Glutathione transferase from Plasmodium falciparum--interaction with malagashanine and selected plant natural products.
A glutathione transferase (PfGST) isolated from Plasmodium falciparum has been associated with chloroquine resistance. A range of natural products including malagashanine (MG) were screened for inhibition of PfGST by a GST assay with 1-chloro-2,4-dinitrobenzene as a substrate. Only the sesquiterpene (JBC 42C), the bicoumarin (Tral-1), ellagic acid and curcumin, were shown to be potent inhibitors of PfGST with IC(50) values of 8.5, 12, 50 and 69 μM, respectively. Kinetic studies were performed on PfGST using ellagic acid as an inhibitor. Uncompetitive and mixed types of inhibition were obtained for glutathione (GSH) and 1-chloro-2, 4-dinitrobenzene (CDNB). The K(i) for GSH and CDNB were -0.015 μM and 0.011 μM, respectively. Malagashanine (100 µM) only reduced the activity of PfGST to 80% but showed a time-dependent inactivation of PfGST with a t(1/2) of 34 minutes compared to >120 minutes in the absence of MG or in the presence of 5 mM GSH. This work facilitates the understanding of the interaction of PfGST with some plant derived compounds.
Biomolecular Interactions Analyses Group, Department of Biochemistry, University of Zimbabwe, Mount Pleasant, Harare, Zimbabwe.
Rumbidzai
R
Mangoyi
Rose
R
Hayeshi
Bonventure
B
Ngadjui
Francois
F
Ngandeu
Merhatibebe
M
Bezabih
Berhanu
B
Abegaz
Solofoniaina
S
Razafimahefa
Philippe
P
Rasoanaivo
Stanley
S
Mukanganyama
D000470:Alkaloids / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology; D004137:Dinitrochlorobenzene / Q000378:metabolism; D055808:Drug Discovery; D004351:Drug Resistance; D004610:Ellagic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D007700:Kinetics; D016778:Malaria, Falciparum / Q000188:drug therapy; D010946:Plants, Medicinal / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D045788:Sesquiterpenes, Germacrane / Q000494:pharmacology
C556778:14-hydroxy, 8, 15-diacetoxy-1(10)4,11(13) germacratrien-12,6-olide; D000470:Alkaloids; D001688:Biological Products; D003374:Coumarins; D004137:Dinitrochlorobenzene; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D045788:Sesquiterpenes, Germacrane; C556777:Tral-1 compound; C103769:malagashanine; D004610:Ellagic Acid; D002738:Chloroquine; C470664:GST1 protein, Plasmodium falciparum; D005982:Glutathione Transferase; D005978:Glutathione; D003474:Curcumin