How formaldehyde reacts with amino acids

• Published in: Communications chemistry Vol. 2; no. 1
• Main Authors: Kamps, Jos J. A. G., Hopkinson, Richard J., Schofield, Christopher J., Claridge, Timothy D. W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-11-2019; Nature Publishing Group
• Subjects: 639/638/403/934; 639/638/403/936; 639/638/92/613; Adducts; Amino acids; Biological activity; Carbonyl compounds; Carbonyls; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Crosslinking; Formaldehyde; Lysine; Methylation; NMR; Nuclear magnetic resonance; Peptides
• ISSN: 2399-3669; 2399-3669
• DOI: 10.1038/s42004-019-0224-2

Formaldehyde is a biological electrophile produced via processes including enzymatic demethylation. Despite its apparent simplicity, the reactions of formaldehyde with even basic biological components are incompletely defined. Here we report NMR-based studies on the reactions of formaldehyde with common proteinogenic and other nucleophilic amino acids. The results reveal formaldehyde reacts at different rates, forming hydroxymethylated, cyclised, cross-linked, or disproportionated products of varying stabilities. Of the tested common amino acids, cysteine reacts most efficiently, forming a stable thiazolidine. The reaction with lysine is less efficient; low levels of an N
ε
-methylated product are observed, raising the possibility of non-enzymatic lysine methylation by formaldehyde. Reactions with formaldehyde are faster than reactions with other tested biological carbonyl compounds, and the adducts are also more stable. The results reveal reactions of formaldehyde with amino acids, and by extension peptides and proteins, have potential roles in healthy and diseased biology, as well as in evolution.
Formaldehyde is the simplest biological electrophile, yet its reactivity with amino acids is not well understood. Here formaldehyde is shown to form a range of products with proteinogenic amino acids and simple peptides, including N-methyl lysine.