Abstract
Ornithine decarboxylase (ODC) of African trypanosomes is an important target for anti-trypanosomal chemotherapy because of its remarkable stability in vivo. The in vivo activity and stability of mammalian ODC are regulated by polyamines. Polyamines induce antizyme, which inactivates ODC by tight association and promotes degradation of ODC by the mammalian 26 S proteasome. Here we found, in contrast to mammalian cells, that polyamines caused no reduction of ODC activity in Trypanosoma brucei. Mouse ODC expressed in T. brucei was also unaffected by exogenous polyamines, suggesting that a mammalian antizyme equivalent may be absent in T. brucei. The rat antizyme expressed in T. brucei was found capable of inhibiting mouse ODC activity by the formation of rat antizyme-mouse ODC complex. However, complex formation did not lead to degradation of mouse ODC in T. brucei. Further in vitro experiments suggested the presence of an inhibitory factor(s) in trypanosome, which interferes with the degradation of mouse ODC. We also demonstrated the presence of proteasomes in T. brucei. But the mobility of the trypanosomal proteasome on native gel is different from that of the mammalian proteasome. Thus, the absence of antizyme, the presence of inhibitory factor(s), and the differences between trypanosomal and mammalian proteasome may account for the stability of mouse ODC in T. brucei cells.
Highlights
From the Departments of tPharmaceutical Chemistry, §Microbiology and Immunology, and 'fIMedicine, University of California, San Francisco, California 94143
In contrast to mammalian cells, that polyamines caused no reduction of Ornithine decarboxylase (ODC) activity in Trypanosoma brucei, Mouse ODC expressed in T. brucei was unaffected by exogenous polyamines, suggesting that a mammalian antizyme equivalent may be absent in T. brucei
Complex formation did not lead to degradation of mouse ODC in T. brucei, Further in vitro experiments suggested the presence of an inhibitory factor'(s) in trypanosome, which interferes with the degradation of mouse ODC
Summary
10264-10271, 1995 Printed in U.S.A. Rat Antizyme Inhibits the Activity but Does Not Promote the Degradation of Mouse Ornithine Decarboxylase in Trypanosoma brucei*. The in vivo activity and stability of mammalian ODC are regulated by polyamines. Polyamines induce antizyme, which inactivates ODC by tight association and promotes degradation of ODC by the mammalian 26 S proteasome. Complex formation did not lead to degradation of mouse ODC in T. brucei, Further in vitro experiments suggested the presence of an inhibitory factor'(s) in trypanosome, which interferes with the degradation of mouse ODC. The absence of antizyme, the presence of inhibitory factor'(s), and the differences between trypanosomal and mammalian proteasome may account for the stability of mouse ODC in T. brucei cells. The costs of publication of this article were defrayed in part by the payment of page charges.
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