Document Detail

Effects of 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-adenine and -3-deazaadenine on the metabolism of S-adenosylhomocysteine in mouse L929 cells.
MedLine Citation:
PMID:  2454388     Owner:  NLM     Status:  MEDLINE    
Neplanocin A [(-)-9-[trans-2',trans-3'-dihydroxy-4'-(hydroxymethyl)-cyclopent-4 '- enyl]-adenine] and 9-[trans-2',trans-3'-dihydroxycyclopent-4'-enyl]-adenine (1) and -3-deazaadenine (2) are potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase (EC in mouse L929 cells. When cells were treated for 15 min with varying concentrations of the drugs, the IC95 values (concentration needed to produce 95% inhibition of AdoHcy hydrolase) for neplanocin A, 1, and 2 were determined to be 0.2 microM, 0.5 microM, and 0.5 microM, respectively. Incubation of L929 cells with 1.0 microM concentrations of neplanocin A, 1, or 2 produced rapid inactivation of AdoHcy hydrolase (within 30 min the enzyme was 95% inhibited), which persisted for at least 72 hr. At lower concentrations (0.032 microM), substantial recovery of AdoHcy hydrolase activity was noted after 48 and 72 hr in cultures treated with neplanocin A but not in cultures treated with 1 or 2. L929 cells treated with neplanocin A, 1 or 2 showed a rapid increase in intracellular levels of AdoHcy (as well as the ratio of AdoHcy/S-adenosylmethionine). Cells treated with neplanocin A also contained significant amounts of S-neplanocylmethionine, whereas cells treated with 1 or 2 showed no evidence of the formation of a similar metabolite. When neplanocin A and adenosine were incubated in cell lysates, rapid conversion to neplanocin D and inosine, respectively, were observed, illustrating the affinity of these nucleosides for cellular adenosine deaminase. In contrast, when 1 and 2 were incubated in cell lysates, no evidence for deamination was observed. These data illustrate that compounds 1 and 2 retain the inhibitory activity of neplanocin A toward cellular AdoHcy hydrolase, producing elevated cellular levels of AdoHcy. However, by removing the 4'-hydroxymethyl group from neplanocin A, analogs 1 and 2 are no longer substrates for adenosine deaminase and adenosine kinase.
M Hasobe; J G Mckee; D R Borcherding; B T Keller; R T Borchardt
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  33     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1988 Jun 
Date Detail:
Created Date:  1988-07-18     Completed Date:  1988-07-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  713-20     Citation Subset:  IM    
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
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MeSH Terms
Adenosine / analogs & derivatives*,  metabolism,  pharmacology
Adenosine Kinase / physiology
Cells, Cultured
DNA / biosynthesis
Dose-Response Relationship, Drug
Homocysteine / analogs & derivatives*
Hydrolases / antagonists & inhibitors*
RNA / biosynthesis
S-Adenosylhomocysteine / metabolism*
S-Adenosylmethionine / metabolism
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
112318-09-9/9-(2',3'-dihydroxycyclopent-4'-enyl)adenine; 112318-10-2/9-(2',3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine; 29908-03-0/S-Adenosylmethionine; 454-28-4/Homocysteine; 58-61-7/Adenosine; 63231-63-0/RNA; 72877-50-0/neplanocin A; 9007-49-2/DNA; 979-92-0/S-Adenosylhomocysteine; EC Kinase; EC 3.-/Hydrolases; EC

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