1T2F

Human B lactate dehydrogenase complexed with NAD+ and 4-hydroxy-1,2,5-oxadiazole-3-carboxylic acid

Summary for 1T2F

• Entry DOI: 10.2210/pdb1t2f/pdb
• Related: 1LDG 1T24 1T25 1T26 1T2C 1T2D 1T2E
• Descriptor: L-lactate dehydrogenase B chain, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 4-HYDROXY-1,2,5-OXADIAZOLE-3-CARBOXYLIC ACID, ... (4 entities in total)
• Functional Keywords: protein-ligand complex, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07195
• Total number of polymer chains: 4
• Total formula weight: 149495.11

Authors

Cameron, A.,Read, J.,Tranter, R.,Winter, V.J.,Sessions, R.B.,Brady, R.L.,Vivas, L.,Easton, A.,Kendrick, H.,Croft, S.L.,Barros, D.,Lavandera, J.L.,Martin, J.J.,Risco, F.,Garcia-Ochoa, S.,Gamo, F.J.,Sanz, L.,Leon, L.,Ruiz, J.R.,Gabarro, R.,Mallo, A.,De Las Heras, F.G. (deposition date: 2004-04-21, release date: 2004-05-11, Last modification date: 2023-08-23)

Primary citation

Cameron, A.,Read, J.,Tranter, R.,Winter, V.J.,Sessions, R.B.,Brady, R.L.,Vivas, L.,Easton, A.,Kendrick, H.,Croft, S.L.,Barros, D.,Lavandera, J.L.,Martin, J.J.,Risco, F.,Garcia-Ochoa, S.,Gamo, F.J.,Sanz, L.,Leon, L.,Ruiz, J.R.,Gabarro, R.,Mallo, A.,De Las Heras, F.G.
Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity.
J.Biol.Chem., 279:31429-31439, 2004

PubMed 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.

PubMed: 15117937
DOI: 10.1074/jbc.M402433200

Experimental method

X-RAY DIFFRACTION (3 Å)