Coordination complexes and catalytic properties of proteins and related substances. 87. Methylation of glucagon, characterization of the sulfonium derivative, and regeneration of the native covalent structure

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Abstract
The methylation of the single methionine residue of [porcine] glucagon is accomplished at a pH of 3.5 in 8 M urea with methyl iodide. The reaction product is a soluble sulfonium derivative, S-methylglucagon, which can be isolated in a highly purified form. This derivative is characterized by amino acid analysis and its effect on the adenylate cyclase system of rat liver plasma membranes. S-Methylglucagon does stimulate the adenylate cyclase system; its activity is approximately 500 times less than that observed with the native hormone. The solubility of this derivative is great enough to allow for further modifications of the molecule which can be followed at a later stage by demethylation. Demethylation of S-methylglucagon regenerates the original covalent structure and is accomplished by treatment with Cleland''s reagents at a pH of 10.5. The regenerated hormone is indistinguishable from native glucagon by its amino acid composition and its ability to stimulate the adenylate cyclase system. The entire methylation-demethylation reaction sequence was carried out with yields that approach 75%. The technique is suitable for the isotopic enrichment of native glucagon and may well be applicable to selected other methionine-containing peptides.

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