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Our data suggest that the likely primary downstream effect of inhibition of hemoglobin degradation in erythrocytic Plasmodium falciparum is blockade of protein synthesis rather than premature host cell lysis. and that the parasite probably degrades globin for nutritional purposes. 49 50

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Mammalian ornithine decarboxylase (ODC), which catalyses the first step in polyamine biosynthesis, has a very fast turnover. It is degraded by the 26S proteasome in an ubiquitin-independent process and the degradation is stimulated by polyamines in a feedback control of the enzyme. Interestingly, there is a major difference in the metabolic stability between ODCs from various trypanosomatids. Trypanosoma brucei and Leishmania donovani both contain stable ODCs, whereas Crithidia fasciculata has an ODC with a rapid turnover. In spite of the difference in stability there is a high degree of sequence homology between C. Fasciculata ODC and L. donovani ODC. In the present study we demonstrate that C. fasciculata ODC is rapidly degraded also in mammalian systems like CHO cells and rabbit reticulocyte lysate, suggesting that the degradation signals of the enzyme are recognised by the mammalian systems. L. donovani ODC, on the other hand, is degraded very slowly in the same systems. The degradation of C. fasciculata ODC in the mammalian systems is markedly reduced by inhibition of the 26S proteasome. However, unlike mammalian ODC, C. Fasciculata ODC is not down-regulated by polyamines. Thus, the turnover of C. fasciculata ODC and L. donovani ODC in the mammalian systems reflects the degradation of the enzyme in the parasites, making such systems potentially useful as complements to parasitic knockout models for further analysis of the mechanisms involved in the rapid degradation of C. fasciculata ODC.

Interestingly, there is a major difference in turnover rate between ornithine decarboxylases (ODCs) from various trypanosomatids. ODCs from Trypanosoma brucei and Leishmania donovani are both stable proteins, whereas ODC from Crithidia fasciculata is a metabolically unstable protein in the parasite. C. fasciculata ODC is also rapidly degraded in mammalian systems, whereas the closely related L. donovani ODC is not. The degradation of C. fasciculata ODC in the mammalian systems is shown to be dependent on a functional 26 S proteasome. However, in contrast to the degradation of mammalian ODC, the degradation of C. fasciculata ODC does not involve antizyme. Instead, it appears the degradation of C. fasciculata ODC may be associated with poly-ubiquitination of the enzyme.