NAD(P)H:quinone oxidoreductase 1
Homo sapiens (human)
Quinones are aromatic dicarbonyl compounds that are often highly hydrophobic. They act as electron carriers in redox reactions, i.e., they can accept or donate one or two electrons. Examples of quinones include ubiquinone, which is an essential component of the respiratory electron transport system, and plastoquinone, which acts as an electron carrier in photosynthesis. However, quinones are also very toxic, when orally ingested. NAD(P)H:quinone acceptor reductase (QR1) is an enzyme that reduces quinones to detoxify them in animal cells. QR1 is also used to active certain cancer drugs, called prodrugs. Prodrugs are precursors of active drugs. They must undergo some form of chemical modification before they become active pharmacological agents and act as drugs. QR1 is found to be constitutively (or always) expressed in human cancer cells, such as those in non-small-cell lung cancer, breast, pancreatic, colorectal and gastric cancers. QR1 is not normally expressed in normal cells but can be induced. Hence it constitutes a good agent to reduce and activate cancer prodrugs. QR1 has the ability to change the conformation of its binding site to accommodate different prodrugs and bind them in different orientations.
One such cancer prodrug that is activated by QR1 is EO9, an aziridinylindolequinone. The structure above is that of QR1 with a bound EO9. QR1 is a homodimer with each monomer consisting of a large catalytic domain and a small C-terminal domain. The EO9 moiety is bound to the catalytic domain with its benzoquinone ring.
Protein Data Bank (PDB)
Faig, M. Bianchet, M.A. Winski, S. Hargreaves, R. Moody, C.J. Hudnott, A.R. Ross, D. Amzel, L.M.; "Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones."; Structure; (2001) 9:659-667 PubMed:11587640.
author: Ashwini Patil