Trypanosoma brucei

African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease) are caused by Trypanosoma brucei and Trypanosoma cruzi, respectively. Sleeping sickness results from being bitten by the insect vector, the tsetse fly. At first there is only local lymphadenitis but about a month later generalized malaise, fever, and systemic disease involving skeletal muscle is seen. 

Harris, E., et al. (1996). Detection of Trypanosoma brucei spp. in human blood by a nonradioactive branched DNA-based technique. J. Clin. Microbiol 34,2401-2407. 

Vincendeau, P. et al., Nitric oxide-mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei, Exp. Parasitol., 75, 353, 1992. 

The first synthetic task assigned to an NPOE was the demanding glycosylation of an axial 2-OH group in the pseudotetrasaccharide 109, en route to the pseudopentasaccharide core of the protein membrane anchor found in Trypanosoma brucei that was obtained in 68% yield (Scheme 5.25) [76]. 

Delarue, M., Duclert-Savatier, N., Miclet, E., Haouz, A., Giganti, D., Ouazzani, J., Lopez, P. Nilges, M. and Stoven, V. (2007) Three dimensional structure and imphcations for the catalytic mechanism of 6-phosphogluconolactonase from Trypanosoma brucei. J. Mol. Biol. 366, 868-881. 

Many pathogenic protozoa. Including Trypanosoma brucei (trypanosomiasis or African sleeping sickness), Plasmodium falciparum (malaria), Leishmania species (leishmaniasis), and the intestinal parasites Giardia lamblia and Entamoeba histolytica, depend on farnesylated proteins for growth... 

S.2.3.3 Treatment of Trypanosomiasis The difluoromethylornithine (DFMO), eflomithine is a mechanism-based inhibitor of ornithine decarboxylase— a pyridoxal-dependent key enzyme of the polyamine s biosynthesis from ornithine. Fluorine atoms are essential for the inhibition process (cf. Chapter 7). Eflornithine was first clinically developed for cancer, but its development has been abandoned for this indication. The activity of eflornithine on trypanosomes was then discovered. Now, despite its very low bioavailability, eflornithine is the best therapy for sleeeping sickness (trypanosomiasis)—in particular, at the cerebral stage—due to Trypanosoma brucei gambiense parasite. Eflornithine is registered with orphan drug status and is distributed by the WHO. 

It is used in the treatment of pneumocystosis (pulmonary and extrapulmonary disease caused by P. carinii), African trypanosomiasis (disease caused by Trypanosoma brucei) and leishmaniasis. Systemic pentamidine is highly toxic and can lead to severe hypotension, tachycardia, dyspnea, dizziness, hypoglycemia. Other adverse effects are skin rash, metallic taste, gastrointestinal symptoms, thrombocytopenia and cardiac arrhythmias. 

Bisser S et al Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis 2007 195 322. [PMID 17205469]... 

Priotto G et al Nifurtimox-eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness A randomized clinical trial in Congo. Clin Infect Dis 2007 45 1435. [PMID 17990225]... 

We just solved the ternary structure of PGK from Trypanosoma brucei in complex with ADP and 3-phosphoglycerate. The enzyme is in the closed conformation that has eluded crystallographers for 20 years. 

Phillips MA, Coffino P, Wang CC. Cloning and sequencing of the ornithine decarboxylase gene from Trypanosoma brucei. Implications for enzyme turnover and selective difluoromethylornithine inhibition. JBiol Chem 1987 262 8721-8727. 

Baltz T, Baltz D, Giroud C, Crockett J. Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei T. equiperdum, I evansi, T. rhodesiense and T. gambiense. EMBO J 1985 4 1273-1277. 

Frataxin is another protein which was shown to be targeted into hydrogenosomes (Dolezal et al. 2007). Importantly, I vaginalis frataxin can, in part, functionally replace mitochondrial frataxin, as demonstrated by its ability to partially restore defects in FeS cluster assembly in Saccharomyces cerevisiae Ayfhl mutants and frataxin-deficient Trypanosoma brucei (our unpublished data). In yeast, I vaginalis frataxin also partially restored defects in heme synthesis, although neither heme-containing proteins nor components involved in heme synthesis have been identified in T. vaginalis (Dolezal et al. 2007). 

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