# Protein Acylation and Methylation Mechanisms

> **NIH NIH R37** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $429,600

## Abstract

This proposal is a competing renewal application of R01 GM62437 that combines the use
of chemical approaches, enzymologic analysis, and cellular studies to enhance our
understanding of enzymes regulating protein acylation and methylation. It is now well-accepted
that post-translational modifications (PTMs) involving lysine acetylation and
reversible methylation on histones and other proteins are central to epigenetics. Such
epigenetic modifying enzymes are viewed as attractive drug targets for cancer and other
diseases. The ghrelin O-acyltransferase (GOAT) enzyme catalyzes the unusual PTM of
octanoyl attachment to a Ser side chain of the peptide hormone ghrelin and inhibitors of
this enzyme may be useful in the treatment of obesity and diabetes. Although there has
been increasing efforts to understand the mechanisms and functions of these PTMs and
the enzymes that catalyze them, there are major gaps in our understanding in these areas.
Filling these knowledge gaps has the potential to provide a clearer understanding of basic
biomedical processes and has the opportunity to enhance the development of novel
therapeutic approaches and disease diagnostic strategies. There are four Specific Aims in
this proposal. 1. Elucidate the molecular basis for protein substrate selectivity for
histone acetyltransferases (HAT) using new chemical and biochemical approaches. We
will develop and apply new techniques to generate histone-CoA conjugates and exploit
protein microarrays to clarify structural and functional features of HAT-substrate
interactions. 2. Develop and apply improved chemical tools for analyzing LSD1 histone
demethylation. A combination of synthetic inhibitors and propargyl-histones will be
prepared to interrogate LSD1 cellular functions and molecular interactions. 3. Clarify the
effects of Lys acetylation on S-adenosyl homocysteine hydrolase and inositol
monophosphate dehydrogenase-2. Expressed protein ligation will be used to install
acetyl-Lys site-specifically into these metabolic enzymes to dissect potentially important
nodes between protein acetylation and cellular metabolism. 4. Define major structural
features of ghrelin O-acyltransferase. A combination of membrane topology mapping
and bisubstrate analog crosslinking will be used to create a blueprint of this key
metabolic regulatory enzyme. We believe that this research effort has the potential to
greatly expand our understanding of protein post-translational modification mechanisms
and functions and identify new therapeutic opportunities for treating metabolic and
neoplastic diseases.

## Key facts

- **NIH application ID:** 9872165
- **Project number:** 5R37GM062437-21
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** PHILIP A COLE
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,600
- **Award type:** 5
- **Project period:** 2001-02-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872165

## Citation

> US National Institutes of Health, RePORTER application 9872165, Protein Acylation and Methylation Mechanisms (5R37GM062437-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9872165. Licensed CC0.

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