We previously showed that
S-adenosylmethionine (SAM) induces movement impairments similar to those observed in
Parkinson's disease (PD) apparently by prenylated
protein methylation; 5 kDa molecules being methylated and the symptoms being inhibited by
prenylcysteine (PC) analogs. In the present study, we explore the biochemical mechanism of action of the PC analogs. N-acetylgeranylcysteine (AGC),
N-acetylfarnesylcysteine (AFC), N-acetylgeranylgeranylcysteine (AGGC),
farnesylthioacetic acid (FTA), farnesyl-2-ethanesulfonic
acid (FTE) and farnesylsuccinic
acid (FMS), but not
farnesylthiotriazole (FTT) and farnesylthiolactic
acid (FTL), inhibited the SAM-induced motor impairments. Incubation of the respective analogs with rat brain membranes containing prenylated
protein methyltransferase (
PPMTase) resulted in the methylation of AGC, AFC and AGGC. FTA, FTE, FMS and FTT, but not FTL, inhibited the
enzyme activity. A single injection of the active analogs remained effective for at least 3 days against repeated
injections of 1 micromol SAM.
Amphetamine-induced hyperactivity in rats was inhibited by SAM but potentiated by FTE. During 60 min, the movement time for
amphetamine-treated rats was 1477 s compared with 633 and 1664 s for amphetamine+SAM- and amphetamine+FTE-treated rats, respectively. The total distance for amphetamine+FTE-treated rats was 82% higher than for
amphetamine. The horizontal activity was 30,728 (
amphetamine), 15,430 (FTE), 18,526 (amphetamine+SAM), 41,736 (amphetamine+FTE) and 7004 (SAM) as compared to the PBS control (4726). The intricate relationship between the actions of SAM, which speeds up prenylated
protein methylation and impairs movement,
amphetamine, which increases synaptic
dopamine levels and movement, and the PC analogs, which prevent the SAM-induced movement impairments, suggests a SAM-induced defect on
dopamine signaling as the likely cause of the symptoms. The data reveal that interaction of PC analogs with
PPMTase may not be an
indicator of anti-PD-like activity.