Relative effects of S-adenosylmethionine depletion on nucleic acid methylation and polyamine biosynthesis.
Treatment of cultured L1210 cells with 1 mM-L-2-amino-4-methoxy-cis-but-3-enoic acid (L-cisAMB), a methionine-analogue inhibitor of S-adenosylmethionine (AdoMet) synthetase (EC 2.5.1.6), produced a rapid and near-total depletion of AdoMet by 4 h. After this, the pools recovered to 60% of control by 48 h, apparently because of an increase in AdoMet synthetase activity. Both AdoMet depletion and the accompanying increase in synthetase activity were substantially enhanced by lowering methionine concentrations in the media from 100 microM to 30 microM, the minimal concentration that supports cell growth at control values. During a 4 h incubation in media containing 30 microM-methionine, 1-5 mM-L-cisAMB depleted cellular AdoMet to undetectable values, and inhibited nucleic acid methylation by 44-72% and RNA methylation by 60-87%. Under these same treatment conditions, putrescine pools increased by about 3-fold, whereas spermidine pools decreased by only 20% and spermine pools remained the same. Pool changes were accompanied by a 2-4-fold increase in ornithine decarboxylase activities and AdoMet activities. Thus the rapid depletion of AdoMet pools by L-cisAMB results immediately in a decrease in methyl-transfer reactions involving nucleic acids, whereas, by contrast, biosynthesis of higher polyamines appears to be minimally affected, owing to compensatory increases in key enzyme activities.
Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY 14263.
D L
DL
Kramer
J R
JR
Sufrin
C W
CW
Porter
D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007939:Leukemia L1210 / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors; D008745:Methylation; D051379:Mice; D009696:Nucleic Acids / Q000378:metabolism*; D011073:Polyamines / Q000096:biosynthesis*; D012436:S-Adenosylmethionine / Q000378:metabolism*
D000613:Aminobutyrates; D009696:Nucleic Acids; D011073:Polyamines; C000264:2-amino-4-methoxy-3-butenoic acid; D012436:S-Adenosylmethionine; D008715:Methionine; D008716:Methionine Adenosyltransferase