# Molecular Mechanisms, Pathways and Inhibition of Acetyl-Transfer Reactions

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2021 · $578,808

## Abstract

The acetylation of proteins and RNA, and acetyl-transfer reactions that produce cellular metabolites, are
evolutionarily conserved modifications that are essential for life. The post- or co-translational acetylation of
proteins provides an essential mechanism for organisms to react to external and internal stimuli; examples
include acetylation of the e-amino group of lysine side chains of histone proteins by histone
acetyltransferases (HATs) or the N-terminal a-amino group by N-terminal acetyltransferases (NATs),
respectively; and the acetylation at the N4 position of cytidine bases by Nat10. Acetyl-transfer reactions
produce cellular metabolites that can mediate the biosynthesis of essential cellular building blocks;
examples include: acetyl-CoA produced by ATP-citrate lyase (ACLY) and acetyl-CoA synthetase short-
chain family member 2 (ACSS2); fatty acids produced by Fatty Acid Synthase (FASN); and cholesterol and
isoprenoids formed through the sequential reactions of many enzymes. The enzymes that mediate acetyl-
transfer reactions often function in the context of multiple domain proteins or multisubunit protein
complexes, which play essential roles in the regulation of cognate substrate recognition and targeting
and/or catalytic fidelity. How the various protein domains and protein cofactors cooperate for their
respective acetyl-transfer reactions remains poorly understood. Correlating with their biological importance,
the aberrant activities of acetyl-transfer enzymes or their regulatory proteins have been associated with
several maladies including cancers, rare genetic disorders, cardiovascular diseases and metabolic and
neurodegenerative syndromes, thus making these enzymes attractive drug targets for therapy. Taken
together, acetyl-transfer reactions play an important regulatory function in the vast majority of the human
proteome, RNAome and metabolome, and aberrant acetyl-transfer reaction function is correlated with
human disease. Despite the importance of acetyl-transfer reactions, mechanistic information regarding
their distinct modes of regulation are poorly understood and pharmacological agents that target them are
not available. In this proposal, we will address the following broad questions underlying acetyl-transfer
reactions: (A) How do protein and RNA acetyltransferases mediate substrate specificity? (B) How do
auxiliary proteins and ribosome association contribute to NAT function? (C) How does acetyl-CoA
metabolism link to chromatin regulation and fatty acid synthesis? (D) Can we leverage mechanistic and
structural information to develop potent and selective inhibitors for acetyl-transfer reactions? Together,
these studies will reveal how a common acetyltransferase fold is modulated by other proteins or domains to
mediate the acetylation of distinct substrates, how N-terminal protein acetylation is modulated by regulatory
and associated factors, dissect the molecular mechanism of essential acetyl-transfer enzymes, and provide
...

## Key facts

- **NIH application ID:** 10163349
- **Project number:** 2R35GM118090-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ronen Marmorstein
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $578,808
- **Award type:** 2
- **Project period:** 2016-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163349

## Citation

> US National Institutes of Health, RePORTER application 10163349, Molecular Mechanisms, Pathways and Inhibition of Acetyl-Transfer Reactions (2R35GM118090-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10163349. Licensed CC0.

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