title: Nanoscale enzyme inhibitors: fullerenes inhibit carbonic anhydrase by occluding the active site entrance.
abstract: We investigated a series of derivatized fullerenes possessing alcohol, amine, and amino acid pendant groups as inhibitors of the zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1). We discovered that fullerenes bind CAs with submicromolar-low micromolar affinity, despite the fact that these compounds do not possess moieties normally associated with CA inhibitors such as the sulfonamides and their isosteres, or the coumarins. The 13 different mammalian CA isoforms showed a diverse inhibition profile with these compounds. By means of computational methods we assessed the inhibition mechanism as being due to occlusion of the active site entrance by means of the fullerene cage (possessing dimension of the same order of magnitude as the opening of the enzyme cavity, of 1nm). The pendant moieties to the fullerene cage make interactions with amino acid residues from the active site, among which His64, His94, His96, Val121, and Thr200. Fullerenes thus represent a totally new class of nanoscale CA inhibitors which may show applications for targeting physiologically relevant isoforms, such as the dominant CA II and the tumor-associated CA IX.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.forename: Nadjmeh
authors.initials: N
authors.lastname: Doostdar
authors.forename: T Amanda
authors.initials: TA
authors.lastname: Strom
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Barron
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D003198:Computer Simulation; D037741:Fullerenes / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D037741:Fullerenes; D020033:Protein Isoforms; D002256:Carbonic Anhydrases