RGD Reference Report - Alpha-phenyl-N-tert-butylnitrone (PBN) prevents light-induced degeneration of the retina by inhibiting RPE65 protein isomerohydrolase activity. - Rat Genome Database

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Alpha-phenyl-N-tert-butylnitrone (PBN) prevents light-induced degeneration of the retina by inhibiting RPE65 protein isomerohydrolase activity.

Authors: Mandal, MN  Moiseyev, GP  Elliott, MH  Kasus-Jacobi, A  Li, X  Chen, H  Zheng, L  Nikolaeva, O  Floyd, RA  Ma, JX  Anderson, RE 
Citation: Mandal MN, etal., J Biol Chem. 2011 Sep 16;286(37):32491-501. Epub 2011 Jul 24.
RGD ID: 6893661
Pubmed: PMID:21785167   (View Abstract at PubMed)
PMCID: PMC3173208   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M111.255877   (Journal Full-text)

alpha-Phenyl-N-tert-butylnitrone (PBN), a free radical spin trap, has been shown previously to protect retinas against light-induced neurodegeneration, but the mechanism of protection is not known. Here we report that PBN-mediated retinal protection probably occurs by slowing down the rate of rhodopsin regeneration by inhibiting RPE65 activity. PBN (50 mg/kg) protected albino Sprague-Dawley rat retinas when injected 0.5-12 h before exposure to damaging light at 2,700 lux intensity for 6 h but had no effect when administered after the exposure. PBN injection significantly inhibited in vivo recovery of rod photoresponses and the rate of recovery of functional rhodopsin photopigment. Assays for visual cycle enzyme activities indicated that PBN inhibited one of the key enzymes of the visual cycle, RPE65, with an IC(50) = 0.1 mm. The inhibition type for RPE65 was found to be uncompetitive with K(i) = 53 mum. PBN had no effect on the activity of other visual cycle enzymes, lecithin retinol acyltransferase and retinol dehydrogenases. Interestingly, a more soluble form of PBN, N-tert-butyl-alpha-(2-sulfophenyl) nitrone, which has similar free radical trapping activity, did not protect the retina or inhibit RPE65 activity, providing some insight into the mechanism of PBN specificity and action. Slowing down the visual cycle is considered a treatment strategy for retinal diseases, such as Stargardt disease and dry age-related macular degeneration, in which toxic byproducts of the visual cycle accumulate in retinal cells. Thus, PBN inhibition of RPE65 catalytic action may provide therapeutic benefit for such retinal diseases.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rpe65Ratretinal metabolic process  IMP  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rpe65Ratall-trans-retinyl-ester hydrolase, 11-cis retinol forming activity  IMP  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RPE65Humanretinoid cycle metabolic pathway   ISORpe65 (Rattus norvegicus) RGD 
Rpe65Ratretinoid cycle metabolic pathway   IMP  RGD 
Rpe65Mouseretinoid cycle metabolic pathway   ISORpe65 (Rattus norvegicus) RGD 
Objects Annotated

Genes (Rattus norvegicus)
Rpe65  (retinoid isomerohydrolase RPE65)

Genes (Mus musculus)
Rpe65  (retinal pigment epithelium 65)

Genes (Homo sapiens)
RPE65  (retinoid isomerohydrolase RPE65)


Additional Information