1T2E

Plasmodium falciparum lactate dehydrogenase S245A, A327P mutant complexed with NADH and oxamate

1T2E の概要

• エントリーDOI: 10.2210/pdb1t2e/pdb
• 関連するPDBエントリー: 1LDG 1T24 1T25 1T26 1T2C 1T2D 1T2F
• 分子名称: L-lactate dehydrogenase, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, OXAMIC ACID, ... (5 entities in total)
• 機能のキーワード: ternary complex, oxidoreductase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35834.21

構造登録者

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. (登録日: 2004-04-21, 公開日: 2004-05-11, 最終更新日: 2023-08-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.85 Å)