RPE65 has an additional function as the lutein to meso -zeaxanthin isomerase in the vertebrate eye

Abstract

Carotenoids are plant-derived pigment molecules that vertebrates cannot synthesize de novo that protect the fovea of the primate retina from oxidative stress and light damage. -Zeaxanthin is an ocular-specific carotenoid for which there are no common dietary sources. It is one of the three major carotenoids present at the foveal center, but the mechanism by which it is produced in the eye is unknown. An isomerase enzyme is thought to be responsible for the transformation of lutein to-zeaxanthin by a double-bond shift mechanism, but its identity has been elusive. We previously found that -zeaxanthin is produced in a developmentally regulated manner in chicken embryonic retinal pigment epithelium (RPE)/choroid in the absence of light. In the present study, we show that RPE65, the isomerohydrolase enzyme of the vertebrate visual cycle that catalyzes the isomerization of all-retinyl esters to 11--retinol, is also the isomerase enzyme responsible for the production of -zeaxanthin in vertebrates. Its RNA is up-regulated 23-fold at the time of-zeaxanthin production during chicken eye development, and we present evidence that overexpression of either chicken or human RPE65 in cell culture leads to the production of -zeaxanthin from lutein. Pharmacologic inhibition of RPE65 function resulted in significant inhibition of-zeaxanthin biosynthesis during chicken eye development. Structural docking experiments revealed that the epsilon ring of lutein fits into the active site of RPE65 close to the nonheme iron center. This report describes a previously unrecognized additional activity of RPE65 in ocular carotenoid metabolism.

All three human scavenger receptor class B proteins can bind and transport all three macular xanthophyll carotenoids

“…Even though meso -zeaxanthin is not a common dietary component and is synthesized in the RPE enzymatically from lutein [28], supplements of this carotenoid are on the market [12]. It is hypothesized that consumption of such supplements may have positive effects on visual function [27], and protein mediated transport and deposition from the RPE to the retina would still be important.…”

Impacts of deletion and ichthyosis prematurity syndrome‐associated mutations in fatty acid transport protein 4 on the function of RPE65

“…It catalyzes the synthesis of 11-cis-retinol from all-trans-retinyl fatty acid esters, such as alltrans-retinyl palmitate, synthesized by lecithin:retinol acyltransferase (LRAT) and other enzymes in the RPE [3][4][5][6][7][8]. RPE65 is also the isomerase enzyme responsible for the production of meso-zeaxanthin, one of the three macular pigments that function as potent antioxidants and light screening pigments to protect macular from blue light damage and reactive oxygen species [9,10]. In agreement with the pivotal roles, mutations in the RPE65 gene cause vision loss and photoreceptor degeneration in affected patients, canines, and mice [11,12].…”

Mechanisms of Transport and Delivery of Vitamin A and Carotenoids to the Retinal Pigment Epithelium

“…Another issue is the origin of mZEA in the retina since it is not present in most diets. Recent elegant work suggests that RPE65 catalyzes the formation of mZEA from LUT and thus RPE is a likely source of this unique macular xanthophyll . Moreover, the presence of a number of xanthophyll‐binding proteins (XBPs) in the retina may well help determine the content of xanthophylls in various cell types in the retina .…”