Methionine sulfoximine

Last updated
l-Methionine sulfoximine
L-Methionine sulfoximine.svg
Names
IUPAC name
(2S)-2-Amino-4-(S-methylsulfonimidoyl)butanoic acid
Other names
l-Methionine sulfoximine; MSO
Identifiers
3D model (JSmol)
1725509
ChEBI
ChemSpider
ECHA InfoCard 100.016.224 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 217-845-8
PubChem CID
UNII
  • InChI=1S/C5H12N2O3S/c1-11(7,10)3-2-4(6)5(8)9/h4,7H,2-3,6H2,1H3,(H,8,9)/t4-,11?/m0/s1
    Key: SXTAYKAGBXMACB-DPVSGNNYSA-N
  • CS(=N)(=O)CC[C@@H](C(=O)O)N
Properties
C5H12N2O3S
Molar mass 180.22 g·mol−1
Related compounds
Related compounds
Buthionine sulfoximine
Glufosinate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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]

Phosphorylation of MSO by glutamine synthetase MSO Phosphorylation Mechanism.svg
Phosphorylation of MSO by glutamine synthetase

Related Research Articles

Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-catalyzed processes where chemical substances absorbed as nutrients serve as enzyme substrates, with conversion by the living organism either into simpler or more complex products. Examples of biosynthetic pathways include those for the production of amino acids, lipid membrane components, and nucleotides, but also for the production of all classes of biological macromolecules, and of acetyl-coenzyme A, adenosine triphosphate, nicotinamide adenine dinucleotide and other key intermediate and transactional molecules needed for metabolism. Thus, in biosynthesis, any of an array of compounds, from simple to complex, are converted into other compounds, and so it includes both the catabolism and anabolism of complex molecules. Biosynthetic processes are often represented via charts of metabolic pathways. A particular biosynthetic pathway may be located within a single cellular organelle, while others involve enzymes that are located across an array of cellular organelles and structures.

<span class="mw-page-title-main">Glutamine synthetase</span> Class of enzymes

Glutamine synthetase (GS) is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine:

Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the excitatory amino acid transporter (EAAT) family and vesicular glutamate transporter (VGLUT) family. In the brain, EAATs remove glutamate from the synaptic cleft and extrasynaptic sites via glutamate reuptake into glial cells and neurons, while VGLUTs move glutamate from the cell cytoplasm into synaptic vesicles. Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues, including the heart, liver, testes, and bone. They exhibit stereoselectivity for L-glutamate but transport both L-aspartate and D-aspartate.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid biosynthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids.

<span class="mw-page-title-main">Glutaminase</span>

Glutaminase is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

<span class="mw-page-title-main">GMP synthase</span>

Guanosine monophosphate synthetase, also known as GMPS is an enzyme that converts xanthosine monophosphate to guanosine monophosphate.

In enzymology, a peptide-methionine (R)-S-oxide reductase (EC 1.8.4.12) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Anthranilate synthase</span>

The enzyme anthranilate synthase catalyzes the chemical reaction

<span class="mw-page-title-main">Aminodeoxychorismate synthase</span>

In enzymology, an aminodeoxychorismate synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Dihydrofolate synthase</span> Class of enzymes

In enzymology, a dihydrofolate synthase is an enzyme that catalyzes the chemical reaction

In enzymology, a tetrahydrofolate synthase is an enzyme that catalyzes the chemical reaction

In enzymology, a 2-isopropylmalate synthase (EC 2.3.3.13) is an enzyme that catalyzes the chemical reaction

In enzymology, a [glutamate—ammonia-ligase] adenylyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">GRIA2</span> Mammalian protein found in Homo sapiens

Glutamate ionotropic receptor AMPA type subunit 2 is a protein that in humans is encoded by the GRIA2 gene and it is a subunit found in the AMPA receptors.

<span class="mw-page-title-main">MSRA (gene)</span> Protein-coding gene in the species Homo sapiens

Peptide methionine sulfoxide reductase (Msr) is a family of enzymes that in humans is encoded by the MSRA gene.

<span class="mw-page-title-main">NADSYN1</span> Protein-coding gene in the species Homo sapiens

Glutamine-dependent NAD(+) synthetase is an enzyme that in humans is encoded by the NADSYN1 gene.

<span class="mw-page-title-main">CTPS2</span> Protein-coding gene in humans

CTP synthase 2 is an enzyme that in humans is encoded by the CTPS2 gene.

<span class="mw-page-title-main">5-Aminoimidazole ribotide</span> Chemical compound

5′-Phosphoribosyl-5-aminoimidazole is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and cobalamin also contain fragments derived from AIR. It is an intermediate in the adenine pathway and is synthesized from 5′-phosphoribosylformylglycinamidine by AIR synthetase.

Peptide-methionine (S)-S-oxide reductase (EC 1.8.4.11, MsrA, methionine sulphoxide reductase A, methionine S-oxide reductase (S-form oxidizing), methionine sulfoxide reductase A, peptide methionine sulfoxide reductase, formerly protein-methionine-S-oxide reductase) is an enzyme with systematic name peptide-L-methionine:thioredoxin-disulfide S-oxidoreductase (L-methionine (S)-S-oxide-forming). This enzyme catalyses the following chemical reaction

References

  1. Carroll, P.; Waddell, S. J.; Butcher, P. D.; Parish, T. (2011). "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. doi:10.1089/mdr.2010.0125. PMC   3161625 . PMID   21875360.
  2. Rowe, WB; Meister, A (June 1970). "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. 66 (2): 500–6. Bibcode:1970PNAS...66..500R. doi: 10.1073/pnas.66.2.500 . PMC   283073 . PMID   4393740.
  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. doi:10.1016/j.neulet.2017.03.029. ISSN   0304-3940. PMID   28323087. S2CID   45664203.
  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. doi:10.1016/j.genm.2012.10.014. ISSN   1550-8579. PMID   23217569.
  5. Krajewski, W. W.; Jones, T. A.; Mowbray, S. L. (18 July 2005). "Structure of Mycobacterium tuberculosis glutamine synthetase in complex with a transition-state mimic provides functional insights". Proceedings of the National Academy of Sciences. 102 (30): 10499–10504. Bibcode:2005PNAS..10210499K. doi: 10.1073/pnas.0502248102 . PMC   1180770 . PMID   16027359.