Modulation of cyclic AMP metabolism by S-adenosylhomocysteine and S-3-deazaadenosylhomocysteine in mouse lymphocytes.

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Abstract
Mouse lymphocytes incubated with micromolar concentrations of adenosine or 3-deazaadenosine, in medium supplemented with L-homocysteine, rapidly accumulated supramillimolar concentrations of S-adenosylhomocysteine (AdoHcy) or S-3-deazaadenosylhomocysteine (c3ADoHcy), respectively. Lymphocytes thus preloaded with high levels of AdoHcy or c3AdoHcy exhibited markedly enhanced (5- to 40-fold) cAMP responses to prostaglandin E1, adenosine, 2-chloroadenosine, isoproterenol and cholera toxin. This enhancement of cAMP response intracellular AdoHcy or c3AdoHcy was attributable both to amplification of the activity of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and to inhibition of cAMP phosphodiesterase (3'',5''-cyclic-nucleotide 5''-nucleotidohydrolase, EC 3.1.4.17). Basal and prostaglandin E1- and isoproterenol-stimulated activities of adenylate cyclase, assayed in lymphocyte homogenates, were increased 1.3- to 2.0-fold after treatment of the cells with homocysteine plus adenosine or 3-deazaadenosine. AdoHcy and c3AdoHcy were competitive inhibitors (with Ki values of 1.7 and 4.8 mM, respectively) of the high-affinity cAMP phosphodiesterase present in lymphocyte homogenates. Increased cellular levels of AdoHcy or c3AdoHcy can affect cellular physiology via perturbation of cAMP metabolism and via inhibition of S-adenosylmethionine-dependent methylation reactions.