Discovery of a new family of carbonic anhydrases in the malaria pathogen Plasmodium falciparum--the η-carbonic anhydrases

Sonia Del Prete; Daniela Vullo; Gillian M Fisher; Katherine T Andrews; Sally-Ann Poulsen; Clemente Capasso; Claudiu T Supuran

doi:10.1016/j.bmcl.2014.08.015

Discovery of a new family of carbonic anhydrases in the malaria pathogen Plasmodium falciparum--the η-carbonic anhydrases

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4389-4396. doi: 10.1016/j.bmcl.2014.08.015. Epub 2014 Aug 12.

Authors

Sonia Del Prete¹, Daniela Vullo², Gillian M Fisher³, Katherine T Andrews³, Sally-Ann Poulsen³, Clemente Capasso⁴, Claudiu T Supuran⁵

Affiliations

¹ Istituto di Bioscienze e Biorisorse (IBBR)-CNR, via P. Castellino 111, 80131 Napoli, Italy.
² Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
³ Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
⁴ Istituto di Bioscienze e Biorisorse (IBBR)-CNR, via P. Castellino 111, 80131 Napoli, Italy. Electronic address: c.capasso@ibp.cnr.it.
⁵ Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 25168745
DOI: 10.1016/j.bmcl.2014.08.015

Abstract

The genome of the protozoan parasite Plasmodium falciparum, the causative agent of the most lethal type of human malaria, contains a single gene annotated as encoding a carbonic anhydrase (CAs, EC 4.2.1.1) thought to belong to the α-class, PfCA. Here we demonstrate the kinetic properties of PfCA for the CO2 hydration reaction, as well as an inhibition study of this enzyme with inorganic and complex anions and other molecules known to interact with zinc proteins, including sulfamide, sulfamic acid, and phenylboronic/arsonic acids, detecting several low micromolar inhibitors. A closer examination of the sequence of this and the CAs from other Plasmodium spp., as well as a phylogenetic analysis, revealed that these protozoa encode for a yet undisclosed, new genetic family of CAs termed the η-CA class. The main features of the η-CAs are described in this report.

Keywords: Anion; Carbonic anhydrase; Inhibitor; Plasmodium falciparum; η-CA-class enzyme.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Sequence Data
Molecular Structure
Organometallic Compounds / chemical synthesis
Organometallic Compounds / chemistry
Organometallic Compounds / pharmacology*
Phylogeny
Plasmodium falciparum / enzymology*
Plasmodium falciparum / metabolism
Sequence Alignment
Structure-Activity Relationship
Zinc / chemistry

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Organometallic Compounds
Carbonic Anhydrases
Zinc