Inhibition mechanism of S-adenosylmethionine-induced movement deficits by prenylcysteine analogs.
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.
Lamango
Nazarius S
NS
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA. nazarius.lamango@famu.edu
Ayuk-Takem
Lambert T
LT
Nesby
Robert
R
Zhao
Wan-Qian
WQ
Charlton
Clivel G
CG
D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D014230:Triazoles; C488644:fernesylthiotriazole; D003553:Cystine; D012436:S-Adenosylmethionine; D000661:Amphetamine; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase