Antagonistic reactions of arginine and lysine against formaldehyde and their relation to cell proliferation, apoptosis, folate cycle and photosynthesis

Abstract

¹H, ¹³C NMR, ESMS and MS/MS investigations proved that there is an antagonism in the spontaneous reaction of formaldehyde with L-lysine and L-arginine. L-Arginine can only be hydroxymethylated on the guanidino group in a very fast reaction forming mono-, di-, and trihydroxymethyl arginines (HMA). L-Lysine can be methylated on the ε-amino group forming mono-, di-, and trimethyl lysine on physiological pH. Hydroxymethyl arginines are relative stable, isolable products, and can also be formed in biological systems, especially in plants. Significant amounts of hydroxymethyl arginines were identified in the aqueous extract of lyophilized kohlrabi, which can be formed in photosynthesis during CO₂ fixation. ¹⁴C-Formaldehyde formed in a short-term (10, 30 sec) ¹⁴CO₂ fixation reaction in Zea mays L. (early maturity variety: Szegedi TC 277) was captured by L-arginine, which occurs in leaves in large amount. Formaldehyde formed during photosynthesis can react not only with the arginine, but with ribulose-1,5-diphosphate present in leaves. In model reactions formaldehyde can react with the ‘ene diole’ group of ribulose-1,5-diphosphate in the absence of Rubisco enzyme, which is a similar reaction to the addition of formaldehyde to L-ascorbic acid. Hydroxymethyl arginines (HMA) are endogenous formaldehyde carrier molecules transferring the bound formaldehyde to thymidylate synthase enzyme system incorporating it into the folate cycle. HMA can also carry the bound formaldehyde to the cells especially to the tumorous cells (HT29 adenocarcinoma), and cause significant inhibition of cell proliferation and causes apoptosis.