Amino acid dependent formaldehyde metabolism in mammals

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. Formaldehyde is known to react with nucleophilic amino acids in solution but its in vivo nonenzymatic reactivity is poorly understood. Here LC/MS and isotopic labeling studies suggest nonenzymatic formaldehyde metabolism may occur in living mice through the direct reactivity of formaldehyde with amino acids, including a possible role of timonacic, a product of formaldehyde and cysteine, as a reservoir.