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Characterization of...
Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts.
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Akoachere, Monique (författare)
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Iozef, Rimma (författare)
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Rahlfs, Stefan (författare)
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Deponte, Marcel (författare)
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- Mannervik, Bengt (författare)
- Uppsala universitet,Institutionen för naturvetenskaplig biokemi,Biokemi
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Creighton, Donald J (författare)
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Schirmer, Heiner (författare)
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Becker, Katja (författare)
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(creator_code:org_t)
- 2005
- 2005
- Engelska.
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Ingår i: Biol Chem. - 1431-6730. ; 386:1, s. 41-52
- Relaterad länk:
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http://www.ncbi.nlm....
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Nyckelord
- Amino Acid Sequence
- Animals
- Binding Sites
- Comparative Study
- Gene Expression Regulation
- Glutathione/*pharmacology
- Humans
- Kinetics
- Lactoylglutathione Lyase/antagonists & inhibitors/chemistry/genetics
- Metals/chemistry
- Models; Molecular
- Molecular Sequence Data
- Plasmodium falciparum/*enzymology
- Protein Conformation
- Protein Structure; Tertiary
- Recombinant Proteins/chemistry/genetics
- Research Support; Non-U.S. Gov't
- Sequence Alignment
- Thiolester Hydrolases/antagonists & inhibitors/chemistry/genetics
- Biochemistry
- Biokemi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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