# How Distinct are the two Chiral Sulfur Epimers of Amyloid Beta Met35 Sulfoxide in their Aggregation, Toxicity and Reactivity with Methionine Sulfoxide Reductases A and B?

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2022 · $183,829

## Abstract

ABSTRACT
Amyloid beta (Aβ)42 is an aggregation-prone peptide and a believed seminal etiological agent of Alzheimer’s
Disease. A common post-translational modification of Aβ42 is its oxidation at the methionine (Met) 35 residue.
Met35 oxidation is physiologically relevant, with a large portion of Alzheimer’s amyloid plaques made up of
Aβ42-Met35SO. There is a remarkable level of disagreement in the Alzheimer’s field with regard to both
biophysical and biological consequences of Aβ42 Met35 oxidation. As such, it has been claimed to both
promote and suppress aggregation and it has also been claimed to both enhance and reduce toxicity.
Oxidation of Aβ42 Met35 renders the sulfur chiral. This means that two and not one Aβ42-Met35SO peptides
are produced. The interconversion barrier between Aβ42-Met35-(R)-SO and Aβ42-Met35-(S)-SO is extremely
high (we calculated it as 45.2 kcal/mol using quantum chemical methods), and the two peptides have to be
considered distinct species under physiological conditions. The formation of two stereochemically stable chiral
sulfur epimers in consequence Aβ42 Met35 oxidation has never been considered in the Alzheimer’s field.
We have recently reported a supercritical CO2-based separation protocol that now allows obtaining Met-(R)-
SO and Met-(S)-SO in gram quantities with purities exceeding 99.5%. Using these building blocks, we were
able to make the Ab42-Met35-(R)-SO and Ab42-Met35-(S)-SO chiral sulfur epimers with no loss of
stereochemical information. Here we propose to determine the degree to which sulfur chirality influences
Aβ42-Met35-(R)-SO and Aβ42-Met35-(S)-SO aggregation, neuronal uptake and toxicity. We also propose to
develop assays that use a combination of LC/MS and NMR to measure kinetics of Aβ42-Met35-(R)-SO and
Aβ42-Met35-(S)-SO reduction by methionine sulfoxide reductases (MSR) A and B.
Research proposed here is expected to resolve a long-standing controversy with regard to the functional
consequences of Aβ42 Met35 oxidation and will set the stage for future R01-funded experiments to study toxic
actions of Aβ42-Met35-(R)-SO and Aβ42-Met35-(S)-SO and their reduction to Aβ42 through MSRA and MSRB
in hippocampal and cortical brain tissue, as well as animal models.

## Key facts

- **NIH application ID:** 10360472
- **Project number:** 5R21AG070888-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Jevgenij Raskatov
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $183,829
- **Award type:** 5
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360472

## Citation

> US National Institutes of Health, RePORTER application 10360472, How Distinct are the two Chiral Sulfur Epimers of Amyloid Beta Met35 Sulfoxide in their Aggregation, Toxicity and Reactivity with Methionine Sulfoxide Reductases A and B? (5R21AG070888-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10360472. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*