Amino acid dependent formaldehyde metabolism in mammals

Abstract

Aldehyde dehydrogenase class 3, encoded by ADH5 in humans, catalyzes the glutathione dependent detoxification of formaldehyde. Here we show that ADH5 deficient cells turn over formaldehyde using alternative pathways starting from the reaction of formaldehyde with free amino acids. When mammalian cells are exposed to formaldehyde, the levels of the reaction products of formaldehyde with the amino acids cysteine and histidine-timonacic and spinacine-are increased. These reactions take place spontaneously and the formation of timonacic is reversible. The levels of timonacic are higher in the plasma of Adh5 −/− mice relative to controls and they are further increased upon administration of methanol. We conclude that mammals possess pathways of cysteine and histidine dependent formaldehyde metabolism and that timonacic is a formaldehyde reservoir.

Impact of Formate Supplementation on Body Weight and Plasma Amino Acids

“…Additionally, we observed a significant reduction of Timonacic in the plasma of female mice ( Figure 2 F). Timonacic is an adduct formed from the reaction of formaldehyde with cysteine [ 13 ] that has been recently identified in mammals [ 14 ]. A reduction in the plasma levels of Timonacic could be due to a reduction on the plasma levels of cysteine.…”

Genetically encoded formaldehyde sensors inspired by a protein intra-helical crosslinking reaction

“…Another interesting question is whether the FA-induced crosslinking on regulator proteins, e.g., HxlR/FrmR, is reversible. Recent works indicated that timonacic, the product of cysteine crosslinked by FA, was able to slowly convert back to formaldehyde and cysteine 47 . The authors incubated 12 C-timonacic with 13 C-FA in PBS solution (pH 7.4) and found the sample switched to almost 100% 13 C-timonacic after 12 h 47 .…”

“…Recent works indicated that timonacic, the product of cysteine crosslinked by FA, was able to slowly convert back to formaldehyde and cysteine 47 . The authors incubated 12 C-timonacic with 13 C-FA in PBS solution (pH 7.4) and found the sample switched to almost 100% 13 C-timonacic after 12 h 47 . As FA-crosslinking resulted a five-member-ring in timonacic, which is highly stable and not existed in the proteins, we hypothesized that the FA-induced crosslinking on regulator proteins can be reversed in a faster kinetics.…”

The toxic side of one-carbon metabolism and epigenetics

“…Formaldehyde was also reported to damage proteins causing proteotoxic stress and triggering the activation of Heat Shock Transcription Factor 1 (HSF1) [ 10 ]. The strong electrophilicity of formaldehyde makes this molecule very reactive against electron-rich moieties, especially those containing thiol groups such as GSH and free cysteine, and also likely against thiol-rich proteins such as thioredoxins [ 66 ]. Indeed, formaldehyde rapidly reacts with GSH, yielding S -hydroxymethyl-GSH (HSMGSH) [ 9 ].…”