Structural differences in triosephosphate isomerase from different species and discovery of a multitrypanosomatid inhibitor.
We examined the interfaces of homodimeric triosephosphate isomerase (TIM) from eight different species. The crystal structures of the enzymes showed that a portion of the interface is markedly similar in TIMs from Trypanosoma cruzi (TcTIM), Trypanosoma brucei, and Leishmania mexicana and significantly different from that of TIMs from human, yeast, chicken, Plasmodium falciparum, and Entamoeba histolytica. Since this interfacial region is central in the stability of TcTIM, we hypothesized that it would be possible to find agents that selectively affect the stability of TIMs from the three trypanosomatids. We found that 6,6'-bisbenzothiazole-2,2' diamine in the low micromolar range causes a desirable irreversible inactivation of the enzymes from the three trypanosomatids and has no effect on the other five TIMs. Thus, the data indicate that it is possible to find compounds that induce selective inactivation of the enzymes from three different trypanosomatids.
Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, D. F., México.
Vanesa
V
Olivares-Illana
Ruy
R
Pérez-Montfort
Francisco
F
López-Calahorra
Miguel
M
Costas
Adela
A
Rodríguez-Romero
Marieta
M
Tuena de Gómez-Puyou
Armando
A
Gómez Puyou
D000818:Animals; D052160:Benzothiazoles; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D004748:Entamoeba histolytica / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005453:Fluorescence; D006801:Humans; D007894:Leishmania mexicana / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D013045:Species Specificity; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism
C509837:6,6'-bisbenzothiazole-2,2'-diamine; D052160:Benzothiazoles; D013844:Thiazoles; D014305:Triose-Phosphate Isomerase; C005465:benzothiazole