Researchers at the University of California, Irvine, have discovered profound similarities and surprising differences between humans and insects in the production of a key light-absorbing molecule in the retina, 11-cis-Retina, also called “visual chromophore”. The findings deepen the understanding of how mutations in the RPE65 enzyme cause retinal diseases, particularly Leber congenital amaurosis, a devastating childhood blindness disease.

for the study, recently published online in the journal Nature Chemical Biology, the team used X-ray crystallography to study NinaB, a protein found in insects that functions similarly to the RPE65 protein found in humans. Both are important for the synthesis of 11 .cis-Retina, and their absence results in severe visual impairment.

“Our study challenges traditional assumptions about the similarities and differences between human and insect vision,” said corresponding author Philip Kaiser, UCI associate professor of physiology and biophysics as well as ophthalmology. “While these enzymes share a common evolutionary origin and three-dimensional architecture, we found that the process by which they 11-cis-The retina is separate.”

Creation of 11cis-The retina begins by consuming foods like carrots or pumpkin that contain compounds used for vitamin A production, such as beta-carotene. These nutrients are metabolized by carotenoid cleavage enzymes, including NinaB and RPE65. It was previously known that humans need two of these enzymes to 11.cisRetinal from beta-carotene, while insects can only achieve transformation with NinaB. Gaining insight into how NinaB can couple the two steps in a single reaction with a functional relationship between NinaB and RPE65 was a major motivation for this study.

“We found that structurally, these enzymes are very similar, but the sites where they carry out their activities are different,” said lead author Yasmin Solano, a graduate student in Kaiser’s laboratory at the UCI Center for Translational Vision Research. Student. “Understanding key features within the NinaB structure has increased our understanding of the catalytic machinery necessary to support retinal visual pigment function. Through our studies of NinaB, we have learned about the structure of an important part of RPE65. ability that had not been previously resolved. This discovery is important for understanding and addressing loss-of-function in RPE65.”

Other team members included Michael Everett, a junior specialist in the Kaiser lab, and Kelly Dang and Jude Abigail, then undergraduates in biological sciences.

This work was supported by National Science Foundation Grant CHE-2107713, the Department of Veterans Affairs under Grant BX004939, and the National Institutes of Health under Grant EY034519-01S1.