Effects of 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-adenine and -3-deazaadenine on the metabolism of S-adenosylhomocysteine in mouse L929 cells
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 3.3.1.1...
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Veröffentlicht in: | Molecular pharmacology 1988-06, Vol.33 (6), p.713-720 |
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Zusammenfassung: | 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 3.3.1.1) 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. |
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ISSN: | 0026-895X 1521-0111 |