Structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum.

The malaria parasite Plasmodium falciparum is responsible for about two million deaths annually, making it important to obtain information about enzymes from this organism that represent potential drug targets. The gene for P. falciparum glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH) has been cloned and the protein expressed as a hexahistidine-tagged recombinant protein in Escherichia coli. The recombinant protein has been crystallized and its three-dimensional structure determined. One molecule of the cofactor NAD+ is bound to each of the four subunits in the tetrameric enzyme. The major structural feature distinguishing human GAPDH from PfGAPDH is the insertion of a dipeptide (-KG-) in the so-called S loop. This insert, together with other characteristic single-amino-acid substitutions, alters the chemical environment of the groove that encompasses the R dyad and that links adjacent cofactor-binding sites and may be responsible for the selective inhibition of the enzyme by ferriprotoporphyrin IX.

[1]  Leann Tilley,et al.  Identification and Characterization of Heme-interacting Proteins in the Malaria Parasite, Plasmodium falciparum* , 2003, Journal of Biological Chemistry.

[2]  Y. Kai,et al.  Phosphoenolpyruvate carboxylase: three-dimensional structure and molecular mechanisms. , 2003, Archives of biochemistry and biophysics.

[3]  N. Nagradova.  Study of the Properties of Phosphorylating D-Glyceraldehyde-3-phosphate Dehydrogenase , 2001, Biochemistry (Moscow).

[4]  I. Kuntz,et al.  Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design. , 2001, Journal of medicinal chemistry.

[5]  M. Gelb,et al.  Conformational changes in Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase induced by designed inhibitors. , 2001, Journal of molecular biology.

[6]  W. Hengstenberg,et al.  Engineering the active center of the 6-phospho-beta-galactosidase from Lactococcus lactis. , 2000, Protein engineering.

[7]  U. Certa,et al.  Identification and recombinant expression of glyceraldehyde-3-phosphate dehydrogenase of Plasmodium falciparum. , 2000, Gene.

[8]  M A Sirover,et al.  New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase. , 1999, Biochimica et biophysica acta.

[9]  P. Michels,et al.  Trypanosoma cruzi glycosomal glyceraldehyde‐3‐phosphate dehydrogenase: structure, catalytic mechanism and targeted inhibitor design , 1998, FEBS letters.

[10]  P. Fürst,et al.  Glyceraldehyde-3-phosphate Dehydrogenase, the Putative Target of the Antiapoptotic Compounds CGP 3466 andR-(−)-Deprenyl* , 1998, The Journal of Biological Chemistry.

[11]  A. Vagin,et al.  MOLREP: an Automated Program for Molecular Replacement , 1997 .

[12]  R. Fletterick,et al.  Role of the Active Site Gate of Glycogen Phosphorylase in Allosteric Inhibition and Substrate Binding* , 1996, The Journal of Biological Chemistry.

[13]  C L Verlinde,et al.  Crystal structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Leishmania mexicana: implications for structure-based drug design and a new position for the inorganic phosphate binding site. , 1995, Biochemistry.

[14]  C. Sander,et al.  Dali: a network tool for protein structure comparison. , 1995, Trends in biochemical sciences.

[15]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[16]  H. Ginsburg,et al.  Hexose-monophosphate shunt activity in intact Plasmodium falciparum-infected erythrocytes and in free parasites. , 1994, Molecular and biochemical parasitology.

[17]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[18]  D. M. Ryan,et al.  Rational design of potent sialidase-based inhibitors of influenza virus replication , 1993, Nature.

[19]  I. Kuntz,et al.  Automated docking with grid‐based energy evaluation , 1992 .

[20]  D. Eisenberg,et al.  Assessment of protein models with three-dimensional profiles , 1992, Nature.

[21]  A. Brunger.  Free R value: a novel statistical quantity for assessing the accuracy of crystal structures. , 1992 .

[22]  C. Corbier,et al.  Role of the histidine 176 residue in glyceraldehyde-3-phosphate dehydrogenase as probed by site-directed mutagenesis. , 1989, Biochemistry.

[23]  R. Rosa,et al.  The enzymes of the glycolytic pathway in erythrocytes infected with Plasmodium falciparum malaria parasites. , 1988, Blood.

[24]  P C Moody,et al.  Structure of holo-glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus at 1.8 A resolution. , 1987, Journal of molecular biology.

[25]  M. L. Connolly.  Solvent-accessible surfaces of proteins and nucleic acids. , 1983, Science.

[26]  T. A. Jones,et al.  A graphics model building and refinement system for macromolecules , 1978 .

[27]  J. Walker,et al.  Sequence and structure of D-glyceraldehyde 3-phosphate dehydrogenase from Bacillus stearothermophilus , 1977, Nature.

[28]  M G Rossmann,et al.  Studies of asymmetry in the three-dimensional structure of lobster D-glyceraldehyde-3-phosphate dehydrogenase. , 1977, The Journal of biological chemistry.

[29]  L. Polgár.  Ion-pair formation as a source of enhanced reactivity of the essential thiol group of D-glyceraldehyde-3-phosphate dehydrogenase. , 1975, European journal of biochemistry.

[30]  D. Trentham,et al.  Kinetic studies on oxidized nicotinamide--adenine dinucleotide-facilitated reactions of D-glyceraldehyde 3-phosphate dehydrogenase. , 1974, The Biochemical journal.

[31]  M. Rossmann,et al.  Structure determination of crystalline lobster D-glyceraldehyde-3-phosphate dehydrogenase. , 1974, Journal of molecular biology.

[32]  D. Trentham.  Rate-determining processes and the number of simultaneously active sties of D-glyceraldehyde 3-phosphate dehydrogenase. , 1971, The Biochemical journal.

[33]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[34]  D. Eisenberg,et al.  VERIFY3D: assessment of protein models with three-dimensional profiles. , 1997, Methods in enzymology.

[35]  E A Merritt,et al.  Raster3D: photorealistic molecular graphics. , 1997, Methods in enzymology.

[36]  E Roth,et al.  Plasmodium falciparum carbohydrate metabolism: a connection between host cell and parasite. , 1990, Blood cells.