Document Detail


CGP 48664, a potent and specific S-adenosylmethionine decarboxylase inhibitor: effects on regulation and stability of the enzyme.
MedLine Citation:
PMID:  9078276     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mammalian S-adenosylmethionine decarboxylase (AdoMetDC) catalyses a regulatory important step in the biosynthesis of polyamines and is a potential target for therapeutic agents against various parasitic diseases and proliferative disorders. In the present study we examined the effects of a newly synthesized AdoMetDC inhibitor. 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664), on polyamine metabolism in the mouse leukaemia cell line L1210. Treatment of the cells with 2 microM CGP 48664 led to a depletion of cellular spermidine and spermine. The putrescine content, in contrast, was markedly increased. Cells seeded in the presence of the inhibitor showed a significant decrease in growth rate, which was fully reversed by the addition of 2 microM spermidine or 1 microM spermine. The syntheses of ornithine decarboxylase and AdoMetDC were greatly increased in cells treated with CGP 48664. These increases were not correlated with similar changes in the mRNA levels, indicating the involvement of a translational mechanism. CGP 48664 was demonstrated to be a very poor competitor of spermidine uptake in the L1210 cells. L1210 cells deficient in polyamine transport were as sensitive to the antiproliferative effect of the inhibitor as were the parental cells, indicating that CGP 48664 did not enter the cells by the polyamine transport system. In addition to inhibiting AdoMetDC, CGP 48664 stabilized the enzyme against degradation. In the present study we also demonstrated that aminoguanidine (AMG), which is frequently used in cellular systems to inhibit any action of serum polyamine oxidase, apparently inhibits AdoMetDC by an irreversible mechanism that markedly stabilizes the enzyme against proteolytic degradation. CGP 48664 and the parental compound methylglyoxal bis(guanylhydrazone), which is also a potent inhibitor of AdoMetDC, contain one or two AMG-like moieties; the importance of these residues in the inhibition of AdoMetDC is discussed.
Authors:
F Svensson; H Mett; L Persson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  322 ( Pt 1)     ISSN:  0264-6021     ISO Abbreviation:  Biochem. J.     Publication Date:  1997 Feb 
Date Detail:
Created Date:  1997-04-15     Completed Date:  1997-04-15     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  297-302     Citation Subset:  IM    
Affiliation:
Department of Physiology and Neuroscience, University of Lund, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Adenosylmethionine Decarboxylase / antagonists & inhibitors*,  drug effects*,  metabolism
Amidines / pharmacology*
Animals
Cell Division / drug effects
Enzyme Activation / drug effects
Enzyme Stability / drug effects
Indans / pharmacology*
Leukemia L1210 / enzymology,  metabolism,  pathology
Mice
Ornithine Decarboxylase / metabolism
Polyamines / metabolism
Chemical
Reg. No./Substance:
0/Amidines; 0/Indans; 0/Polyamines; 149400-88-4/4-amidinoindan-1-one 2'-amidinohydrazone; EC 4.1.1.17/Ornithine Decarboxylase; EC 4.1.1.50/Adenosylmethionine Decarboxylase
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