Content, Synthesis, and Function of Polyamines in Trypanosomatids: Relationship to Chemotherapy1<sup>,</sup>2

Bacchi, Cyrus J.

doi:10.1111/j.1550-7408.1981.tb02798.x

Cited by 82 publications

(23 citation statements)

References 50 publications

(27 reference statements)

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“…Thus, it would appear that at least the membrane-penetrating capacity of the flagellate was seriously compromised by F2MeArg. The low degree of parasite-macrophage interaction observed at 4°C suggested reminiscent of the rapid turnover of OrnDCase in other trypanosomatids where this enzyme plays a key role in polyamine production (14).…”

Section: Discussionmentioning

confidence: 99%

Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.

Kierszenbaum

Wirth

McCann

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.

Kierszenbaum

Wirth

McCann

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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“…3; n ϭ 9) (38,39). Incubation in DFMO was ultimately lethal for promastigote cultures (data not shown).…”

Section: Inducible Resistance To Hydrogenmentioning

confidence: 91%

Inducible Resistance to Oxidant Stress in the Protozoan Leishmania chagasi

Miller¹,

McGowan²,

Gantt³

et al. 2000

Journal of Biological Chemistry

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Leishmania sp. protozoa are introduced into a mammalian skin by a sandfly vector, whereupon they encounter increased temperature and toxic oxidants generated during phagocytosis. We studied the effects of 37°C "heat shock" or sublethal menadione, which generates superoxide and hydrogen peroxide, on Leishmania chagasi virulence. Both heat and menadione caused parasites to become more resistant to H 2 O 2 -mediated toxicity. Peroxide resistance was also induced as promastigotes developed in culture from logarithmic to their virulent stationary phase form. Peroxide resistance was not associated with an increase in reduced thiols (trypanothione and glutathione) or increased activity of ornithine decarboxylase, which is rate-limiting in trypanothione synthesis. Membrane lipophosphoglycan increased in size as parasites developed to stationary phase but not after environmental exposures. Instead, parasites underwent a heat shock response upon exposure to heat or sublethal menadione, detected by increased levels of HSP70. Transfection of promastigotes with L. chagasi HSP70 caused a heat-inducible increase in resistance to peroxide, implying it is involved in antioxidant defense. We conclude that leishmania have redundant mechanisms for resisting toxic oxi-

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“…S-Adenosyl-L-methionine (AdoMet) decarboxylase (DC) (EC 4.1.1.50) is another obligatory enzyme in the biosynthesis of spermidine and spermine in higher eucaryotes (22) and spermidine in African trypanosomes (1). This enzyme catalyzes the formation of decarboxy AdoMet, which then donates an aminopropyl group to one of the amines of putrescine in a reaction catalyzed by spermidine synthase (Fig.…”

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confidence: 99%

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase

Bitonti¹,

Byers²,

Bush³

et al. 1990

Antimicrob Agents Chemother

109

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A structural analog, 5'-{[(Z)4-amino-2-butenyl]methylamino}-5'-deoxyadenosine (MDL 73811), of decarboxy S-adenosyl-L-methionine, the product of the reaction catalyzed by S-adenosyl-L-methionine (AdoMet) decarboxylase (DC), was found to inhibit Trypanosoma brucei brucei AdoMet DC. The inhibition was time dependent (T.s, 0.3 min), exhibited pseudo-first-order kinetics (Ki, 1.5 ,uM), and was apparently irreversible.The natural substrate of the reaction, AdoMet, protected the enzyme from inactivation, suggesting that MDL 73811 was directed at the enzyme active site and was probably catalytically activated. Administration of MDL 73811 to T. b. brucei-infected rats resulted in rapid inhibition of AdoMet DC activity, a decrease in spermidine, and an increase in putrescine in the trypanosomes isolated from treated rats. Treatment of T. b. brucei-infected mice with MDL 73811 (20 mg/kg of body weight intraperitoneally twice daily for 4 days) resulted in cures of the trypanosome infections. Additionally, drug-resistant T. brucei rhodesiense infections in mice were cured by either a combination of MDL 73811 (50 mg/kg intraperitoneally three times per day for 5 days) and relatively low oral doses of a-difluoromethylornithine or MDL 73811 (50 mg/kg per day for 7 days) administered alone in implanted miniosmotic pumps. These data suggest that MDL 73811 and, perhaps, other inhibitors of AdoMet DC have potential for therapeutic use in various forms of African trypanosomiasis.

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Content, Synthesis, and Function of Polyamines in Trypanosomatids: Relationship to Chemotherapy1^,2

Cited by 82 publications

References 50 publications

Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.

Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.

Inducible Resistance to Oxidant Stress in the Protozoan Leishmania chagasi

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase

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Content, Synthesis, and Function of Polyamines in Trypanosomatids: Relationship to Chemotherapy1,2

Cited by 82 publications

References 50 publications

Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.

Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.

Inducible Resistance to Oxidant Stress in the Protozoan Leishmania chagasi

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase

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Product

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Content, Synthesis, and Function of Polyamines in Trypanosomatids: Relationship to Chemotherapy1^,2