title: Ibuprofen and warfarin modulate allosterically ferrous human serum heme-albumin nitrosylation.
abstract: Ferrous human serum heme-albumin (HSA-heme-Fe(II)) displays globin-like properties. Here, the effect of ibuprofen and warfarin on kinetics of HSA-heme-Fe(II) nitrosylation is reported. Values of the second-order rate constant for HSA-heme-Fe(II) nitrosylation (k(on)) decrease from 6.3 × 10(6)M(-1)s(-1) in the absence of drugs, to 4.1 × 10(5)M(-1)s(-1) and 4.8 × 10(5)M(-1)s(-1), in the presence of saturating amounts of ibuprofen and warfarin, respectively, at pH 7.0 and 20.0°C. From the dependence of k(on) on the drug concentration, values of the dissociation equilibrium constant for ibuprofen and warfarin binding to HSA-heme-Fe(II) (i.e., K=3.2 × 10(-3)M and 2.6 × 10(-4)M, respectively) were determined. The observed allosteric effects could indeed reflect ibuprofen and warfarin binding to the regulatory fatty acid binding site FA2, which brings about an alteration of heme coordination, slowing down HSA-heme-Fe(II) nitrosylation. Present data highlight the allosteric modulation of HSA-heme-Fe(II) reactivity by heterotropic effectors.
authors: Department of Biology and Interdepartmental Laboratory for Electron Microscopy, University Roma Tre, Via della Vasca Navale 79, I-00146 Roma, Italy. ascenzi@uniroma3.it
authors: Paolo
authors: P
authors: Ascenzi
authors: Yu
authors: Y
authors: Cao
authors: Grazia R
authors: GR
authors: Tundo
authors: Massimo
authors: M
authors: Coletta
authors: Gabriella
authors: G
authors: Fanali
authors: Mauro
authors: M
authors: Fasano
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007052:Ibuprofen / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D011487:Protein Conformation; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D014859:Warfarin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012709:Serum Albumin; D009569:Nitric Oxide; D006418:Heme; D014859:Warfarin; D007052:Ibuprofen