Aerobic nitroreduction by flavoproteins: enzyme structure, mechanisms and role in cancer chemotherapy.
NQO1 (DT-diaphorase) and its truncated isoenzyme, the metalloenzyme NQO2, can reduce quinone substrates by two-electron transfer. While NQO1 is a known detoxification enzyme, the function of NQO2 is less well understood. Both rat NQO1 and human NQO2 reductively bioactivate the dinitroarene CB 1954 to a cytotoxic product that behaves as a difunctional DNA-crosslinking species with potent anti-tumour activity, although human NQO1 is much less effective. A FMN-dependent nitroreductase from E. coli B also reduces quinones and reductively bioactivates CB 1954. However, this enzyme reduces CB 1954 to the 2- and 4-hydroxylamines in equivalent yield, whereas NQO1 and NQO2 generate only the 4-isomer. The reduction profile is a key factor in the development of anti-tumour prodrugs, where distinct delivery strategies are being evaluated: prodrug therapy, antibody-, macromolecule and gene-directed enzyme prodrug therapy (ADEPT, MDEPT or GDEPT). The flavoprotein enzymes are explored in terms of structure and bioreduction mechanism, particularly for use in the design of novel prodrugs with potential application as chemotherapeutic agents.
D000332:Aerobiosis; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D004579:Electron Transport; D005420:Flavoproteins / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D011808:Quinone Reductases / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005420:Flavoproteins; D009566:Nitrates; D009573:Nitrites; D011355:Prodrugs; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases