# Isomerization in cell-to-cell signaling peptides: from discovery to function

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $329,873

## Abstract

Project Summary
In the effort to understand brain function in both healthy and disease states, it is important to identify the active
structures of cell-to-cell signaling neuropeptides and elucidate their cellular signaling pathways. This
information enables the design of therapeutic compounds to modulate these pathways for treating a variety of
human health conditions. Neuropeptides can undergo a subtle post-translational modification (PTM) that
isomerizes one amino acid residue from the L-stereoisomer to the D-stereoisomer. L- to D-residue isomerization
alters the three-dimensional structure of the resulting D-amino acid-containing peptide (DAACP), often leading
to significantly higher biological potency and stability relative to the all-L-residue analogue. A related PTM is
the formation of isoaspartate from aspartate residues to form isoaspartate-containing peptides (IsoAspPs), a
modification that has been implicated in a number of neurological disorders. However, both L- to D-residue
isomerization and isoaspartate formation are difficult to detect because these modifications do not change a
compound’s mass or chemical composition, rendering these PTMs “invisible” to most peptide characterization
approaches. The central hypothesis is that DAACPs and IsoAspPs are present as cell-to-cell signaling
peptides in many animals, including mammals, but have been mischaracterized due to technological
deficiencies in detecting peptide residue isomerization. There is currently an unmet requirement for methods to
detect and predict the occurrence of these functionally important PTMs. This need is addressed with a DAACP
and IsoAspP discovery funnel, a new technology designed to study the synthesis and signaling of peptides that
undergo isomerization, with the long-term objective being to use this information to establish the
neurobiological role these PTMs play in healthy organisms and in neurological disorders. Aim 1 will develop a
non-targeted method to screen for DAACPs and IsoAspPs in a variety of animals and biological tissues. The
method will be used to fully characterize the suite of DAACPs and IsoAspPs present in the central nervous
system of the model organism Aplysia californica, as well as in central nervous, endocrine, and heart tissues of
mouse. Simultaneously, Aim 2 will create a method to identify DAACPs and IsoAspPs at the level of the single
cell using on-slide enzymatic digestion coupled to sensitive single cell mass spectrometry techniques. Finally,
Aim 3 will fully characterize the biosynthesis and signaling of known DAACPs in Aplysia, including identifying
the first L/D-isomerase enzyme that acts on cell-to-cell signaling peptides, which will allow for the identification
of homologous enzymes in other animals, including mammals. Together, these efforts will define the
importance of cell-to-cell signaling DAACPs and IsoAspPs and characterize their synthesis and function
throughout the nervous system. The tools developed will have wide ap...

## Key facts

- **NIH application ID:** 10136117
- **Project number:** 5R01NS031609-26
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Jonathan V. Sweedler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,873
- **Award type:** 5
- **Project period:** 1993-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136117

## Citation

> US National Institutes of Health, RePORTER application 10136117, Isomerization in cell-to-cell signaling peptides: from discovery to function (5R01NS031609-26). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10136117. Licensed CC0.

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