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<StructureSection load='2f1o.pdb' size='450' scene='2f1o/Com_view/2'  caption='NADPH dehydrogenase complex with FAD (red) and dicoumarol (blue) [[2f1o]]'>
<StructureSection load='' size='350' scene='2f1o/Com_view/2'  caption='NADPH dehydrogenase complex with FAD (red) and dicoumarol (blue) [[2f1o]]'>
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'''Quinone reductase type 1 (QR1)''' reduces quinines to the non-toxic hydroquinone. '''Quinone reductase type 2 (QR2)''' catalyzes the reduction of adrenochrome.    The '''sulfide-quinone reductase (SQR)''' reduces sulfide and thus provides electrons for phototropic processes in bacteria. '''NADPH-quinone reductase (NQR)''' catalyzes the reduction of quinone to semiquinone. The images at the left and at the right correspond to one representative Quinone reductase, ''i.e.'' the crystal structure of NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol ([[2f1o]]).
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==Function==
*'''Quinone reductase type 1 (QR1)''' reduces quinines to the non-toxic hydroquinone.  
*'''Quinone reductase type 2 (QR2)''' or '''ribosyldihydronicotinamide dehydrogenase [quinone]''' catalyzes the reduction of adrenochrome.     
* '''Sulfide-quinone reductase (SQR)''' reduces sulfide and thus provides electrons for phototropic processes in bacteria.  
* '''NADPH-quinone reductase (NQR)''' catalyzes the reduction of quinone to semiquinone.  
*'''Na(+)-translocating NADH-quinone reductase''' is the Na(+) pumping respiratory complex found in prokaryotes<ref>PMID:25052842</ref>. 
See [[Electron Transport & Oxidative Phosphorylation]].


== NADH Quinone oxidoreductase type 1 (NQO1) in complex with its potent inhibitor dicoumarol ==
== NADH Quinone oxidoreductase type 1 (NQO1) in complex with its potent inhibitor dicoumarol ==
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Certain [http://en.wikipedia.org/wiki/Coumarin coumarins], [http://en.wikipedia.org/wiki/Flavones flavones] and the reactive dye cibacron blue are [http://en.wikipedia.org/wiki/Competitive_inhibition competitive inhibitors] of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin)),
Certain [http://en.wikipedia.org/wiki/Coumarin coumarins], [http://en.wikipedia.org/wiki/Flavones flavones] and the reactive dye cibacron blue are [http://en.wikipedia.org/wiki/Competitive_inhibition competitive inhibitors] of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin)),
is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the [http://en.wikipedia.org/wiki/Electron_transfer electron transfer] to FAD.
is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the [http://en.wikipedia.org/wiki/Electron_transfer electron transfer] to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the [http://en.wikipedia.org/wiki/Tumor_suppressor_gene tumor suppressor] p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase (ODC, ''i.e.'' [[7odc]]). NQO1 binds and stabilizes [[p53]], protecting p53 from [http://en.wikipedia.org/wiki/Proteasome#Ubiquitin-independent_degradation ubiquitin-independent 20S proteasomal degradation]. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the [http://en.wikipedia.org/wiki/Tumor_suppressor_gene tumor suppressor] p53 and several other short-lived proteins including p73α and ornithine decarboxylase (ODC, ''i.e.'' [[7odc]]). NQO1 binds and stabilizes [[p53]], protecting p53 from [http://en.wikipedia.org/wiki/Proteasome#Ubiquitin-independent_degradation ubiquitin-independent 20S proteasomal degradation]. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.


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The crystal structure of human NQO1 in complex with dicoumarol was determined at 2.75 Å resolution ([[2f1o]]). NQO1 is a <scene name='2f1o/Com_view/6'>physiological homodimer</scene> composed of two interlocked monomers. <scene name='2f1o/Com_view/7'>Two catalytic sites</scene> are formed and are present at the dimer interface (<font color='red'><b>FAD is colored red</b></font> and <font color='blue'><b>dicoumarol is colored blue</b></font>). Therefore, each from these two <scene name='2f1o/Active_site/3'>dicoumarol-hNQO1 binding sites</scene> is formed by both monomers. <font color='cyan'><b>Dicoumarol is colored cyan</b></font>, <font color='orange'><b>FAD in orange</b></font>, nitrogens and oxygens are shown in [http://en.wikipedia.org/wiki/CPK_coloring CPK colors]. NQO1 <font color='blueviolet'><b>chain A is colored blueviolet</b></font> and <font color='lime'><b>chain C in lime</b></font>.  NQO1 residues, participating in ligand interactions, are shown as stick representation and are labeled (A and C refer to the NQO1 chains). H-bonds are shown by dashed lines with their distances.  
The crystal structure of human NQO1 in complex with dicoumarol was determined at 2.75 Å resolution ([[2f1o]]). NQO1 is a <scene name='2f1o/Com_view/6'>physiological homodimer</scene> composed of two interlocked monomers. <scene name='2f1o/Com_view/7'>Two catalytic sites</scene> are formed and are present at the dimer interface (<font color='red'><b>FAD is colored red</b></font> and <font color='blue'><b>dicoumarol is colored blue</b></font>). Therefore, each from these two <scene name='2f1o/Active_site/3'>dicoumarol-hNQO1 binding sites</scene> is formed by both monomers. <span style="color:cyan;background-color:black;font-weight:bold;">Dicoumarol is colored cyan</span>, <span style="color:orange;background-color:black;font-weight:bold;">FAD in orange</span>, nitrogens and oxygens are shown in [http://en.wikipedia.org/wiki/CPK_coloring CPK colors]. NQO1 <font color='blueviolet'><b>chain A is colored blueviolet</b></font> and <span style="color:lime;background-color:black;font-weight:bold;">chain C in green</span>.  NQO1 residues, participating in ligand interactions, are shown as stick representation and are labeled (A and C refer to the NQO1 chains). H-bonds are shown by dashed lines with their distances.  
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<scene name='2f1o/Align/8'>Structural comparison</scene> of the active site of <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font> (residues important for ligand interactions are <font color='magenta'><b>colored magenta</b></font>) with that of <font color='blue'><b>apo hNQO1</b></font> dimer ([[1d4a]], residues important for ligand interactions are <font color='blue'><b>colored blue</b></font>) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. <font color='cyan'><b>Dicoumarol is colored in cyan</b></font>; <font color='orange'><b>FAD is colored in orange</b></font>. The RMSD between the apo hNQO1 ([[1d4a]]) and hNQO1 in complex with dicoumarol is 0.36Å for the 546 Cα atoms. The dicoumarol-hNQO1 binding causes several structural changes. The most prominent of them is Tyr 128 and Phe 232 movement in the first monomer. These residues are located on the surface of the NQO1 catalytic pocket. The <scene name='2f1o/Align/9'>distance</scene> between these residues increases from ~5 Å in the <font color='blue'><b>apo hNQO1</b></font> to ~12 Å in the <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font>.  
<scene name='2f1o/Align/8'>Structural comparison</scene> of the active site of <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font> (residues important for ligand interactions are <font color='magenta'><b>colored magenta</b></font>) with that of <font color='blue'><b>apo hNQO1</b></font> dimer ([[1d4a]], residues important for ligand interactions are <font color='blue'><b>colored blue</b></font>) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. <span style="color:cyan;background-color:black;font-weight:bold;">Dicoumarol is colored cyan</span>; <span style="color:orange;background-color:black;font-weight:bold;">FAD in orange</span>. The RMSD between the apo hNQO1 ([[1d4a]]) and hNQO1 in complex with dicoumarol is 0.36Å for the 546 Cα atoms. The dicoumarol-hNQO1 binding causes several structural changes. The most prominent of them is Tyr 128 and Phe 232 movement in the first monomer. These residues are located on the surface of the NQO1 catalytic pocket. The <scene name='2f1o/Align/9'>distance</scene> between these residues increases from ~5 Å in the <font color='blue'><b>apo hNQO1</b></font> to ~12 Å in the <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font>.  
Quinones (including duroquinone (2,3,5,6-tetramethyl-''p''-benzoquinone) are substrates of NQO1 (it catalyzes two-electron reduction of them to hydroquinones). Duroquinone <font color='black'><b>(yellow)</b></font> binds to the <scene name='2f1o/Align1/4'>active site</scene> by interactions involving the FAD and several hydrophobic and hydrophilic residues in the duroquinone-NQO1 complex ([[1dxo]]). The structure of the hNQO1 dimer in complex with duroquinone is also similar to that of hNQO1 in complex with dicoumarol (RMSD is 0.33Å for the 546 Cα atoms). In this case, the main differences between these two structures, as well as to that of apo hNQO1, involve the distance between residues <scene name='2f1o/Align1/5'>Tyr 128 and Phe 232</scene> of the first monomer. The FAD molecule has very similar conformation in both hNQO1-duroquinone <font color='pink'><b>(pink)</b></font> and hNQO1−dicoumarol <font color='orange'><b>(orange)</b></font> complexes. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
Quinones (including duroquinone (2,3,5,6-tetramethyl-''p''-benzoquinone) are substrates of NQO1 (it catalyzes two-electron reduction of them to hydroquinones). <span style="color:yellow;background-color:black;font-weight:bold;">Duroquinone (yellow)</span> binds to the <scene name='2f1o/Align1/4'>active site</scene> by interactions involving the FAD and several hydrophobic and hydrophilic residues in the duroquinone-NQO1 complex ([[1dxo]]). The structure of the hNQO1 dimer in complex with duroquinone is also similar to that of hNQO1 in complex with dicoumarol (RMSD is 0.33Å for the 546 Cα atoms). In this case, the main differences between these two structures, as well as to that of apo hNQO1, involve the distance between residues <scene name='2f1o/Align1/5'>Tyr 128 and Phe 232</scene> of the first monomer. The FAD molecule has very similar conformation in both <span style="color:pink;background-color:black;font-weight:bold;">hNQO1-duroquinone (pink)</span> and <span style="color:orange;background-color:black;font-weight:bold;">hNQO1−dicoumarol (orange)</span> complexes. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.


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The quinone ES936 causes irreversible inhibition of the NQO1. <scene name='2f1o/Align2/5'>Alignment</scene> of the hNQO1 dimer in complex with <font color='red'><b>ES936 (red)</b></font> ([[1kbq]]) with the hNQO1−dicoumarol complex ([[2f1o]]) yields 0.45Å RMSD for the 546 Cα atoms. The ES936 causes structural change only in the position of Phe 232. The movement of this residue is smaller than that caused by dicoumarol. The <scene name='2f1o/Align2/6'>distance</scene> between Tyr 128 and Phe 232 in the hNQO1−ES936 complex is only ~7 Å, while in the hNQO1−dicoumarol complex it is ~12 Å.
The quinone ES936 causes irreversible inhibition of the NQO1. <scene name='2f1o/Align2/5'>Alignment</scene> of the hNQO1 dimer in complex with <font color='red'><b>ES936 (red)</b></font> ([[1kbq]]) with the hNQO1−dicoumarol complex ([[2f1o]]) yields 0.45Å RMSD for the 546 Cα atoms. The ES936 causes structural change only in the position of Phe 232. The movement of this residue is smaller than that caused by dicoumarol. The <scene name='2f1o/Align2/6'>distance</scene> between Tyr 128 and Phe 232 in the hNQO1−ES936 complex is only ~7 Å, while in the hNQO1−dicoumarol complex it is ~12 Å.
</StructureSection>


== 3D Structures of Quinone reductase ==
== 3D Structures of Quinone reductase ==


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
[[Quinone reductase 3D structures]]
{{#tree:id=OrganizedByTopic|openlevels=0|
 
*Quinone reductase type 1
 
**[[3jsx]] – hQR1 + coumarine derivative<br />
**[[2f1o]] – hQR1 + dicoumarol<br />
**[[1kbo]], [[1kbq]] – hQR1 + indole derivative<br />
 
*Quinone reductase type 2
 
**[[3fw1]], [[1qr2]] – hQR2 - human<br />
**[[3o2n]], [[3g5m]], [[3gam]] – hQR2 + PET agent<br />
**[[3ovm]], [[3owh]], [[3owx]] – hQR2 + carbamate derivative<br />
**[[3ox1]], [[2qx4]], [[2qx6]], [[2qx8]], [[2qx9]], [[2qwx]] – hQR2 + acetamide derivative<br />
**[[3ox2]] - hQR2 + indole derivative<br />
**[[3ox3]] - hQR2 + carboxamide derivative<br />
**[[2qmy]] – hQR2 + adrenochrome<br />
**[[2qr2]] – hQR2 + menadione<br />
**[[2qmz]] – hQR2 + dopamine<br />
**[[1sg0]] – hQR2 + resveratol<br />
**[[3nhu]], [[3nhs]], [[3nhr]], [[3nhp]], [[3nhl]], [[3nhk]], [[3nhj]], [[3nhf]], [[3nfr]], [[3nhw]], [[3nhy]], [[3uxe]], [[3uxh]] - hQR2 + quinoline derivative<br />
**[[3te7]], [[3tem]], [[3tzb]] – hQR2 + acridine derivative<br />
**[[2bzs]], [[1xi2]], [[1zx1]], [[3o73]] – hQR2 + anti-cancer prodrug<br />
**[[4fgj]], [[4fgk]], [[4fgl]] – hQR2 + anti-malaria drug<br />
**[[4gqi]], [[4gr9]] – hQR2 + ligand<br />
 
*Sulfide-quinone reductase
 
**[[3hyv]] – AaSQR – ''Aquifex aeolicus''<br />
**[[3hyw]] – AaSQR + decylubiquinone<br />
**[[3hyx]] – AaSQR + Aurachin C<br />
 
*NADPH-quinone reductase
 
**[[3ha2]] – NQR – ''Pediococcus pentosaceus''<br />
**[[1dxq]], [[1d4a]] - hNQR<br />
**[[1yb5]] – hNQR + NADP<br />
**[[1gg5]], [[1h66]], [[1h69]], [[1qbg]] - hNQR + anti-cancer prodrug<br />
**[[1dxo]] - hNQR + quinone derivative<br />
 
*Quinone reductase


**[[1qrd]] – QR + bicarbon blue + duroquinone - rat<br />
**[[4gi5]] – QR + FAD – ''Klebsiella pneumoniae''
}}
==References==
==References==
<ref group="xtra">PMID:10706635</ref> <ref group="xtra">PMID:16700548</ref> <references group="xtra"/>
<ref group="xtra">PMID:10706635</ref> <ref group="xtra">PMID:16700548</ref> <references group="xtra"/>
 
<references/>
</StructureSection>
[[Category:Topic Page]]
[[Category:Topic Page]]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky, Michal Harel, Joel L. Sussman
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