Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones.
Bianchet, Mario A
Hargreaves, Robert H J
Moody, Christopher J
Hudnott, Anna R
Amzel, L Mario
AffiliationDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins Medical School, Baltimore, MD 21205, USA.
MetadataShow full item record
AbstractBACKGROUND: NAD(P)H:quinone acceptor oxidoreductase (QR1) protects animal cells from the deleterious and carcinogenic effects of quinones and other electrophiles. Remarkably, the same enzyme activates cancer prodrugs that become cytotoxic only after two-electron reduction. QR1's ability to bioactivate quinones and its elevated expression in many human solid tumors makes this protein an excellent target for enzyme-directed drug development. Until now, structural analysis of the mode of binding of chemotherapeutic compounds to QR1 was based on model building using the structures of complexes with simple substrates; no structure of complexes of QR1 with chemotherapeutic prodrugs had been reported. RESULTS: Here we report the high-resolution crystal structures of complexes of QR1 with three chemotherapeutic prodrugs: RH1, a water-soluble homolog of dimethylaziridinylbenzoquinone; EO9, an aziridinylindolequinone; and ARH019, another aziridinylindolequinone. The structures, determined to resolutions of 2.0 A, 2.5 A, and 1.86 A, respectively, were refined to R values below 21% with excellent geometry. CONCLUSIONS: The structures show that compounds can bind to QR1 in more than one orientation. Surprisingly, the two aziridinylindolequinones bind to the enzyme in different orientations. The results presented here reveal two new factors that must be taken into account in the design of prodrugs targeted for activation by QR1: the enzyme binding site is highly plastic and changes to accommodate binding of different substrates, and homologous drugs with different substituents may bind to QR1 in different orientations. These structural insights provide important clues for the optimization of chemotherapeutic compounds that utilize this reductive bioactivation pathway.
CitationStructure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones. 2001, 9 (8):659-67 Structure
- Structure, function, and mechanism of cytosolic quinone reductases.
- Authors: Bianchet MA, Erdemli SB, Amzel LM
- Issue date: 2008
- Structures of mammalian cytosolic quinone reductases.
- Authors: Foster CE, Bianchet MA, Talalay P, Faig M, Amzel LM
- Issue date: 2000 Aug
- Mechanism of NAD(P)H:quinone reductase: Ab initio studies of reduced flavin.
- Authors: Cavelier G, Amzel LM
- Issue date: 2001 Jun 1
- The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction.
- Authors: Li R, Bianchet MA, Talalay P, Amzel LM
- Issue date: 1995 Sep 12
- Kinetic and docking studies of the interaction of quinones with the quinone reductase active site.
- Authors: Zhou Z, Fisher D, Spidel J, Greenfield J, Patson B, Fazal A, Wigal C, Moe OA, Madura JD
- Issue date: 2003 Feb 25