Journal article
Substrate and cofactor specificity and selective inhibition of lactate dehydrogenase from the malarial parasite P. falciparum
Molecular and biochemical parasitology, Vol.90(1), pp.235-246
1997
DOI: 10.1016/S0166-6851(97)00140-0
PMID: 9497046
Abstract
Lactate dehydrogenase from the malarial parasite
Plasmodium falciparum has many amino acid residues that are unique compared to any other known lactate dehydrogenase. This includes residues that define the substrate and cofactor binding sites. Nevertheless, parasite lactate dehydrogenase exhibits high specificity for pyruvic acid, even more restricted than the specificity of human lactate dehydrogenases M
4 and H
4. Parasite lactate dehydrogenase exhibits high catalytic efficiency in the reduction of pyruvate,
k
cat/
K
m=9.0×10
8 min
−1 M
−1. Parasite lactate dehydrogenase also exhibits similar cofactor specificity to the human isoforms in the oxidation of
l-lactate with NAD
+ and with a series of NAD
+ analogs, suggesting a similar cofactor binding environment in spite of the numerous amino acid differences. Parasite lactate dehydrogenase exhibits an enhanced
k
cat with the analog 3-acetylpyridine adenine dinucleotide (APAD
+) whereas the human isoforms exhibit a lower
k
cat. This differential response to APAD
+ provides the kinetic basis for the enzyme-based detection of malarial parasites. A series of inhibitors structurally related to the natural product gossypol were shown to be competitive inhibitors of the binding of NADH. Slight changes in structure produced marked changes in selectivity of inhibition of lactate dehydrogenase. 7-
p-Trifluoromethylbenzyl-8-deoxyhemigossylic acid inhibited parasite lactate dehydrogenase,
K
i=0.2
μM, which was 65- and 400-fold tighter binding compared to the M
4 and H
4 isoforms of human lactate dehydrogenase. The results suggest that the cofactor site of parasite lactate dehydrogenase may be a potential target for structure-based drug design.
Details
- Title: Subtitle
- Substrate and cofactor specificity and selective inhibition of lactate dehydrogenase from the malarial parasite P. falciparum
- Creators
- Manuel S Gomez - University of New MexicoRobert C Piper - University of OregonLucy A Hunsaker - University of New MexicoRobert E Royer - University of New MexicoLorraine M Deck - University of New MexicoMichael T Makler - Oregon Health & Science UniversityDavid L Vander Jagt - Department of Biochemistry, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
- Resource Type
- Journal article
- Publication Details
- Molecular and biochemical parasitology, Vol.90(1), pp.235-246
- Publisher
- Elsevier B.V
- DOI
- 10.1016/S0166-6851(97)00140-0
- PMID
- 9497046
- ISSN
- 0166-6851
- eISSN
- 1872-9428
- Language
- English
- Date published
- 1997
- Academic Unit
- Molecular Physiology and Biophysics; Medicine Administration; Internal Medicine
- Record Identifier
- 9984297497102771
Metrics
9 Record Views