Glutathione-dependent formaldehyde dehydrogenase (FDH (also commonly called FALDH or ADH3))

Glutathione-dependent formaldehyde dehydrogenase is a zinc-containing enzyme essential for formaldehyde detoxification in most eukaryotes, including humans, where it is identical to class III alcohol dehydrogenase (ADH3)[2][4][5]. It catalyzes the NAD+-dependent oxidation of S-hydroxymethylglutathione (formed from the spontaneous reaction of glutathione with formaldehyde) to S-formylglutathione, thus neutralizing toxic formaldehyde[2]. Uniquely, this enzyme is also a potent S-nitrosoglutathione (GSNO) reductase, influencing NO signaling and cellular redox states[7][8]. The enzyme operates via a zinc-assisted mechanism, with critical roles described for Glu-67 and Arg-368 in catalysis and cofactor binding[1][3][5]. Expression and activity of this enzyme affect glutathione homeostasis and have been implicated in the regulation of cell proliferation, redox biology, stress responses, and potentially in disease contexts such as cancer, neurodegeneration, and inflammation[7][8]. In plants and animals alike, the enzyme’s broad substrate specificity and evolutionary conservation indicate its fundamental metabolic importance[4].

Other names

Formaldehyde dehydrogenaseS-nitrosoglutathione reductaseGSNO reductaseClass III alcohol dehydrogenase (ADH3)Glutathione-dependent alcohol dehydrogenaseS-(hydroxymethyl)glutathione dehydrogenase

Catalytic oxidation of S-hydroxymethylglutathione, formed from formaldehyde and glutathione, using NAD+ as a cofactor, producing S-formylglutathione[2]. Reduces S-nitrosoglutathione (GSNO), regulating NO signaling[7][8]. Mechanistic sequence involves a zinc-dependent catalytic site[1][3][5].