Polyamine biosynthesis in Cryptosporidium parvum and its implications for chemotherapy.
This study demonstrates that polyamine biosynthesis in Cryptosporidium parvum occurs via a pathway chiefly found in plants and some bacteria. The lead enzyme of this pathway, arginine decarboxylase (ADC) was sensitive to the specific, irreversible inhibitor DL-alpha-difluoromethyl-arginine (IC50 30 microM), and intracellular growth of C. parvum was significantly reduced by inhibitors of ADC. No activity was detected using ornithine as substrate, and the irreversible inhibitor of ornithine decarboxylase, DL-alpha-difluoromethyl-ornithine, had no effect upon ADC activity or upon growth of the parasite. Back-conversion of spermine to spermidine and putrescine via spermidine:spermine-N1-acetyltransferase (SSAT) was also detected. Compounds such as his(ethyl)norspermine, which have been demonstrated to down-regulate SSAT activity in tumor cells, were synergistic in the inhibition of growth when used in combination with inhibitors of the forward pathway. Thus, C. parvum differs fundamentally in its polyamine metabolism from the majority of eukaryotes, including humans. Such differences indicate that polyamine metabolism may serve as a chemotherapeutic target in this organism.
Keithly
J S
JS
Wadsworth Center, New York State Department of Health, Albany 12201-2002, USA.
Zhu
G
G
Upton
S J
SJ
Woods
K M
KM
Martinez
M P
MP
Yarlett
N
N
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003049:Coccidiostats / Q000494:pharmacology; D003457:Cryptosporidiosis / Q000150:complications / Q000188:drug therapy; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D011073:Polyamines / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D002262:Carboxy-Lyases; D003049:Coccidiostats; D000518:Eflornithine; D004791:Enzyme Inhibitors; D011073:Polyamines; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C059685:N(1),N(11)-diethylnorspermine; C019722:arginine decarboxylase