# Metabolic regulation and inhibition of ATP-citrate lyase

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $602,995

## Abstract

The overall goal of this proposal is to dissect the molecular mechanisms of metabolic regulation of ATP-citrate
lyase (ACLY) and to characterize ACLY inhibitors for cancer therapy. ACLY is the predominant source of
nucleocytosolic acetyl-CoA, an essential building block for the production of fatty acids, cholesterol,
isoprenoids and protein acetylation. Elevated ACLY activity is found in metabolic disorders, cardiovascular
diseases and many cancers, prompting the development of several ACLY inhibitors. While many ACLY
inhibitors have been developed, only bempedoic acid, which forms an active bempedoyl-CoA adduct in
hepatocytes, has been approved by the FDA for therapeutic use. Risk of hepatocellular carcinoma is elevated
in individuals with metabolic disorders, many of whom may be candidates for treatment with bempedoic acid;
yet metabolic regulation of ACLY activity and its functional role in hepatocellular carcinoma remain poorly
understood. Elevated levels of ACLY acetylation at K540, K546 and K554 and phosphorylation at S455 and
S481, and retention of exon 14 encoding a region with S481, have also been correlated with cancer, thus also
suggesting roles for ACLY posttranslational and posttranscriptional modification in cancer metabolism. ACLY
is an ~500 kD multidomain homotetrameric enzyme that uses citrate, CoA and ATP cosubstrates to produce
oxaloacetate (OAA) and acetyl-CoA. Until recently, the lack of structural information on intact human ACLY has
hampered understanding of its molecular mechanism of catalysis and the structure-based development of
inhibitors. The Wellen lab recently reported on various disease-associated phenotypes associated with
dysregulated ACLY function; and the Marmorstein lab reported on the cryo-EM structures of ACLY in different
reaction states, along with associated biochemical and biophysical studies, to elucidate the molecular basis for
acetyl-CoA production by ACLY. The latter findings lead to several unresolved questions underlying the
metabolic regulation of ACLY and set the stage for the structure-based development of more potent and
selective ACLY inhibitors for therapeutic applications. These recent studies now position the Wellen and
Marmorstein labs to work together to resolve important gaps in knowledge in metabolic regulation and
inhibition of ACLY, through the following specific aims: (1) Evaluate the role of metabolic binders in ACLY
activity, (2) Determine the molecular mechanism of how posttranslational modifications and exon 14 retention
impact ACLY regulation, and (3) Evaluate the molecular mode of action of ACLY inhibitors. Together, these
studies will reveal the molecular mechanisms for how ACLY activity and regulation is mediated by the binding
of metabolites, and posttranscriptional and posttranslational modification and will lead to the rational
development of ACLY drugs to treat cancer.

## Key facts

- **NIH application ID:** 10819229
- **Project number:** 5R01CA262055-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** George Burslem
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $602,995
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819229

## Citation

> US National Institutes of Health, RePORTER application 10819229, Metabolic regulation and inhibition of ATP-citrate lyase (5R01CA262055-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10819229. Licensed CC0.

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