Cycloleucine is a specific inhibitor of S-adenosylmethionine-mediated methylation, which blocks the methylation modification process of various biological molecules by competitively binding to the active site of methyltransferases[1]. Cycloleucine is an antagonist of the glycine allosteric site of the N-methyl-D-aspartate (NMDA) receptor with a Ki value of 600μM and has an anxiolytic effect[2, 3]. Cycloleucine is also a competitive inhibitor of ATP:L-methionine-S-adenosyltransferase in vitro, which can interfere with the biosynthesis of S-adenosylmethionine (SAM), thereby affecting the supply of methyl donors[4]. Cycloleucine can significantly inhibit plant growth, resulting in the disappearance of plant apical dominance, a significant decrease in plant height and dry weight, the retardation of leaf hair development on the back, and the inhibition of net photosynthetic rate and the activity of key enzymes in the Calvin cycle[5].
In vitro, treatment of rat hepatocytes with Cycloleucine (20mM) for 24 or 48h significantly reduced intracellular S-adenosyl-L-methionine (SAM) levels and induced hepatocyte cytotoxicity[6]. Treatment of RAW cells with Cycloleucine (40 mM) for 2h depleted intracellular SAM[7].
In vivo, intracerebroventricular administration of Cycloleucine (0.5, 1, 2, 4µg) to rats with bilateral nucleus accumbens (NAS) cannulation increased the time the rats spent in the open arm, the time they entered the open arm, and the time they reached the extreme end of the arm in the elevated plus maze test[8].
References:
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[2] Hershkowitz N, Rogawski M A. Cycloleucine blocks NMDA responses in cultured hippocampal neurones under voltage clamp: antagonism at the strychnine‐insensitive glycine receptor[J]. British journal of pharmacology, 1989, 98(3): 1005-1013.
[3] Gottlieb A, Stein G Y, Ruppin E, et al. PREDICT: a method for inferring novel drug indications with application to personalized medicine[J]. Molecular systems biology, 2011, 7(1): 496.
[4] Caboche M, Hatzfeld J. Methionine metabolism in BHK cells: preliminary characterization of the physiological effects of cycloleucine, an inhibitor of S‐adenosylmethionine biosynthesis[J]. Journal of Cellular Physiology, 1978, 97(3): 361-370.
[5] Niu T, Zhang J, Li J, et al. Effects of exogenous glycine betaine and cycloleucine on photosynthetic capacity, amino acid composition, and hormone metabolism in Solanum melongena L[J]. Scientific Reports, 2023, 13(1): 7626.
[6] Zhuge J, Cederbaum A I. Depletion of S-adenosyl-l-methionine with cycloleucine potentiates cytochrome P450 2E1 toxicity in primary rat hepatocytes[J]. Archives of biochemistry and biophysics, 2007, 466(2): 177-185.
[7] Song Z, Chen T, Deaciuc I V, et al. Modulation of endotoxin stimulated interleukin-6 production in monocytes and Kupffer cells by S-adenosylmethionine (SAMe)[J]. Cytokine, 2004, 28(6): 214-223.
[8] Gargiulo A P I, Acuña A, Gargiulo M M L, et al. Effects of cycloleucine in the nucleus accumbens septi on the elevated plus maze test in rats[J]. Neuropsychobiology, 2020, 79(3): 191-197.
Cycloleucine是一种S-腺苷甲硫氨酸介导的甲基化的特异性抑制剂，通过竞争性结合甲基转移酶活性位点来阻断多种生物分子的甲基化修饰过程[1]。Cycloleucine是N-甲基-D-天冬氨酸（NMDA）受体甘氨酸变构位点的拮抗剂，Ki值为600μM，具有抗焦虑作用[2, 3]。Cycloleucine在体外也是ATP:L-蛋氨酸-S-腺苷基转移酶的竞争性抑制剂，能够干扰S-腺苷甲硫氨酸（SAM）的生物合成，从而影响甲基供体的供应[4]。Cycloleucine能够明显抑制植物的生长，导致植物顶端优势消失，株高和干鲜重明显下降，背面叶毛发育受阻，净光合速率和卡尔文循环关键酶活性受到抑制[5]。
在体外，Cycloleucine（20mM）处理大鼠肝细胞24或48h，显著降低了细胞内S-腺苷-L-蛋氨酸（SAM）的水平，诱导了肝细胞的细胞毒性[6]。Cycloleucine（40mM）处理RAW细胞2h，细胞内SAM被耗尽[7]。
在体内，Cycloleucine（0.5, 1, 2, 4µg）通过脑室内注射治疗双侧伏隔核（NAS）插管处理的大鼠，在高架十字迷宫试验中增加了大鼠在开放臂中停留的时间、开放臂进入时间和极端到达时间[8]。