Polyamine-mediated regulation of S-adenosylmethionine decarboxylase expression in mammalian cells. Studies using 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine, a suicide inhibitor of the enzyme.

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.

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