NADH Dehydrogenase - Inhibitors

Inhibitors

The best-known inhibitor of Complex I is rotenone (commonly used as an organic pesticide). Rotenone and rotenoids are isoflavonoids occurring in several genera of tropical plants such as Antonia (Loganiaceae), Derris and Lonchocarpus (Faboideae, Fabaceae). There have been reports of Indians using rotenone-containing plants to fish - due to its ichthyotoxic effect - as early as the 17th century. Rotenone binds to the ubiquinone binding site of Complex I as well as piericidin A, another potent inhibitor with a close structural homologue to ubiquinone.

Despite more than 50 years of study of NADH dehydrogenase, no inhibitors blocking the electron flow inside the enzyme have been found. Hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal FeS cluster N2 and ubiquinone. It has been shown that long-term systemic inhibition of Complex I by rotenone can induce selective degeneration of dopaminergic neurons.

NADH dehydrogenase is also blocked by adenosine diphosphate ribose – a reversible competitive inhibitor of NADH oxidation by binding to the enzyme at the nucleotide binding site. Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively.

The acetogenin family are the most potent Complex I inhibitors. They have been shown to cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding. Interestingly, Rolliniastatin-2, an acetogenin, is the first Complex I inhibitor found that does not share the same binding site as rotenone.