# Role of crystallin racemization and isomerization in cataract

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $373,450

## Abstract

Project Summary
Age-related cataract is associated with extensive deamidation, racemization, and isomerization of crystallins,
the major refractive proteins of the lens. Extensive studies by our laboratories and others have found
deamidation significantly decreases the stability of crystallins with minimal structural perturbations. However,
these deamidation mimics created using mutagenesis did not readily aggregate in vitro. We hypothesize that
this is because they were lacking racemization and isomerization, two modifications accompanying
deamidation that may be more disruptive to crystallin structure than deamidation alone. Unlike deamidation,
these modifications cannot be introduced into crystallins by genetic means. This has prevented studies to
gauge the importance of these additional modifications in age-related cataract. Therefore, the purpose of
these experiments is to create γS-crystallins containing specific sites of physiologically relevant racemized and
isomerized aspartates that result from the age-related deamidation process and determine their effect on
protein structure. The specific aims are to: 1) use synthetic heavy peptide standards and high-resolution mass
spectrometry to determine the relative proportion of different racemized and isomerized aspartates in γS-
crystallin from the insoluble protein of aged cataractous human lenses so that relevant species can be
selected, 2) introduce these racemized and isomerized residues into γS-crystallin using semi-synthetic
processes that have never before been used in the lens field, and 3) examine the result of these modifications
on γS-crystallin structure using protein stability and light scattering measurements, hydrogen/deuterium
exchange mass spectrometry, and nuclear magnetic resonance spectroscopy. These experiments will, for the
first time, critically test the potential impact of age-related racemization and isomerization on crystallin
structure. These results could play an important role in slowing cataract development by developing drugs that
specifically prevent the aggregation and light scatter of racemized and isomerized crystallins in aged lenses.

## Key facts

- **NIH application ID:** 10242798
- **Project number:** 5R01EY027768-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** LARRY L DAVID
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,450
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242798

## Citation

> US National Institutes of Health, RePORTER application 10242798, Role of crystallin racemization and isomerization in cataract (5R01EY027768-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242798. Licensed CC0.

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