PDBsum entry 1t25

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Oxidoreductase PDB id
Jmol PyMol
Protein chain
315 a.a. *
Waters ×233
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Plasmodium falciparum lactate dehydrogenase complexed with n hydroxyisoxazole-4-carboxylic acid
Structure: L-lactate dehydrogenase. Chain: a. Synonym: ldh-p. Engineered: yes
Source: Plasmodium falciparum. Malaria parasite p. Falciparum. Organism_taxid: 5833. Gene: ldh. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PDB file)
1.90Å     R-factor:   0.154     R-free:   0.186
Authors: A.Cameron,J.Read,R.Tranter,V.J.Winter,R.B.Sessions,R.L.Brady A.Easton,H.Kendrick,S.L.Croft,D.Barros,J.L.Lavandera,J.J.Ma F.Risco,S.Garcia-Ochoa,F.J.Gamo,L.Sanz,L.Leon,J.R.Ruiz,R.Ga A.Mallo,F.G.De Las Heras
Key ref:
A.Cameron et al. (2004). Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity. J Biol Chem, 279, 31429-31439. PubMed id: 15117937 DOI: 10.1074/jbc.M402433200
20-Apr-04     Release date:   11-May-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q27743  (LDH_PLAFD) -  L-lactate dehydrogenase
316 a.a.
315 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - L-lactate dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (S)-lactate + NAD+ = pyruvate + NADH
Bound ligand (Het Group name = GAG)
matches with 50.00% similarity
Bound ligand (Het Group name = NAI)
corresponds exactly
= pyruvate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   3 terms 
  Biochemical function     catalytic activity     4 terms  


DOI no: 10.1074/jbc.M402433200 J Biol Chem 279:31429-31439 (2004)
PubMed id: 15117937  
Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity.
A.Cameron, J.Read, R.Tranter, V.J.Winter, R.B.Sessions, R.L.Brady, L.Vivas, A.Easton, H.Kendrick, S.L.Croft, D.Barros, J.L.Lavandera, J.J.Martin, F.Risco, S.García-Ochoa, F.J.Gamo, L.Sanz, L.Leon, J.R.Ruiz, R.Gabarró, A.Mallo, F.Gómez de las Heras.
Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.
  Selected figure(s)  
Figure 1.
FIG. 1. Azole-based inhibitors of pfLDH. Schematic showing chemical structures of OXD1, IOA1, and TDA1 parent compounds.
Figure 3.
FIG. 3. Azole-based inhibitors at the active site of pfLDH. Figure shows the active site region in the crystal structures of pfLDH co-crystallized with NAD^+ and OXD1 (green), NADH and IOA1 (blue), and NADH with TDA1 (magenta).
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 31429-31439) copyright 2004.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18298458 N.K.Sahu, S.Sahu, and D.V.Kohli (2008).
Novel molecular targets for antimalarial drug development.
  Chem Biol Drug Des, 71, 287-297.  
17459101 D.K.Shoemark, M.J.Cliff, R.B.Sessions, and A.R.Clarke (2007).
Enzymatic properties of the lactate dehydrogenase enzyme from Plasmodium falciparum.
  FEBS J, 274, 2738-2748.  
17710128 T.Stoeck, J.Kasper, J.Bunge, C.Leslin, V.Ilyin, and S.Epstein (2007).
Protistan diversity in the arctic: a case of paleoclimate shaping modern biodiversity?
  PLoS ONE, 2, e728.  
16138106 R.Pink, A.Hudson, M.A.Mouriès, and M.Bendig (2005).
Opportunities and challenges in antiparasitic drug discovery.
  Nat Rev Drug Discov, 4, 727-740.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.