title: The zinc coordination pattern in the η-carbonic anhydrase from Plasmodium falciparum is different from all other carbonic anhydrase genetic families.
abstract: In this Letter we reinvestigate the sequence analysis and report a homology model of the carbonic anhydrase (CA, EC 4.2.1.1) from the protozoan parasite Plasmodium falciparum, recently reported by us to belong to a new genetic family, the η-CA class. Our findings show that the metal ion coordination pattern of this CA is unique among all five other genetic families encoding for such enzymes, comprising two His and one Gln residues, in addition to the water molecule/hydroxide ion acting as nucleophile in the catalytic cycle. Although the η- and α-CAs present the same 3D fold, strongly suggesting the first ones to be evolutionary derived from the last, there are significant differences between the two families to allow optimism for the drug design of selective inhibitors for the parasite over the host enzymes. The preliminary studies reported here are relevant for drug design campaigns of anti-plasmodium CA inhibitors but further work by X-ray crystallography should validate the proposed model.
authors.affiliation: Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
authors.affiliation: Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Fiore
authors.affiliation: Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.affiliation: Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, and Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000235:genetics* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000201:enzymology*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D015032:Zinc
keywords: Carbonic anhydrase; Homology modeling; Plasmodium falciparum; Zinc coordination; α-Class; η-Class