# The role of NAGK cysteine deprotonation in nutrient stress and cancer progression

> **NIH NIH R03** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $84,750

## Abstract

PROJECT SUMMARY/ ABSTRACT
Changes in cellular glycosylation support cancer growth and progression, but the biosynthetic pathways that
supply the required nucleotide-sugar precursors are resource intensive. The cell therefore utilizes salvage
pathways to recycle free sugars following glycan degradation or extracellular uptake, offsetting the need for their
de novo synthesis. Little is known about the extent to which cancer cells rely on sugar salvage pathways or how
these pathways are regulated. Recently, the salvage kinase responsible for phosphorylating N-
acetylglucosamine (GlcNAc) for reuse by the hexosamine biosynthetic pathway, N-acetyl-D-glucosamine kinase
(NAGK), was found to support tumor growth, providing early evidence that cancer cells may indeed rely heavily
on salvage. Preliminary data presented here show that NAGK is deprotonated at two cysteines in response to
nutrient limitation, a condition frequently encountered in the tumor microenvironment. Cysteine deprotonation
can alter protein activity and promote subsequent oxidation. This deprotonation is observed not just on NAGK,
but on proteins throughout the cell in what may be a previously unrecognized adaptation to stress. Cysteines,
especially in the deprotonated thiolate state, serves as ready sites of covalent inhibition by small molecule
electrophiles. Thus, the wide-spread increase in thiolates in response to nutrient limitation may represent a class
of proteins that are more responsive to covalent inhibition within stressed tumor cells than when in their
protonated thiol state in healthy, perfused tissue. The aims detailed in this proposal will first characterize the
effect of cysteine deprotonation on NAGK activity and its role in tumor growth and will then focus on identifying
the global changes in cysteine protonation status in response to nutrient limitation as well as the environmental
factors that promote this deprotonation. This work will characterize, both mechanistically and broadly, a novel
stress response that may promote tumor progression despite nutrient limitation but that may also render the
tumor more vulnerable to therapeutic intervention with small molecule electrophiles.

## Key facts

- **NIH application ID:** 10831534
- **Project number:** 5R03CA280299-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** JOHN BLENIS
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $84,750
- **Award type:** 5
- **Project period:** 2023-04-21 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831534

## Citation

> US National Institutes of Health, RePORTER application 10831534, The role of NAGK cysteine deprotonation in nutrient stress and cancer progression (5R03CA280299-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10831534. Licensed CC0.

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