The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin.
Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule. By Scatchard analysis, there appear to be 2 hemin binding sites on TCTP with dissociation constants of approximately 18 microM. When the single cysteine moiety is blocked by pretreatment with iodoacetamide, hemin binding is not affected, whereas drug binding is reduced by two-thirds. Thus, TCTP reacts with artemisinin in situ and in vitro in the presence of hemin and appears to bind to hemin. The function of the malarial TCTP and the role of this reaction in the mechanism of action of artemisinin await elucidation.
Bhisutthibhan
J
J
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2029, USA.
Pan
X Q
XQ
Hossler
P A
PA
Walker
D J
DJ
Yowell
C A
CA
Carlton
J
J
Dame
J B
JB
Meshnick
S R
SR
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D037621:Artemisinins; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D004365:Drugs, Chinese Herbal / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D012717:Sesquiterpenes / Q000378:metabolism*; D000090324:Tumor Protein, Translationally-Controlled 1
D000962:Antimalarials; D037621:Artemisinins; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D004365:Drugs, Chinese Herbal; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; C039060:artenimol; C031327:artemisinin