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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

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1437-4315
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Volume 386, Issue 1

Issues

Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts

Monique Akoachere
  • Interdisciplinary Research Center, Heinrich-Buff-Ring 26-32, Justus-Liebig University, D-35392 Giessen, Germany
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/ Rimma Iozef
  • Interdisciplinary Research Center, Heinrich-Buff-Ring 26-32, Justus-Liebig University, D-35392 Giessen, Germany
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/ Stefan Rahlfs
  • Interdisciplinary Research Center, Heinrich-Buff-Ring 26-32, Justus-Liebig University, D-35392 Giessen, Germany
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/ Marcel Deponte
  • Interdisciplinary Research Center, Heinrich-Buff-Ring 26-32, Justus-Liebig University, D-35392 Giessen, Germany
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/ Bengt Mannervik
  • Department of Biochemistry, Uppsala University, Biomedical Center, Box 576, S-751 23 Uppsala, Sweden
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/ Donald J. Creighton
  • Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21228, USA
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/ Heiner Schirmer
  • Biochemistry Center, Im Neuenheimer Feld 504, Ruprecht-Karls University, D-69120 Heidelberg, Germany
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/ Katja Becker
  • Interdisciplinary Research Center, Heinrich-Buff-Ring 26-32, Justus-Liebig University, D-35392 Giessen, Germany
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Published Online: 2005-06-01 | DOI: https://doi.org/10.1515/BC.2005.006

Abstract

The glyoxalase system consisting of glyoxalase I (GloI) and glyoxalase II (GloII) constitutes a glutathione-dependent intracellular pathway converting toxic 2-oxoaldehydes, such as methylglyoxal, to the corresponding 2-hydroxyacids. Here we describe a complete glyoxalase system in the malarial parasite Plasmodium falciparum. The biochemical, kinetic and structural properties of cytosolic GloI (cGloI) and two GloIIs (cytosolic GloII named cGloII, and tGloII preceded by a targeting sequence) were directly compared with the respective isofunctional host enzymes. cGloI and cGloII exhibit lower K m values and higher catalytic efficiencies (k cat/K m) than the human counterparts, pointing to the importance of the system in malarial parasites. A Tyr185Phe mutant of cGloII shows a 2.5-fold increase in K m, proving the contribution of Tyr185 to substrate binding. Molecular models suggest very similar active sites/metal binding sites of parasite and host cell enzymes. However, a fourth protein, which has highest similarities to GloI, was found to be unique for malarial parasites; it is likely to act in the apicoplast, and has as yet undefined substrate specificity. Various S-(N-hydroxy-N-arylcarbamoyl)glutathiones tested as P. falciparum Glo inhibitors were active in the lower nanomolar range. The Glo system of Plasmodium will be further evaluated as a target for the development of antimalarial drugs.

Keywords: drug development; enzyme inhibition; glutathione derivatives; methylglyoxal; molecular modeling

About the article

Corresponding author


Received: October 11, 2004

Accepted: November 19, 2004

Published Online: 2005-06-01

Published in Print: 2005-01-01


Citation Information: Biological Chemistry, Volume 386, Issue 1, Pages 41–52, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2005.006.

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