title: Stearoyl-CoA desaturase is an essential enzyme for the parasitic protist Trypanosoma brucei.
abstract: Trypanosoma brucei, the etiologic agent of sleeping sickness, is exposed to important changes in nutrients and temperature during its life cycle. To adapt to these changes, the fluidity of its membranes plays a crucial role. This fluidity, mediated by the fatty-acid composition, is regulated by enzymes named desaturases. We have previously shown that the oleoyl desaturase is essential for Trypanosoma cruzi and T. brucei. In this work, we present experimental support for the relevance of stearoyl-CoA desaturase (SCD) for T. brucei's survival, in both its insect or procyclic-form (PCF) and bloodstream-form (BSF) stages. We evaluated this essentiality in two different ways: by generating a SCD knocked-down parasite line using RNA interference, and by chemical inhibition of the enzyme with two compounds, Isoxyl and a thiastearate with the sulfur atom at position 10 (10-TS). The effective concentration for 50% growth inhibition (EC(50)) of PCF was 1.0 ± 0.2 μM for Isoxyl and 5 ± 2 μM for 10-TS, whereas BSF appeared more susceptible with EC(50) values 0.10 ± 0.03 μM (Isoxyl) and 1.0 ± 0.6 μM (10-TS). RNA interference showed to be deleterious for both stages of the parasite. In addition, T. brucei-infected mice were fed with Isoxyl, causing a reduction of the parasitemia and an increase of the rodents' survival.
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario, CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Santa Fe, Argentina.
authors.forename: Andrés
authors.initials: A
authors.lastname: Alloatti
authors.forename: Shreedhara
authors.initials: S
authors.lastname: Gupta
authors.forename: Melisa
authors.initials: M
authors.lastname: Gualdrón-López
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nguewa
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Altabe
authors.forename: Gladys
authors.initials: G
authors.lastname: Deumer
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.forename: Paul A M
authors.initials: PA
authors.lastname: Michels
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Uttaro
mesh_terms: D000818:Animals; D005260:Female; D055785:Gene Knockdown Techniques; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy / Q000382:microbiology*; D010670:Phenylthiourea / Q000031:analogs & derivatives / Q000627:therapeutic use; D034622:RNA Interference; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000382:microbiology*
chemical_list: C100189:thiocarlide; D010670:Phenylthiourea; D013230:Stearoyl-CoA Desaturase