THE 3-DIMENSIONAL STRUCTURE OF NAD(P)H-QUINONE REDUCTASE, A FLAVOPROTEIN INVOLVED IN CANCER CHEMOPROTECTION AND CHEMOTHERAPY - MECHANISM OFTHE 2-ELECTRON REDUCTION

Quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.9 9.2], also called DT diaphorase, is a homodimeric FAD-containing enzym e that catalyzes obligatory NAD(P)H-dependent two-electron reductions of quinones and protects cells against the toxic and neoplastic effect s of free radicals and reactive oxygen species arising from one-electr on reductions, These two electron reductions participate in the reduct ive bioactivation of cancer chemotherapeutic agents such as mitomycin C in tumor cells, Thus, surprisingly, the same enzymatic reaction that protects normal cells activates cytotoxic drugs used in cancer chemot herapy, The 2.1-Angstrom crystal structure of rat liver quinone reduct ase reveals that the folding of a portion of each monomer is similar t o that of flavodoxin, a bacterial FMN-containing protein, Two addition al portions of the polypeptide chains are involved in dimerization and in formation of the two identical catalytic sites to which both monom ers contribute, The crystallographic structures of two FAD-containing enzyme complexes (one containing NADP(+), the other containing duroqui none) suggest that direct hydride transfers from NAD(P)H to FAD and fr om FADH(2) to the quinone [which occupies the site vacated by NAD(P)H] provide a simple rationale for the obligatory two-electron reductions involving a ping-pong mechanism.