron complexes is described. The nonheme ligands N4Py (1) and derivative 3CG-N4Py (2), which contains a pendant guanidinium group, were used as ligands for iron. Ferryl (Fe(IV)O) species derived from these ligands, [Fe(IV)(O)(N4Py)](2+) (7) and [Fe(IV)(O)(3CG-N4Py)](3+) (8), inactivate trypsin and chymotrypsin by the oxidation of amino acid side chains. Ferryl 8 is most effective with chymotrypsin (IC(50) value of 26 μM for 8 vs 119 μM for 7). IC(50) values of 71 and 54 μM were obtained for trypsin with 7 and 8, respectively. Amino acid analysis confirmed that residues cysteine, tyrosine, and tryptophan are oxidized under these conditions. Trypsin is inactivated preferentially over chymotrypsin under catalytic conditions, where the enzyme was pulsed with H(2)O(2) in the presence of ferrous complexes [Fe(II)(OH(2))(N4Py)](2+)(5) and [Fe(II)(Cl)(3CG-N4Py)](2+) (6). Control experiments support the action of a unique oxidant, other than ferryls or hydroxyl radicals, under these conditions, where tyrosine residues are targeted selectively.
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, USA.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Kodanko
mesh_terms: D000818:Animals; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D007501:Iron / Q000737:chemistry*; D008024:Ligands; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D013379:Substrate Specificity; D014357:Trypsin / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D009942:Organometallic Compounds; D014361:Trypsin Inhibitors; D007501:Iron; D002918:Chymotrypsin; D014357:Trypsin