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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Inhibition mechanism of S-adenosylmethionine-induced movement deficits by prenylcysteine analogs.
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Inhibition mechanism of S-adenosylmethionine-induced movement deficits by prenylcysteine analogs.

机译：异戊二烯半胱氨酸类似物对S-腺苷甲硫氨酸诱导的运动缺陷的抑制机制。

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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.
机译：我们以前的研究表明，S-腺苷甲硫氨酸（SAM）诱导的运动损伤与帕金森氏病（PD）中观察到的运动损伤相似，显然是由于异戊二烯化的蛋白质甲基化所致。 5 kDa分子被甲基化，异戊二烯半胱氨酸（PC）类似物抑制了症状。在本研究中，我们探讨了PC类似物作用的生化机制。 N-乙酰基香叶基半胱氨酸（AGC），N-乙酰基香叶基香叶基半胱氨酸（AGFC），N-乙酰基香叶基香叶基半胱氨酸（AGGC），法呢基硫代乙酸（FTA），法呢基-2-乙磺酸（FTE）和法呢基琥珀酸（FMS）和法呢基硫代三唑（FTT）和法呢基硫代乳酸（FTL）抑制SAM诱导的运动障碍。将各自的类似物与含有异戊烯基化的蛋白质甲基转移酶（PPMTase）的大鼠脑膜一起温育导致AGC，AFC和AGGC的甲基化。 FTA，FTE，FMS和FTT而非FTL抑制了酶的活性。相对于重复注射1 micromol SAM，单次注射活性类似物至少有效3天。苯丙胺可抑制苯丙胺诱导的大鼠活动亢进，但可通过FTE增强。在60分钟内，苯丙胺治疗的大鼠的运动时间为1477 s，而苯丙胺+ SAM-和苯丙胺+ FTE的大鼠分别为633和1664 s。苯丙胺+ FTE处理的大鼠的总距离比苯丙胺高82％。与PBS对照（4726）相比，水平活性为30,728（苯丙胺），15,430（FTE），18,526（苯丙胺+ SAM），41,736（苯丙胺+ FTE）和7004（SAM）。 SAM的作用之间的错综复杂的关系可以加快SAM诱导的运动障碍，而PC的类似物可以阻止SAM引起的运动障碍，而SAM的作用可以加速异戊烯基化的蛋白质甲基化并损害运动，而苯丙胺可以增加突触多巴胺的水平和运动。多巴胺信号传导可能是症状的原因。数据表明，PC类似物与PPMTase的相互作用可能不是抗PD样活性的指标。

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