title: Cloning, characterization, and inhibition studies of a β-carbonic anhydrase from Leishmania donovani chagasi, the protozoan parasite responsible for leishmaniasis.
abstract: Leishmaniasis is an infection provoked by protozoans belonging to the genus Leishmania. Among the many species and subsepecies of such protozoa, Leishmania donovani chagasi causes visceral leishmaniasis. A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized from this organism, denominated here LdcCA. LdcCA possesses effective catalytic activity for the CO2 hydration reaction, with kcat of 9.35 × 10(5) s(-1) and kcat/KM of 5.9 × 10(7) M(-1) s(-1). A large number of aromatic/heterocyclic sulfonamides and 5-mercapto-1,3,4-thiadiazoles were investigated as LdcCA inhibitors. The sulfonamides were medium potency to weak inhibitors (KI values of 50.2 nM-9.25 μM), whereas some heterocyclic thiols inhibited the enzyme with KIs in the range of 13.4-152 nM. Some of the investigated thiols efficiently inhibited the in vivo growth of Leishmania chagasi and Leishmania amazonensis promastigotes, by impairing the flagellar pocket and movement of the parasites and causing their death. The β-CA from Leishmania spp. is proposed here as a new antileishmanial drug target.
authors: Institute of Biomedical Technology and BioMediTech, University of Tampere , 33520 Tampere, Finland.
authors: Leo
authors: L
authors: Syrjänen
authors: Alane Beatriz
authors: AB
authors: Vermelho
authors: Igor de Almeida
authors: Ide A
authors: Rodrigues
authors: Suzana
authors: S
authors: Corte-Real
authors: Terhi
authors: T
authors: Salonen
authors: Peiwen
authors: P
authors: Pan
authors: Daniela
authors: D
authors: Vullo
authors: Seppo
authors: S
authors: Parkkila
authors: Clemente
authors: C
authors: Capasso
authors: Claudiu T
authors: CT
authors: Supuran
mesh_terms: D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D055162:Biocatalysis; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular; D018314:Leishmania infantum / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D007896:Leishmaniasis / Q000469:parasitology*; D008969:Molecular Sequence Data
chemical_list: D000981:Antiprotozoal Agents; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases