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CLONING, CHARACTERIZATION, AND INHIBITION STUDIES OF A β‑CARBONIC ANHYDRASE FROM LEISHMANIA DONOVANI CHAGASI, THE PROTOZOAN PARASITE RESPONSIBLE FOR LEISHMANIASIS
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Affilliation
University of Tampere. Institute of Biomedical Technology and BioMediTech. Tempere, Finland / University of Tampere and Tampere University Hospital. School of Medicine. Tempere, Finland.
Universidade Federal do Rio de Janeiro. Centro Biotecnológico - BIOINOVAR: Bioenergia, Biocatálise e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Centro Biotecnológico - BIOINOVAR: Bioenergia, Biocatálise e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Estrutural. Rio de Janeiro, RJ, Brasil.
University of Tampere. Institute of Biomedical Technology and BioMediTech. Tempere, Finland / University of Tampere and Tampere University Hospital. School of Medicine. Tempere, Finland.
University of Tampere. Institute of Biomedical Technology and BioMediTech. Tempere, Finland / University of Tampere and Tampere University Hospital. School of Medicine. Tempere, Finland.
Università degli Studi di Firenze. Dipartimento di Chimica. Laboratorio di Chimica Bioinorganica. Firenze, Italy.
University of Tampere. Institute of Biomedical Technology and BioMediTech. Tempere, Finland / University of Tampere and Tampere University Hospital. School of Medicine. Tempere, Finland / Fimlab Laboratories Ltd, 33101 Tampere, Finland .
Istituto di Biochimica delle Proteine−CNR. Napoli, Italy.
Università degli Studi di Firenze. Dipartimento di Chimica. Laboratorio di Chimica Bioinorganica. Firenze, Italy / Università degli Studi di Firenze. Neurofarba Dipartimento, Sezione di Scienza Farmaceutiche e Nutraceutiche. Firenze, Italy.
Universidade Federal do Rio de Janeiro. Centro Biotecnológico - BIOINOVAR: Bioenergia, Biocatálise e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Centro Biotecnológico - BIOINOVAR: Bioenergia, Biocatálise e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Estrutural. Rio de Janeiro, RJ, Brasil.
University of Tampere. Institute of Biomedical Technology and BioMediTech. Tempere, Finland / University of Tampere and Tampere University Hospital. School of Medicine. Tempere, Finland.
University of Tampere. Institute of Biomedical Technology and BioMediTech. Tempere, Finland / University of Tampere and Tampere University Hospital. School of Medicine. Tempere, Finland.
Università degli Studi di Firenze. Dipartimento di Chimica. Laboratorio di Chimica Bioinorganica. Firenze, Italy.
University of Tampere. Institute of Biomedical Technology and BioMediTech. Tempere, Finland / University of Tampere and Tampere University Hospital. School of Medicine. Tempere, Finland / Fimlab Laboratories Ltd, 33101 Tampere, Finland .
Istituto di Biochimica delle Proteine−CNR. Napoli, Italy.
Università degli Studi di Firenze. Dipartimento di Chimica. Laboratorio di Chimica Bioinorganica. Firenze, Italy / Università degli Studi di Firenze. Neurofarba Dipartimento, Sezione di Scienza Farmaceutiche e Nutraceutiche. Firenze, Italy.
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 × 105 s−1 and kcat/KM
of 5.9 × 107 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.
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