title: The β-carbonic anhydrase from the malaria mosquito Anopheles gambiae is highly inhibited by sulfonamides.
abstract: A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned, purified and characterized from Anopheles gambiae, the mosquito species mainly involved in the transmission of malaria. The new enzyme, AgaCA, showed a significant catalytic activity for the physiologic reaction, CO2 hydration to bicarbonate and protons, with a kcat of 7.2×10(5)s(-1) and kcat/Km of 5.6×10(7)M(-1)s(-1), being thus similar to parasite β-CAs which were discovered earlier as drug targets for antifungal or anti-protozoan agents. An inhibition study of AgaCA with a panel of aromatic, aliphatic and heterocyclic sulfonamides allowed us to identify several low nanomolar inhibitors of the enzyme. Benzolamide and aminobenzolamide showed inhibition constants of 6.8-9.8nM, whereas a structurally related aromatic derivative, 4-(2-hydroxymethyl-4-nitrophenyl-sulfonamidoethyl)-benzenesulfonamide was the strongest inhibitor with a KI of 6.1nM. As β-CAs are not present in mammals, including humans, finding effective and selective A. gambiae CA inhibitors may lead to alternative procedures for controlling malaria by impairing the growth of its transmission vector, the mosquito.
authors.affiliation: School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Leo
authors.initials: L
authors.lastname: Syrjänen
authors.affiliation: School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Kuuslahti
authors.affiliation: School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland; Department of Information Technology, University of Turku, Turku, Finland; Department of Information Technology, University of Turku, Turku, Finland.
authors.forename: Martti
authors.initials: M
authors.lastname: Tolvanen
authors.affiliation: Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd, Tampere, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.affiliation: Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy; Università degli Studi di Firenze, Neurofarba Dipartment, Sezione di Scienza Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000852:Anopheles / Q000737:chemistry* / Q000145:classification / Q000201:enzymology; D016367:Baculoviridae / Q000235:genetics; D001639:Bicarbonates / Q000737:chemistry; D002245:Carbon Dioxide / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D019476:Insect Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry*; D007700:Kinetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D011522:Protons; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D061987:Sf9 Cells; D018411:Spodoptera; D013424:Sulfanilamides / Q000737:chemistry*
chemical_list: D001639:Bicarbonates; D002257:Carbonic Anhydrase Inhibitors; D019476:Insect Proteins; D007306:Insecticides; D011522:Protons; D011994:Recombinant Proteins; D013424:Sulfanilamides; D002245:Carbon Dioxide; D002256:Carbonic Anhydrases
keywords: Anopheles gambiae; Carbonic anhydrase; Malaria; Sulfonamide; β-Class enzyme