Mouse ornithine decarboxylase is stable in Trypanosoma brucei.

Bass, Kathryn E.; Sommer, Jürg M.; Cheng, Qi-Lin; Wang, C. C.

doi:10.1016/s0021-9258(19)49871-2

Cited by 17 publications

(1 citation statement)

References 15 publications

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“…Mouse ODC has one-seventh the affinity for putrescine as for Om, while putrescine binds to both T. brucei and L. donovani ODC with nearly the same affinity as Om (Table 2). Thus, product inhibition maybe a more potent form of cellular regulation for the parasite enzymes than for host ODC, consistent with the findings that mammalian ODC is highly regulated by other mechanisms (e.g., intracellular turnover; Li & Coffino, 1994), while the parasite enzymes are not (Phillips et al, 1987;Bass et al, 1992). Thus, in vivo, putrescine analogs may be more toxic to the parasite than the host.…”

Section: Discussionsupporting

confidence: 81%

Formation of Functional Cross-Species Heterodimers of Ornithine Decarboxylase

Osterman¹,

Grishin²,

Kinch³

et al. 1994

Biochemistry

108

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The two active sites in ornithine decarboxylase (ODC) are formed at the dimer interface with Lys-69 and Cys-360 contributing to each active site from opposite monomers [Tobias, K. E., & Kahana, C. (1993) Biochemistry 32, 5842-5847]. To gain insight into the organization of the substrate binding site and the nature of the dimer interface, analysis of ornithine decarboxylase from two parasitic protozoa, Trypanosoma brucei and Leishmania donovani, and from mouse was undertaken. Though T. brucei and mouse ornithine decarboxylase share only 60% sequence identity, the cross-species heterodimers form spontaneously, as measured by the restoration of enzyme activity upon mixing inactive K69A and C360A mutant enzymes. Thus, the amino acid composition of the dimer interface is apparently highly conserved between the T. brucei and mouse enzymes. Cross-species heterodimers were not formed between either T. brucei or mouse ODC and L. donovani ODC. Unlike the mouse and T. brucei ODC, the subunits of L. donovani ODC are not in rapid equilibrium, and incubation with a denaturant is required to induce reassociation. Kinetic analysis of the wild-type mouse and parasite ODCs revealed differences in the substrate binding sites between the three enzymes. The substrate binding properties of the restored active site in the T. brucei:mouse cross-species heterodimer mimic the characteristics of the wild-type enzyme from the species which contributes the subunit with a functional Lys-69.

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Section: Discussionsupporting

confidence: 81%

Formation of Functional Cross-Species Heterodimers of Ornithine Decarboxylase

Osterman¹,

Grishin²,

Kinch³

et al. 1994

Biochemistry

108

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Antiprotozoal Agents

Friès¹,

Fairlamb²

2003

Burger's Medicinal Chemistry and Drug Discovery

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The chapter provides coverage of all drugs currently used for the treatment of human African trypanosomiasis (African sleeping sickness), American trypanosomiases (Chagas' disease), and leishmaniasis. Collectively, this group of diseases is caused by flagellated protozoan of the order Kinetoplastida. The drugs currently used to treat these diseases include melarsoprol, suramin, pentamidine, organic antimonials, and several nitroheterocyclic agents. The agents have all been in use for 25–75 years. They have a high degree of toxicity and the first four in the preceding list must be given by parenteral injection over a 2‐ to 6‐week time period. Tolerance has developed to most of the drugs in at least some geographical areas. Eflornithine is the only agent approved in the last 50 years for the treatment of African trypanosomiasis, although it is expensive, requires prolonged systemic dosage, and is effective only against T. brucei gambiense . Megazol, trybazine, DB289, and CGP 40215A have all yielded encouraging results in in vivo preclinical studies against African trypanosomiasis. All four of these agents have entered or are scheduled to enter clinical trials. Nifurtimox and benznidazole are the only agents approved to treat Chagas' disease. The agents are toxic, rarely produce long‐term cures, and resistance to them has developed. The third‐generation triazole antifungal agents posaconazole and UR‐9825 have given encouraging preclinical results against Chagas' disease. Meltefosine has been found to be orally active and to produce 98% cure rates of visceral leishmaniasis. New classes of experimental antitrypanosomal agents include the bisphosphonates, which disrupt lipid metabolism, and cysteine protease inhibitors. Agents from both of these mechanistic classes are being advanced as potential antitrypanosomal agents. Kinetoplastid biochemistry offers numerous opportunities for the development of chemotherapeutic agents having a high degree of selective toxicity. Trypanothione, the N 1 , N 8 ‐bis(glutathionyl)spermidine metabolite that replaces glutathione in redox protection reactions in kinetoplastids, is one hopeful target for drug design. A second possible target is the kinetoplastid organelle named the glycosome. African trypanosomes and perhaps other kinetoplastids are highly dependent on glycolysis for energy production. Enclosing the enzymes for glycolysis in glycosomes increases the efficiency of glycolysis compared to its rate in mammalian cells. Any potent inhibitor of an enzyme contained in the glycosome, or of any of the biochemical processes associated with glycosomal function, might be an effective drug against these parasites.

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Degradation of Ornithine Decarboxylase

Coffino

1998

Ubiquitin and the Biology of the Cell

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Mouse ornithine decarboxylase is stable in Trypanosoma brucei.

Cited by 17 publications

References 15 publications

Formation of Functional Cross-Species Heterodimers of Ornithine Decarboxylase

Formation of Functional Cross-Species Heterodimers of Ornithine Decarboxylase

Antiprotozoal Agents

Degradation of Ornithine Decarboxylase

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