TY - JOUR
T1 - Lipofuscin Formation Catalyzed by the Milk Protein β-Lactoglobulin
T2 - Lysine Residues in Cycloretinal Synthesis
AU - Gowda, Vishruth
AU - Foulke-Abel, Jennifer
AU - Agbo, Hillary
AU - Bench, Bennie J.
AU - Chae, Jooyeon
AU - Russell, William K.
AU - Watanabe, Coran M.H.
N1 - Funding Information:
*E-mail: [email protected]. ORCID Coran M. H. Watanabe: 0000-0003-1332-8155 Funding The authors are grateful to the National Science Foundation (CHE-1608580) and the Welch Foundation (A-1828). Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2017 American Chemical Society.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/10/31
Y1 - 2017/10/31
N2 - Lipofuscins are toxic autofluorescent byproducts of the visual cycle. The accumulation of lipofuscins such as cycloretinal in the retina is thought to play a role in the progression of age-related macular degeneration (AMD). Intriguingly, the milk protein β-lactoglobulin (BLG) can promote the cyclodimerization of all-trans-retinal to cycloretinal both in vitro and in vivo. Here, site-directed mutagenesis of BLG and mass spectrometric analysis with substrate analogues demonstrate that lysine residues play a key role in catalysis. It is also shown that catalytic activity necessitates the presence of a physical binding site and cannot be mediated by a peptide chain. These studies provide insight into the mechanism of the cyclodimerization process and provide a model system for biocatalysis and biosynthesis of cycloretinal in vivo. In the long term, these studies may pave the way for drug development and inhibitor design as an early treatment regimen for AMD.
AB - Lipofuscins are toxic autofluorescent byproducts of the visual cycle. The accumulation of lipofuscins such as cycloretinal in the retina is thought to play a role in the progression of age-related macular degeneration (AMD). Intriguingly, the milk protein β-lactoglobulin (BLG) can promote the cyclodimerization of all-trans-retinal to cycloretinal both in vitro and in vivo. Here, site-directed mutagenesis of BLG and mass spectrometric analysis with substrate analogues demonstrate that lysine residues play a key role in catalysis. It is also shown that catalytic activity necessitates the presence of a physical binding site and cannot be mediated by a peptide chain. These studies provide insight into the mechanism of the cyclodimerization process and provide a model system for biocatalysis and biosynthesis of cycloretinal in vivo. In the long term, these studies may pave the way for drug development and inhibitor design as an early treatment regimen for AMD.
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U2 - 10.1021/acs.biochem.7b00709
DO - 10.1021/acs.biochem.7b00709
M3 - Article
C2 - 28960961
AN - SCOPUS:85032634550
SN - 0006-2960
VL - 56
SP - 5715
EP - 5719
JO - Biochemistry
JF - Biochemistry
IS - 43
ER -