Crystal Structures of Prostaglandin D2 11-Ketoreductase (AKR1C3) in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin

• Andrew L. Lovering

  1Biosciences and The Schools of

• Jon P. Ride

  1Biosciences and The Schools of

• Christopher M. Bunce

  1Biosciences and The Schools of

• Julian C. Desmond

  2Medicine, The University of Birmingham, Birmingham, United Kingdom

• Stephen M. Cummings

  1Biosciences and The Schools of

• Scott A. White

  1Biosciences and The Schools of

Abstract

It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 Å resolution) or flufenamic acid (1.7 Å resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the β-hairpin loop, at the opposite end of the central β-barrel. Two other crystal structures (1.20 and 2.1 Å resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.

Journal

• Cancer Research

  Cancer Research 64 (5), 1802-1810, 2004-03-01

  American Association for Cancer Research (AACR)

Keywords

• Cancer Research
• Oncology

Details

• CRID: 1362262944208261504
• NII Article ID: 30018589566
• DOI: 10.1158/0008-5472.can-03-2847
• ISSN: 15387445
• ISSN: 00085472
• Web Site: https://aacrjournals.org/cancerres/article-pdf/64/5/1802/2523469/zch00504001802.pdf
• Data Source:
  • Crossref
  • CiNii Articles