Trypanosomes mechanism

M. Degano, S. C. Almo, J. C. Sacchettini, and V. L. Schramm, Trypanosomal nucleoside hydrolase. A novel mechanism from the structure with a transition-state inhibitor, Biochemistry, 37 (1998) 6277-6285. 

Nifurtimox (Lampit) is a nitrofuran derivative whose likely mechanism of action for kUhng of trypanosomes is through the production of activated forms of oxygen. Nifurtimox is reduced to the nitro anion radical, which reacts with oxygen to produce superoxide and hydrogen peroxide. The free radical metabolites, an absence of parasite catalase, and a peroxide dehciency lead to hpid peroxidation and cell damage. This production of activated oxygen results in toxicity to the protozoal cells. 

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. 

African sleeping sickness, or African trypanosomiasis, is caused by protists (single-celled eukaryotes) called trypanosomes (Fig. 1). This disease (and related trypanosome-caused diseases) is medically and economically significant in many developing nations. Until recently, the disease was virtually incurable. Vaccines are ineffective, because the parasite has a novel mechanism to evade the host immune system. 

RNA editing. Many uridine molecules are inserted into some mitochondrial mRNAs in trypanosomes. The uridine residues come from the poly(U) tail of a donor strand. Nucleoside triphosphates do not participate in this reaction. Propose a reaction mechanism that accounts for these findings. (Hint Relate RNA editing to RNA splicing.)... 

The hemoflagellates are responsible for some of our most terrible diseases. Trypanosomes (genus Trypanosoma) invade the cells of the nervous system causing African sleeping sickness. Mutating their surface proteins frequently by genescrambling mechanisms, these and other parasites are able to evade the immune response of the host. ... 

The pathology of the infection is due to inflammatory changes associated with an induced autoimmune demyelination of nerve cells. Interestingly, the immunosuppressive action of components of the parasite s membrane are probably responsible for frequent secondary infections such as pneumonia. Liberation of common surface antigens (the mechanism involved in immune evasion) in every trypanolytic crisis (episode of trypanosome lysis) leads to antibody and cell-mediated hypersensitivity reactions. It is believed that some cytotoxic and pathological processes are the result of biochemical and immune mechanisms. 

Curiously, this chemical modification of Gonococci living in the host is possible by a sialyltransferase expressed by the bacterium itself and the sialic acid donor substrate, CMP-Neu5Ac, produced by the host. The properties of the sialyltransferase extracted from the bacteria have been reported [974]. It would be very interesting to compare the primary structure of this enzyme with those of host sialyltransferases. This mechanism is different from that used by trypanosomes for sialylation, although in both cases sialic acids are acquired from the host. 

Suramin is a colorless dye that evolved from Ehrlich s early work with azo dyes such as Trypan Red that cured mice infected with trypanosomes (Ehrlich and Shiga, 1904). It has therefore been viewed as the first synthetic chemotherapeutic drug (it was inactive in humans). A decade later, suramin, which is, however, trypanocidal in humans, was introduced. It is still in use today for this purpose. Even though the drug has since been shown to inhibit various enzyme systems in parasitic protozoa and worms such as filaria (see avermectin later), its mechanism of action and basis of selective toxicity has still not been elucidated. 

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