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.

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