Antimalarial activity of neplanocin A with perturbations in the metabolism of purines, polyamines and S-adenosylmethionine.
Neplanocin A, a novel carbocyclic analog of adenosine, was found to be a mixed type inhibitor of S-adenosylhomocysteine hydrolase of human red blood cells with a Ki of 2 nM and an inactivating constant, Ki, of 3 nM. When tested against Plasmodium falciparum cultured in human red blood cells, neoplanocin A inhibited malarial growth with an ED50 of 3 microM. Above 2.5 microM, some red blood cells showed morphological aberrations and became echinocytes (spiculated red blood cells). In infected red blood cells, neplanocin A caused an elevation of the concentrations of S-adenosylmethionine and S-adenosylhomocysteine in a dose-dependent manner. Concurrently, a new analog of S-adenosylmethionine, S-neplanocinylmethionine, was formed. Analysis of polyamines showed that only putrescine was decreased significantly; the others were not changed. Purine analyses showed two putative neplanocinyl nucleotides, possibly the di-and the triphosphates. Neplanocin A most likely exerted its in vitro antimalarial effect via the inhibition of S-adenosylhomocysteine hydrolase and the attendant perturbation of methylation reactions.
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D011073:Polyamines / Q000378:metabolism*; D011687:Purines / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D000962:Antimalarials; D011073:Polyamines; D011687:Purines; C031096:neplanocin A; D012436:S-Adenosylmethionine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine