Cell proliferation is dependent on an adequate supply of the
polyamines putrescine,
spermidine and
spermine. One of the key steps in the
polyamine biosynthetic pathway is catalyzed by
S-adenosylmethionine decarboxylase (AdoMetDC). In the present study we have used a newly synthesized
enzyme-activated irreversible AdoMetDC inhibitor, 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-
deoxyadenosine [(Z)-
AbeAdo], to investigate the regulation of this
enzyme. Treatment of mouse
L1210 leukemia cells with (Z)-
AbeAdo resulted in a total inhibition of their AdoMetDC activity followed by depletion of the
spermidine and
spermine content. The
putrescine content, however, was dramatically increased
after treatment with (Z)-
AbeAdo. In spite of the cellular depletion of
spermidine and
spermine, only a minor inhibitory effect was obtained on cell growth, indicating that
putrescine at a high concentration might partly replace
spermidine and
spermine in their growth-promoting functions. Cells grown in the presence of (Z)-
AbeAdo exhibited an increased synthesis of AdoMetDC, which was counteracted by the addition of either
spermidine or
spermine. The change in AdoMetDC synthesis could not be fully explained by a change in the level of AdoMetDC
mRNA, indicating also a translational control. Mammalian AdoMetDC is synthesized as a larger
proenzyme, which is then cleaved into two subunits of different sizes. The conversion of the
proenzyme into the subunits is a very rapid process, which is stimulated greatly by
putrescine in vitro. However, the processing of the
proenzyme in the (Z)-
AbeAdo-treated L1210 cells was not affected by their very high
putrescine content, indicating that the conversion might be saturated at low levels of
putrescine, or that most of the
putrescine in the (Z)-
AbeAdo-treated L1210 cells might be bound to sites normally occupied by
spermidine and
spermine.