Researchers at the University of California, Irvine have discovered profound similarities and surprising differences between humans and insects in the production of the retina's critical light-absorbing molecule, 11-cis-retinal, also known as “visual chromophore”. The findings deepen the understanding of how mutations in the RPE65 enzyme cause retinal diseases, especially Leber congenital amaurosis, a devastating disease that blinds children.
For the study, recently published online in the journal Nature Chemistry 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 crucial for the synthesis of 11-cis-retinal, and its absence produces serious visual impairment.
“Our study challenges traditional assumptions about the similarities and differences of human and insect vision,” said corresponding author Philip Kiser, associate professor of physiology and biophysics, as well as of ophthalmology at UCI. “While these enzymes share a common evolutionary origin and three-dimensional architecture, we discovered that the process by which they produce 11-cis-The retina is different.”
Creation of 11-cis-retinal begins with the consumption of foods such as carrots or pumpkins that contain compounds used for the generation of vitamin A, such as beta-carotene. These nutrients are metabolized by carotenoid-cleaving enzymes, including NinaB and RPE65. It was previously known that humans need two of these enzymes to produce 11-cis-retinal from beta-carotene, while insects can achieve the conversion with only NinaB. A key motivation for the study was to gain insight into how NinaB can combine the two steps into a single reaction along with the functional relationships between NinaB and RPE65.
“We found that structurally these enzymes are very similar, but the places where they perform their activity are different,” said lead author Yasmeen Solano, a graduate student in Kiser's lab at the Center for Translational Vision Research. ICU. “Understanding key features within the structure of NinaB has led to a better understanding of the catalytic machinery necessary to support the function of retinal visual pigments. Through our study of NinaB, we were able to learn about the structure of a key portion of RPE65 that “had not been previously resolved. “This discovery is vital to understanding and addressing loss-of-function mutations in RPE65.”
Other members of the team included Michael Everett, a junior specialist in Kiser's lab, and Kelly Dang and Jude Abueg, undergraduate biological sciences students at the time.
This work was supported by the National Science Foundation under grant CHE-2107713, the Department of Veterans Affairs under grant BX004939, and the National Institutes of Health under grant EY034519-01S1.