L-Methionine-(S,R)-Sulfoximine is a potent and irreversible inhibitor of glutamine synthetase (GS)[1-2]. By inhibiting the activity of glutamine synthetase, L-Methionine-(S,R)-Sulfoximine blocks the synthesis of glutamine, thereby affecting cellular nitrogen metabolism. L-Methionine-(S,R)-Sulfoximine is also a convulsant that primarily affects the metabolism and morphology of astrocytes, and can be used as a research model for convulsions and related neurological disorders[3-4].
In vitro, L-Methionine-(S,R)-Sulfoximine (25-75μM) is used for routine passage culture of GS-CHOK1SV cell lines. By inhibiting the activities of glutamine synthetase (GS) and glutamylcysteine ligase (GCL), L-Methionine-(S,R)-Sulfoximine induces endoplasmic reticulum stress and oxidative stress, thereby upregulating the protein expression of the GCL catalytic subunit (GCLc) and the mRNA level of the regulatory subunit (GCLm), enhancing the specific production rate of recombinant monoclonal antibodies (mAb) and the antibody concentration in the harvest[5]. In Klebsiella aerogenes, L-Methionine-(S,R)-Sulfoximine (0.001–100mM) exhibits strong growth inhibition against the MK-275 mutant lacking glutamate dehydrogenase (gltD), with the mechanism involving irreversible inhibition of glutamine synthetase activity and blockade of the glutamine synthesis pathway[6].
In vivo, L-Methionine-(S,R)-Sulfoximine (75mg/kg; intraperitoneal injection) administered to 8-10-week-old C57BL/6J and CBA/J mice induces rapid epileptic seizures in the highly responsive CBA/J strain; whereas in the low-responsive C57BL/6J strain, L-Methionine-(S,R)-Sulfoximine causes delayed epileptic seizures, with significantly elevated brain glycogen content prior to seizure onset[7]. L-Methionine-(S,R)-Sulfoximine (1mmol/kg; intraperitoneal injection) administered to AH/J strain mice (observed 2-6 hours post-injection) induces epileptic seizures in mice and significantly inhibits glutamine synthetase activity in the brain and liver [8].
References:
[1] ROTH JS, WASE A, EICHEL HJ. Studies with methionine sulfoximine. J Biol Chem. 1953 Feb;200(2):647-56.
[2] Davies AM, Tata R, Beavil RL, et al. l-Methionine sulfoximine, but not phosphinothricin, is a substrate for an acetyltransferase (gene PA4866) from Pseudomonas aeruginosa: structural and functional studies. Biochemistry. 2007 Feb 20;46(7):1829-39.
[3] Sumida S, Ito M, Galis I, et al. Phosphoinositide 3-kinase participates in l-methionine sulfoximine-induced cell death via salicylic acid mediated signaling in Nicotiana benthamiana. J Plant Physiol. 2017 Nov;218:167-170.
[4] Cloix JF, Tahi Z, Martin B, et al. Selection of two lines of mice based on latency to onset of methionine sulfoximine seizures. Epilepsia. 2010 Jan;51(1):118-28.
[5] Feary M, Racher AJ, Young RJ, et al. Methionine sulfoximine supplementation enhances productivity in GS-CHOK1SV cell lines through glutathione biosynthesis. Biotechnol Prog. 2017 Jan;33(1):17-25.
[6] Brenchley JE. Effect of methionine sulfoximine and methionine sulfone on glutamate synthesis in Klebsiella aerogenes. J Bacteriol. 1973 May;114(2):666-73.
[7] Wang H, Miao F, Ning D, et al. Ellagic acid Alleviates hepatic ischemia-reperfusion injury in C57 mice via the Caspase-1-GSDMD pathway. BMC Vet Res. 2022 Jun 18;18(1):229.
[8] Rowe WB, Meister A. Identification of L-methionine-S-sulfoximine as the convulsant isomer of methionine sulfoximine. Proc Natl Acad Sci U S A. 1970 Jun;66(2):500-6.
L-Methionine-(S,R)-Sulfoximine是一种有效的、不可逆的谷氨酰胺合成酶（GS）抑制剂[1-2]。L-Methionine-(S,R)-Sulfoximine通过抑制谷氨酰胺合成酶的活性，阻断谷氨酰胺的合成，从而影响细胞的氮代谢，L-Methionine-(S,R)-Sulfoximine也是一种惊厥剂，主要影响星形胶质细胞的代谢和形态，并可用于惊厥及相关神经系统疾病的研究模型[3-4]。
在体外，L-Methionine-(S,R)-Sulfoximine（25-75μM）用于GS-CHOK1SV细胞系的常规传代培养，L-Methionine-(S,R)-Sulfoximine通过抑制谷氨酰胺合成酶（GS）和谷氨酰半胱氨酸连接酶（GCL）活性，诱导内质网应激和氧化应激，从而上调GCL催化亚基（GCLc）蛋白表达和调节亚基（GCLm）mRNA水平，增强重组单克隆抗体（mAb）的比生产速率和收获液中的抗体浓度[5]。在Klebsiella aerogenes中，L-Methionine-(S,R)-Sulfoximine（0.001–100mM）对缺乏谷氨酸脱氢酶（gltD）的突变体MK-275表现出强烈生长抑制，其机制为不可逆抑制谷氨酰胺合成酶活性，阻断谷氨酰胺合成途径[6]。
在体内，L-Methionine-(S,R)-Sulfoximine（75mg/kg；腹腔注射）处理8-10周龄的C57BL/6J和CBA/J小鼠，L-Methionine-(S,R)-Sulfoximine在高反应性CBA/J品系中诱发快速癫痫发作；而在低反应性C57BL/6J品系中，L-Methionine-(S,R)-Sulfoximine诱发延迟性癫痫发作，发作前脑糖原含量显著升高 [7]。L-Methionine-(S,R)-Sulfoximine（1mmol/kg；腹腔注射）处理AH/J品系小鼠（注射后2-6小时观察），L-Methionine-(S,R)-Sulfoximine诱发小鼠癫痫发作，并显著抑制脑和肝脏谷氨酰胺合成酶活性[8]。