PDBsum entry 1t2c

Oxidoreductase

PDB id: 1t2c

Contents

Protein chain

315 a.a. *

Ligands

NAI

GOL

Waters ×225

* Residue conservation analysis

PDB id:

1t2c

Name:

Oxidoreductase

Title:

Plasmodium falciparum lactate dehydrogenase complexed with nadh

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)

Resolution:

2.01Å R-factor: 0.145 R-free: 0.184

Authors:

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.Garcia-Ochoa,F.J.Gamo,L.Sanz,L.Leon,J.R.Ruiz,R.Gabarro, 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

Date:

21-Apr-04 Release date: 11-May-04

Protein chain

Q27743  (LDH_PLAFD) -  L-lactate dehydrogenase from Plasmodium falciparum (isolate CDC / Honduras)

Seq: 316 a.a.

Struc: 315 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.27 - L-lactate dehydrogenase.
• Reaction: (S)-lactate + NAD⁺ = pyruvate + NADH + H⁺

(S)-lactate (Bound ligand (Het Group name = GOL) matches with 71.43% similarity) + NAD(+) (Bound ligand (Het Group name = NAI) corresponds exactly) = pyruvate + NADH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

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.

ABSTRACT

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.