Methionine sulfoximine explained

Methionine sulfoximine (MSO, also known as MetSox^[1]) is an irreversible glutamine synthetase inhibitor. It is the sulfoximine derivative of methionine with convulsant effects.^[2]

Methionine sulfoximine is composed of two different diastereomers, which are L-S-Methionine sulfoximine and L-R-Methionine sulfoximine. These affect the longevity of the model mouse for Lou Gehrig's disease.^[3] Overproduction of glutamate results to excitotoxicity, which kills the cell. Since methionine sulfoximine inhibits glutamate production in the brain, it prevents excitotoxicity. Thus, increasing the longevity of the mice.^[4]

Mechanism of action

MSO is phosphorylated by glutamine synthetase. The resulting product acts as a transition state analog that is unable to diffuse from the active site, thereby inhibiting the enzyme.^[5]

Notes and References

1. 21875360 . 2011 . Carroll . P. . Waddell . S. J. . Butcher . P. D. . Parish . T. . Methionine sulfoximine resistance in Mycobacterium tuberculosis is due to a single nucleotide deletion resulting in increased expression of the major glutamine synthetase, GlnA1 . Microbial Drug Resistance . 17 . 3 . 351–355 . 10.1089/mdr.2010.0125 . 3161625 .
2. Rowe . WB . Meister . A . Identification of L-methionine-S-sulfoximine as the convulsant isomer of methionine sulfoximine. . Proceedings of the National Academy of Sciences of the United States of America . June 1970 . 66 . 2 . 500–6 . 4393740 . 283073 . 10.1073/pnas.66.2.500. 1970PNAS...66..500R . free .
3. Brusilow. William S. A.. 2017-04-24. Identification of the isomer of methionine sulfoximine that extends the lifespan of the SOD1 G93A mouse. Neuroscience Letters. 647. 165–167. 10.1016/j.neulet.2017.03.029. 28323087. 45664203. 0304-3940.
4. Bame. Monica. Pentiak. Patricia A.. Needleman. Richard. Brusilow. William S. A.. 2012-12-01. Effect of Sex on Lifespan, Disease Progression, and the Response to Methionine Sulfoximine in the SOD1 G93A Mouse Model for ALS. Gender Medicine. 9. 6. 524–535. 10.1016/j.genm.2012.10.014. 23217569. 1550-8579.
5. Krajewski . W. W. . Jones . T. A. . Mowbray . S. L. . Structure of Mycobacterium tuberculosis glutamine synthetase in complex with a transition-state mimic provides functional insights . Proceedings of the National Academy of Sciences . 18 July 2005 . 102 . 30 . 10499–10504 . 10.1073/pnas.0502248102 . 16027359 . 1180770. 2005PNAS..10210499K . free .