PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasite Plasmodium falciparum

Keizo Yuasa, Fumika Mi-Ichi, Tamaki Kobayashi, Masaya Yamanouchi, Jun Kotera, Kiyoshi Kita, Kenji Omori

Research output: Contribution to journalArticle

Abstract

This is the first report of molecular characterization of a novel cyclic nucleotide PDE (phosphodiesterase), isolated from the human malaria parasite Plasmodium falciparum and designated PfPDE1. PfPDE1 cDNA encodes an 884-amino-acid protein, including six putative transmembrane domains in the N-terminus followed by a catalytic domain. The PfPDE1 gene is a single-copy gene consisting of two exons and a 170 bp intron. PfPDE1 transcripts were abundant in the ring form of the asexual blood stages of the parasite. The C-terminal catalytic domain of PfPDE1, produced in Escherichia coli, specifically hydrolysed cGMP with a Km value of 0.65 μM. Among the PDE inhibitors tested, a PDE5 inhibitor, zaprinast, was the most effective, having an IC50 value of 3.8 μM. The non-specific PDE inhibitors IBMX (3-isobutyl-1-methylxanthine), theophylline and the antimalarial chloroquine had IC50 values of over 100 μM. Membrane fractions prepared from P. falciparum at mixed asexual blood stages showed potent cGMP hydrolytic activity compared with cytosolic fractions. This hydrolytic activity was sensitive to zaprinast with an IC50 value of 4.1 μM, but insensitive to IBMX and theophylline. Furthermore, an in vitro antimalarial activity assay demonstrated that zaprinast inhibited the growth of the asexual blood parasites, with an ED50 value of 35 μM. The impact of cyclic nucleotide signalling on the cellular development of this parasite has previously been discussed. Thus this enzyme is suggested to be a novel potential target for the treatment of the disease malaria.

Original languageEnglish (US)
Pages (from-to)221-229
Number of pages9
JournalBiochemical Journal
Volume392
Issue number1
DOIs
StatePublished - Nov 15 2005
Externally publishedYes

Fingerprint

Falciparum Malaria
Phosphoric Diester Hydrolases
Parasites
Inhibitory Concentration 50
1-Methyl-3-isobutylxanthine
Blood
Phosphodiesterase Inhibitors
Cyclic Nucleotides
Antimalarials
Theophylline
Catalytic Domain
Genes
Phosphodiesterase 5 Inhibitors
Chloroquine
Plasmodium falciparum
Introns
Escherichia coli
Malaria
Exons
Assays

Keywords

  • Antimalarial drug
  • cGMP
  • Malaria parasite
  • Phosphodiesterase (PDE)
  • Plasmodium
  • Zaprinast

ASJC Scopus subject areas

  • Biochemistry

Cite this

PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasite Plasmodium falciparum. / Yuasa, Keizo; Mi-Ichi, Fumika; Kobayashi, Tamaki; Yamanouchi, Masaya; Kotera, Jun; Kita, Kiyoshi; Omori, Kenji.

In: Biochemical Journal, Vol. 392, No. 1, 15.11.2005, p. 221-229.

Research output: Contribution to journalArticle

Yuasa, Keizo ; Mi-Ichi, Fumika ; Kobayashi, Tamaki ; Yamanouchi, Masaya ; Kotera, Jun ; Kita, Kiyoshi ; Omori, Kenji. / PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasite Plasmodium falciparum. In: Biochemical Journal. 2005 ; Vol. 392, No. 1. pp. 221-229.
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