Enzymatic Degradation of A2E, a Retinal Pigment Epithelial Lipofuscin Bisretinoid

Wu, Yalin; Zhou, Jilin; Fishkin, Nathan; Rittmann, Bruce E.; Sparrow, Janet R.

doi:10.1021/ja107195u

Cited by 50Retinal Diseases and TreatmentsRetinal Development and DisordersAntioxidant Activity and Oxidative Stress

Enzymatic Degradation of A2E, a Retinal Pigment Epithelial Lipofuscin Bisretinoid

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Wu, Yalin, Zhou, Jilin, Fishkin, Nathan, Rittmann, Bruce E., Sparrow, Janet R.·2011·Journal of the American Chemical Society

DOI 10.1021/ja107195uPMC PMC4112458

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Abstract

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.

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A2E can be further metabolized by horseradish peroxidase, but there is no evidence that this process occurs in vivo.
“A2E was shown to be further metabolized by horseradish peroxidase,543 but there is yet no evidence that this process occurs in vivo.”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [543]
Cockayne syndrome, with nucleotide excision repair deficiency limited to actively transcribed genes and a mild oxidative damage repair effect, also includes hearing loss with hair cell and spiral ganglion death.
“Cockayne syndrome, with a deficiency in nucleotide excision repair limited to actively transcribed genes (plus a mild effect on repair of oxidative damage (198)), also features hearing loss with death of hair cells and the spiral ganglion (175, 199).”
From Chemiexcitation: Mammalian Photochemistry in the Dark† (2023) · cites this paper as [175]
The Introduction and Discussion address retinal lipofuscin and enzymatic degradation of A2E, not Cockayne syndrome. Searches for Cockayne syndrome, hearing loss, hair-cell and spiral-ganglion death, and the specified DNA-repair deficiencies found no relevant passage in our copy. (LLM, conf=0.75)
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Authors: Wu, Y., Zhou, J., Fishkin, N., Rittmann, B. E., & Sparrow, J. R.
Affiliations: Columbia University (US)
Columbia University Irving Medical Center (US)
ImmunoGen (United States) (US)
Arizona State University (US)
Corresponding author: Sparrow, Janet R.
ORCID: Wu, Yalin
Rittmann, Bruce E.
Sparrow, Janet R.
Venue: Journal of the American Chemical Society
Publisher: American Chemical Society (ACS)
Published: 2010-12-17
Volume: 133
Issue: 4
Pages: 849-857
ISSN: 0002-7863 (ISSN-L)
1520-5126
DOI: 10.1021/ja107195u
PMC: PMC4112458
OpenAlex: W2017973973
Cited by: 50
References: 45
Citations by year: 2026: 3 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 8 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 2
FWCI: 2.80
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of the American Chemical Society (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Eye Institute (R01EY012951, EY 12951, P30EY019007)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords: A2E, bisretinoids, lipofuscin, retinal pigment epithelium, horseradish peroxidase, enzymatic degradation, macular degeneration, lysosomal enzyme deficiency, cleavage products, 18O labeling, 1H NMR, UPLC-ESI-MS
MeSH terms: Adult, Aldehydes, Cell Line, Cell Survival, Cell-Free System, Chromatography, High Pressure Liquid, Horseradish Peroxidase, Humans, Lipofuscin, Magnetic Resonance Spectroscopy, Pyridinium Compounds, Retinoids, Mass Spectrometry, Intracellular Space, Retinal Pigment Epithelium

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Enzymatic Degradation of A2E, a Retinal Pigment Epithelial Lipofuscin Bisretinoid

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