Inhibition of S-adenosyl-L-methionine (AdoMet) decarboxylase by the decarboxylated AdoMet analog 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811) decreases the capacities of Trypanosoma cruzi to infect and multiply within a mammalian host cell.
A decarboxylated S-adenosyl-L-methionine (AdoMet) analog, 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811), that specifically and irreversibly inhibits AdoMet decarboxylase (DC) was used to investigate the role of AdoMetDC in the regulation of host cell invasion and intracellular replication by Trypanosoma cruzi. The presence of MDL 73811 in cocultures of T. cruzi and rat heart myoblasts (RHM) significantly inhibited host cell infection in a dose-dependent manner. This effect, evidenced by reductions in the proportion of infected RHM and the number of parasites per 100 RHM, was due to MDL 73811 action on T. cruzi as it was reproduced when the parasites, but not the RHM, were pretreated with the inhibitor. Significant inhibition of infectivity required a 10-min treatment with MDL 73811 although greater effects ensued with additional incubation time. We could not detect signs of recovered infectivity up to 6 hr after the removal of nonincorporated MDL 73811, suggesting that either AdoMetDC turnover in T. cruzi is a relatively slow process or the amounts of MDL 73811 taken up could not be blocked or eliminated during this time period. MDL 73811-mediated inhibition of infectivity was not bypassed by the addition of exogenous spermidine or spermine, suggesting that the mechanism of action does not involve reduced production of these polyamines due to AdoMetDC inhibition. Intracellular accumulation of AdoMet appeared to be a more plausible explanation in view of the fact that exogenous AdoMet significantly inhibited infectivity. When added to infected RHM cultures, MDL 73811 or AdoMet inhibited also intracellular T. cruzi growth.(ABSTRACT TRUNCATED AT 250 WORDS)
Yakubu
M A
MA
Department of Microbiology and Public Health, Michigan State University, East Lansing 48824.
Majumder
S
S
Kierszenbaum
F
F
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D003839:Deoxyadenosines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015203:Reproducibility of Results; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology
D003839:Deoxyadenosines; C065859:MDL 73811; D012437:Adenosylmethionine Decarboxylase