Abstract
Aldehyde dehydrogenases (ALDHs) are a large family of enzymes that oxidize aldehydes into carboxylic acids. All ALDHs have a conserved catalytic cysteine residue but different cofactor preferences for NAD(+) or NADP(+). We discovered a CC motif composed of the catalytic and an adjacent cysteine, which are prone to disulfide bond formation under oxidative stress. This facilitates rapid detection of and response to oxidants, as well as protects the catalytic cysteine from overoxidation into irreversible products. In ALDHs, the CC motif only exists in NAD(+)-dependent ones, which leads to selective inhibition of NAD(+)-dependent ALDHs under oxidative stress, diverting carbon sources to the NADPH producing ALDHs. This alleviates the oxidative stress and promotes cell survival. Our findings revealed a novel regulatory mechanism for ALDHs that functions in the oxidative stress response. Many enzymes with catalytic cysteine residues have proximal cysteine, suggesting that such a regulatory mechanism may be general.