Amino acid dependent formaldehyde metabolism in mammals

Matthias Pietzke,Guillermo Burgos-Barragan,David Sumpton,Gillian M Mackay,Jacqueline Tait-Mulder,Ketan J Patel,Niek Wit,Alexei Vazquez

doi:10.1038/s42004-020-0324-z

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.

Highlights

Aldehyde dehydrogenase class 3, encoded by ADH5 in humans, catalyzes the glutathione dependent detoxification of formaldehyde
The fragments with m/z 195–197 exhibit a lower intensity, their peak is proportional to the formaldehyde concentration in the range between 2 and 100 μM, which is sensitive to the presence of different stable isotopes in the formaldehyde carbon (Fig. 1c; Supplementary Fig. 1)
We developed a deconvolution method that estimates the concentration of 12C- and 13Cformaldehyde using as input the peak areas of the m/z 195–197 fragments and 2H2-formaldehyde as an internal standard ('Methods')

Summary

Introduction

Aldehyde dehydrogenase class 3, encoded by ADH5 in humans, catalyzes the glutathione dependent detoxification of formaldehyde. 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. Aldehyde dehydrogenase class 3 catalyses the glutathionedependent detoxification of formaldehyde in the cytosol[11] This enzyme is encoded by the gene ADH5 in humans, Adh[5] in mice and it is ubiquitously expressed across tissues. The 50% lethal dose of formaldehyde goes down from 0.2 g/kg in Adh5-competent mice to 0.13 g/kg in mice with homozygous deletion of Adh[512]

Methods

Results

Conclusion