NO donors inhibit Leishmania infantum cysteine proteinase activity

Luca Salvati, Marco Mattu, Marco Colasanti, Aldo Scalone, Giorgio Venturini, Luigi Gradoni, Paolo Ascenzi

Research output: Contribution to journalArticle

Abstract

Nitric oxide (NO) releasing drugs (e.g., glyceryl trinitrate) were successfully used in the treatment of cutaneous leishmaniasis in man. In the present study, the effect of NO donors on the catalytic activity of the cysteine proteinase from promastigotes of Leishmania infantum, an agent of Old World visceral and cutaneous leishmaniases, is reported. In particular, one equivalent of NO, released by the NO donors S-nitrosoglutathione, glyceryl trinitrate, (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide, 3-morpholinosydnonimine, S-nitrosoacetylpenicillamine and sodium nitroprusside, inhibited one equivalent of the parasite cysteine proteinase. As expected, NO-deprived compounds did not affect the catalytic activity of the parasite cysteine proteinase. Furthermore, the absorption spectrum of the (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide-treated inactive L. infantum enzyme displayed a maximum in the 330-350 nm wavelength range. The reducing agents dithiothreitol and L-ascorbic acid completely prevented parasite cysteine proteinase inhibition by NO, fully restored the catalytic activity, and reversed the NO-induced absorption spectrum of the inactive enzyme. Moreover, S-nitrosoacetylpenicillamine displayed a leishmanicidal effect, inhibiting the cysteine proteinase activity in vivo. As expected, the NO-deprived compound N-acetylpenicillamine did not affect significantly the parasite viability and the enzyme activity in vivo. These data suggest that the L. infantum cysteine proteinase undergoes NO-mediated S-nitrosylation, thereby representing a possible mechanism of antiparasitic host defence.

Original languageEnglish
Pages (from-to)357-366
Number of pages10
JournalBiochimica et Biophysica Acta (BBA)/Protein Structure and Molecular
Volume1545
Issue number1-2
DOIs
Publication statusPublished - Feb 9 2001

Keywords

  • Cysteine proteinase
  • Enzyme inhibition
  • Leishmania infantum
  • Leishmanicidal effect
  • Nitric oxide
  • Nitric oxide donor

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology
  • Structural Biology

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  • Cite this

    Salvati, L., Mattu, M., Colasanti, M., Scalone, A., Venturini, G., Gradoni, L., & Ascenzi, P. (2001). NO donors inhibit Leishmania infantum cysteine proteinase activity. Biochimica et Biophysica Acta (BBA)/Protein Structure and Molecular, 1545(1-2), 357-366. https://doi.org/10.1016/S0167-4838(00)00297-1