Enzymatic Degradation of A2E, a Retinal Pigment Epithelial Lipofuscin Bisretinoid

Some forms of blinding macular disease are associated with excessive accumulation of bisretinoid lipofuscin in retinal pigment epithelial (RPE) cells of the eye. This material is refractory to lysosomal enzyme degradation. In addition to gene and drug-based therapies, treatments that reverse the acc...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2011-02, Vol.133 (4), p.849-857
Main Authors: Wu, Yalin, Zhou, Jilin, Fishkin, Nathan, Rittmann, Bruce E, Sparrow, Janet R
Format: Article
Language:English
Subjects:
Adult
Aldehydes - chemistry
Cell Line
Cell Survival - drug effects
Cell-Free System
Chromatography, High Pressure Liquid
Horseradish Peroxidase - metabolism
Humans
Intracellular Space - metabolism
Lipofuscin - chemistry
Lipofuscin - metabolism
Lipofuscin - toxicity
Magnetic Resonance Spectroscopy
Mass Spectrometry
Pyridinium Compounds - chemistry
Pyridinium Compounds - metabolism
Pyridinium Compounds - toxicity
Retinal Pigment Epithelium - cytology
Retinal Pigment Epithelium - drug effects
Retinal Pigment Epithelium - metabolism
Retinoids - chemistry
Retinoids - metabolism
Retinoids - toxicity
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Summary:Some forms of blinding macular disease are associated with excessive accumulation of bisretinoid lipofuscin in retinal pigment epithelial (RPE) cells of the eye. This material is refractory to lysosomal enzyme degradation. In addition to gene and drug-based therapies, treatments that reverse the accumulation of bisretinoid would be beneficial. Thus, we have examined the feasibility of degrading the bisretinoids by delivery of exogenous enzyme. As proof of principle we report that horseradish peroxidase (HRP) can cleave the RPE bisretinoid A2E. In both cell-free and cell-based assays, A2E levels were decreased in the presence of HRP. HRP-associated cleavage products were detected by ultraperformance liquid chromatography (UPLC) coupled to electrospray ionization mass spectrometry, and the structures of the aldehyde-bearing cleavage products were elucidated by 18O-labeling and 1H NMR spectroscopy and by recording UV−vis absorbance spectra. These findings indicate that RPE bisretinoids such as A2E can be degraded by appropriate enzyme activities.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja107195u