PMID- 26636353
OWN - NLM
STAT- MEDLINE
DCOM- 20160422
LR  - 20151229
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Linking)
VI  - 54
IP  - 51
DP  - 2015 Dec 29
TI  - Binding of DNA-Intercalating Agents to Oxidized and Reduced Quinone Reductase 2.
PG  - 7438-48
LID - 10.1021/acs.biochem.5b00884 [doi]
AB  - Quinone reductase 2 (NQO2) is an enzyme that might have intracellular signaling 
      functions. NQO2 can exist in either an oxidized state or a reduced state, and 
      binding of compounds to one or both of these states inhibits enzymatic activity 
      and could also affect intracellular signaling. A wide range of planar aromatic 
      compounds bind NQO2, and we have identified three DNA-intercalating agents 
      [ethidium bromide, acridine orange (AO), and doxorubicin] as novel nanomolar 
      inhibitors of NQO2. Ethidium and AO, which carry a positive charge in their 
      aromatic ring systems, bound reduced NQO2 with an affinity 50-fold higher than 
      that of oxidized NQO2, while doxorubicin bound only oxidized NQO2. 
      Crystallographic analyses of oxidized NQO2 in complex with the inhibitors 
      indicated that the inhibitors were situated deep in the active site. The aromatic 
      faces were sandwiched between the isoalloxazine ring of FAD and the phenyl ring 
      of F178, with their edges making direct contact with residues lining the active 
      site. In reduced NQO2, ethidium and AO occupied a more peripheral position in the 
      active site, allowing several water molecules to interact with the polar end of 
      the negatively charged isoalloxazine ring. We also showed that AO inhibited NQO2 
      at a nontoxic concentration in cells while ethidium was less effective at 
      inhibiting NQO2 in cells. Together, this study shows that reduced NQO2 has 
      structural and electrostatic properties that yield a preference for binding of 
      planar, aromatic, and positively charged molecules that can also function as 
      DNA-intercalating agents.
FAU - Leung, Kevin K K
AU  - Leung KK
AD  - Department of Biochemistry, University of Western Ontario , 1151 Richmond Street, 
      London, Ontario, Canada N6A 5C1.
FAU - Shilton, Brian H
AU  - Shilton BH
AD  - Department of Biochemistry, University of Western Ontario , 1151 Richmond Street, 
      London, Ontario, Canada N6A 5C1.
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151214
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Intercalating Agents)
RN  - 9007-49-2 (DNA)
RN  - EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone))
SB  - IM
MH  - Calorimetry
MH  - Cell Line, Tumor
MH  - Crystallography, X-Ray
MH  - DNA/*chemistry
MH  - Humans
MH  - Intercalating Agents/*chemistry
MH  - NAD(P)H Dehydrogenase (Quinone)/*chemistry
MH  - Oxidation-Reduction
MH  - Protein Conformation
EDAT- 2015/12/05 06:00
MHDA- 2016/04/23 06:00
CRDT- 2015/12/05 06:00
PHST- 2015/12/05 06:00 [entrez]
PHST- 2015/12/05 06:00 [pubmed]
PHST- 2016/04/23 06:00 [medline]
AID - 10.1021/acs.biochem.5b00884 [doi]
PST - ppublish
SO  - Biochemistry. 2015 Dec 29;54(51):7438-48. doi: 10.1021/acs.biochem.5b00884. Epub 
      2015 Dec 14.