Structural features of Plasmodium cytochrome b that may underlie susceptibility to 8-aminoquinolines and hydroxynaphthoquinones.
Appropriate functioning of mitochondria is critical for survival and growth of erythrocytic stages of malarial parasites, making it an attractive target for antimalarial drugs which may take advantage of unique features of parasite mitochondrial metabolism. We have sequenced the presumptive mitochondrial DNA, the 6-kb element, of Plasmodium falciparum, permitting an analysis of the predicted structure of parasite electron transport proteins. Although the overall structures of the 3 polypeptides, cytochrome c oxidase subunit 1, cytochrome c oxidase subunit 3, and cytochrome b (cyt b), were similar to those from other species, some striking differences were observed, especially for the cyt b. Analysis of the cyt b structure showed that the critical quinone binding sites of the protein are quite divergent from those of other species. Comparative analysis suggests that these changes are the likely cause for the resistance of parasite cytochrome bc1 complex to antimycin and related inhibitors. We suggest that the same features are responsible for increased affinity of the parasite cyt b for antimalarial compounds of class 8-aminoquinolines and hydroxynaphthoquinones, explaining the therapeutic value of these drugs.
Vaidya
A B
AB
Department of Microbiology and Immunology, Hahnemann University, Philadelphia, PA 19102-1192.
Lashgari
M S
MS
Pologe
L G
LG
Morrisey
J
J
D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D003001:Cloning, Molecular; D003573:Cytochrome b Group / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D008969:Molecular Sequence Data; D009285:Naphthoquinones / Q000494:pharmacology*; D016366:Open Reading Frames; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D003573:Cytochrome b Group; D004272:DNA, Mitochondrial; D009285:Naphthoquinones; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C080436:8-aminoquinoline