Crystal structure of quinone reductase 2 in complex with cancer prodrug CB1954.

Abstract

CB1954 is a cancer pro-drug that can be activated through reduction by Escherichia coli nitro-reductases and quinone reductases. Human quinone reductase 2 is very efficient in the activation of CB1954, approximately 3000 times more efficient than human QR1 in terms of k(cat)/K(m). We have solved the three-dimensional structure of QR2 in complex with CB1954 to a nominal resolution of 1.5A. The complex structure indicates the essentiality of the two nitro groups: one nitro group forms hydrogen bonds with the side-chain of Asn161 of QR2 to hold the other nitro group in position for the reduction. We further conclude that residue 161, an Asn in QR2 and a His in QR1, is critical in differentiating the substrate specificities of these two enzymes. Mutation of Asn161 to His161 in QR2 resulted in the total loss of the enzymatic activity towards activation of CB1954, whereas the rates of reduction towards menadione are not altered.

• Authors: Yue Fu, Leonid Buryanovskyy, Zhongtao Zhang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 336 Issue 1 Pg. 332-8 (Oct 14 2005) ISSN: 0006-291X [Print] United States
• PMID: 16129418 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Aziridines
• Prodrugs
• tretazicar
• NRH - quinone oxidoreductase2
• Quinone Reductases

Topics

• Antineoplastic Agents (chemistry)
• Aziridines (chemistry)
• Crystallography
• Humans
• Hydrogen Bonding
• Models, Molecular
• Molecular Structure
• Prodrugs (chemistry)
• Quinone Reductases (chemistry)