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

被引:44
作者
Akoachere, M
Iozef, R
Rahlfs, S
Deponte, M
Mannervik, B
Creighton, DJ
Schirmer, H
Becker, K
机构
[1] Univ Giessen, Interdisciplinary Res Ctr, D-35392 Giessen, Germany
[2] Uppsala Univ, Biomed Ctr, Dept Biochem, S-75123 Uppsala, Sweden
[3] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Catonsville, MD 21228 USA
[4] Heidelberg Univ, Biochem Ctr, D-69120 Heidelberg, Germany
关键词
drug development; enzyme inhibition; glutathione derivatives; methylglyoxal; molecular modeling;
D O I
10.1515/BC.2005.006
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Km 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 Km, 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.
引用
收藏
页码:41 / 52
页数:12
相关论文
共 48 条
[1]   Different activity of glyoxalase system enzymes in specimens of Sparus auratus exposed to sublethal copper concentrations [J].
Antognelli, C ;
Romani, R ;
Baldracchini, F ;
De Santis, A ;
Andreani, G ;
Talesa, V .
CHEMICO-BIOLOGICAL INTERACTIONS, 2003, 142 (03) :297-305
[2]   Mechanistic diversity in a metalloenzyme superfamily [J].
Armstrong, RN .
BIOCHEMISTRY, 2000, 39 (45) :13625-13632
[3]   PROBING THE ACTIVE-SITE OF GLYOXALASE I FROM HUMAN-ERYTHROCYTES BY USE OF THE STRONG REVERSIBLE INHIBITOR S-P-BROMOBENZYLGLUTATHIONE AND METAL SUBSTITUTIONS [J].
ARONSSON, AC ;
SELLIN, S ;
TIBBELIN, G ;
MANNERVIK, B .
BIOCHEMICAL JOURNAL, 1981, 197 (01) :67-75
[4]   Passive cigarette smoke and renal glyoxalase system [J].
Biswas, S ;
Gairola, CG ;
Das, SK .
MOLECULAR AND CELLULAR BIOCHEMISTRY, 2002, 229 (1-2) :153-156
[5]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[6]   Crystal structure of human glyoxalase II and its complex with a glutathione thiolester substrate analogue [J].
Cameron, AD ;
Ridderström, M ;
Olin, B ;
Mannervik, B .
STRUCTURE, 1999, 7 (09) :1067-1078
[7]   Reaction mechanism of glyoxalase I explored by an X-ray crystallographic analysis of the human enzyme in complex with a transition state analogue [J].
Cameron, AD ;
Ridderström, M ;
Olin, B ;
Kavarana, MJ ;
Creighton, DJ ;
Mannervik, B .
BIOCHEMISTRY, 1999, 38 (41) :13480-13490
[8]   Identification of glyoxalase I sequences in Brassica oleracea and Sporobolus stapfianus:: Evidence for gene duplication events [J].
Clugston, SL ;
Daub, E ;
Honek, JF .
JOURNAL OF MOLECULAR EVOLUTION, 1998, 47 (02) :230-234
[9]   Identification of sequences encoding the detoxification metalloisomerase glyoxalase I in microbial genomes from several pathogenic organisms [J].
Clugston, SL ;
Honek, JF .
JOURNAL OF MOLECULAR EVOLUTION, 2000, 50 (05) :491-495
[10]   The human hydroxyacylglutathione hydrolase (HAGH) gene encodes both cytosolic and mitochondrial forms of glyoxalase II [J].
Cordell, PA ;
Futers, TS ;
Grant, PJ ;
Pease, RJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (27) :28653-28661