Methionine (Met, M)
Methionine is a hydrophobic, sulfur-containing amino acid with a thioether side chain. It starts most protein chains and is one of the most oxidation-prone residues in synthetic peptides.
Structure and properties
Methionine has a flexible, unbranched side chain containing a thioether sulfur and ending in a methyl group. It is hydrophobic, favours helical structure, and is often found buried in proteins or at binding interfaces where its flexible chain can mould to irregular surfaces. Unlike cysteine, the thioether cannot form disulfides, but its sulfur is easily oxidised. Methionine is encoded by the start codon, so it begins nearly all newly synthesised proteins, though it is often removed afterwards. Its sulfur can also weakly coordinate some metal ions.
Role in peptides
Methionine is the first residue of Semax (Met-Glu-His-Phe-Pro-Gly-Pro), which is derived from the ACTH(4-7) region. Alpha-melanocyte-stimulating hormone also contains methionine; synthetic analogues such as Melanotan II and PT-141 replace it with norleucine, which has a similar shape but no sulfur, to remove the oxidation liability. Methionine occurs in many larger hormones and enzymes. In recombinant peptides, an extra N-terminal methionine left from expression is a known product-related variant that analytical methods should check for.
Stability and analysis
Oxidation to methionine sulfoxide is the main concern. It occurs on exposure to air, light, peroxides from excipients or solvents, and trace metals, and it adds one oxygen atom, which mass spectrometry detects readily. Sulfoxide forms usually elute earlier on reversed-phase HPLC, sometimes as a pair of diastereomers. Further oxidation to the sulfone is irreversible. Methionine can also be alkylated during acid cleavage without scavengers. Store protected from light and oxygen, and avoid peroxide-containing solvents.
In PeptideWiki compounds
Compounds whose sequence contains methionine, with the number of occurrences.
- IGF-1 LR3 (3)
- MOTS-c (2)
- Teriparatide (2)
- Argireline (acetyl hexapeptide-8) (1)
- Exenatide (1)
- Humanin (1)
- Semax (1)
- Sermorelin (1)
- Snap-8 (1)
- Tesamorelin (1)
- Thymosin β4 (1)
- VIP (vasoactive intestinal peptide) (1)
Frequently asked questions
What is methionine sulfoxide?
Methionine sulfoxide forms when the thioether sulfur gains one oxygen atom. It is more polar than methionine, so it usually elutes earlier on reversed-phase HPLC, and it is easy to see as a mass increase in mass spectrometry. Because the oxidised sulfur becomes a new stereocentre, two diastereomers can form. In biology, methionine sulfoxide reductases can reverse it, but in a vial it is an impurity that reduces purity.
How can methionine oxidation be limited?
Store lyophilized material cold, dry and protected from light, and keep containers sealed under inert gas where practical. Avoid solvents and excipients that may contain peroxides, such as aged ethers or some polymers, and use high-purity water. Minimise time in solution and limit freeze-thaw cycles. In design, norleucine is often substituted for methionine when the sulfur is not needed for activity.
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