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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[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.
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[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.