A cytochrome c is the natural electron acceptor for nicotine oxidoreductase

Nicotine oxidoreductase (NicA2), a member of the flavin-containing amine oxidase family, is of medical relevance as it shows potential as a therapeutic to aid cessation of smoking due to its ability to oxidize nicotine into a non-psychoactive metabolite. However, the use of NicA2 in this capacity is stymied by its dismal O(2)-dependent activity. Unlike other enzymes in the amine oxidase family, NicA2 reacts very slowly with O(2), severely limiting its nicotine-degrading activity. Instead of using O(2) as an oxidant, we discovered that NicA2 donates electrons to a cytochrome c, which means that NicA2 is actually a dehydrogenase. This is surprising, as enzymes of the flavin-containing amine oxidase family were invariably thought to use O(2) as an electron acceptor. Our findings establish new perspectives for engineering this potentially useful therapeutic and prompt a reconsideration of the term “oxidase” in referring to members of the flavin-containing amine “oxidase” family.