C326
Source C326 at Peptiology
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Summary
C326 denotes a cysteine residue at position 326 found in several human proteins, including the m6A methyltransferase METTL3, the glycolytic enzyme PKM2, the iron exporter ferroportin, and the E3 ligase FBXO22. Across recent studies, this thiol side chain serves as a reactive hotspot for post‑translational modifications such as S‑nitrosylation, sulfhydration, and covalent binding by small‑molecule degraders, thereby influencing protein stability, enzymatic activity, and cellular signaling pathways.
Mechanism of Action
The sulfhydryl group of C326 can undergo reversible modifications (e.g., S‑nitrosylation, sulfhydration) that alter the local conformation of the host protein. In METTL3, S‑nitrosylation enhances methyltransferase activity, modulating m6A‑dependent mRNA stability. In PKM2, sulfhydration at C326 destabilises the tetramer, shifting metabolism toward glycolysis. In ferroportin, mutation of C326 disrupts hepcidin binding, preventing receptor internalisation. In FBXO22, covalent attachment of aldehyde‑bearing degraders to C326 creates a new interaction surface that recruits neosubstrates for ubiquitination and proteasomal degradation.
What the Research Shows
Multiple 2024‑2026 reports have characterised C326 as a functional hotspot. In β‑cells, redox‑dependent S‑nitrosylation of METTL3 C276/C326 supports m6A‑mediated dampening of innate immune genes, and prolonged METTL3 overexpression delays type‑1 diabetes in NOD mice. H2S‑mediated sulfhydration of PKM2 C326 disrupts tetramer formation, promoting the Warburg effect and tumor growth; mutation to C326S restores oxidative phosphorylation and suppresses xenograft growth. Ferroportin C326 mutations abolish hepcidin binding, causing dominant‑negative hemochromatosis. Covalent degraders (e.g., UNC8732, UNC10088) engage FBXO22 C326, enabling targeted proteasomal degradation of the oncogenic methyltransferase NSD2 in acute lymphoblastic leukaemia models. These findings derive from cell‑based assays, mutagenesis, structural biology, and mouse disease models.
Reported Benefits
Understanding C326‑mediated regulation offers potential therapeutic angles: enhancing METTL3 C326 nitrosylation could protect β‑cells in early type‑1 diabetes; inhibiting PKM2 C326 sulfhydration may re‑wire cancer metabolism toward oxidative phosphorylation; correcting ferroportin C326 defects might inform strategies for hemochromatosis; and designing covalent degraders that target FBXO22 C326 provides a novel route to eliminate oncogenic proteins such as NSD2. Early experimental data suggest disease‑modifying effects in animal models.
Limitations of the Evidence
Evidence for C326‑focused interventions remains pre‑clinical; most data are from cell lines, mutagenesis, or mouse models, with no human clinical trials. The cysteine is present in multiple proteins, raising concerns about off‑target reactivity of covalent modifiers. Structural insights are limited to specific contexts, and the long‑term consequences of altering C326 chemistry are unknown. Translation to safe, selective drugs will require extensive validation.
Safety Considerations
No safety data exist for agents that specifically modify C326 in humans. Covalent electrophiles that react with C326 could also modify other cysteines, potentially causing unintended protein dysfunction or toxicity. Redox‑modulating approaches (e.g., H2S donors, nitric oxide donors) have broad systemic effects. Until rigorous toxicology studies are performed, the risk profile of C326‑targeting strategies remains uncertain.
How It Is Administered
C326 is a protein residue, not a standalone drug. Reported interventions have been delivered as gene‑therapy vectors (METTL3 overexpression), small‑molecule H2S donors, or covalent degraders administered in vitro or via injection in animal studies. Formulation and dosing details are experimental and not applicable to clinical use.
Routes of Administration
No administration routes recorded yet.
Goals & Uses
No goal associations recorded yet.
Contraindications
No contraindications recorded yet.
Adverse Effects
No adverse effects recorded yet.
Drug Interactions
No drug interactions recorded yet.
Population Constraints
No population constraints recorded yet.
Regulatory Status
No regulatory status recorded yet.
Evidence & Sources
- Journal ArticleLowDe Jesus DF, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleLowWang RH, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleLowFernandes A, et al.2009-01-01T00:00:00.000000Z
- Journal ArticleLowNie DY, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleLowRobertson KC, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleLowRobertson KC, et al.2026-01-01T00:00:00.000000Z
Frequently Asked Questions
What does C326 refer to in biomedical research?
C326 designates a cysteine amino acid at position 326 in several human proteins. Its thiol side chain is chemically reactive and can be modified by nitric oxide, hydrogen sulfide, or covalent small‑molecule degraders, influencing the host protein’s function.
Why is C326 considered a therapeutic target?
Modifying C326 can alter key pathways: enhancing METTL3 activity protects β‑cells, blocking PKM2 sulfhydration may reverse cancer metabolism, and covalent recruitment of FBXO22 via C326 enables degradation of oncogenic proteins such as NSD2. These effects have been demonstrated in cell and mouse models.
Are there any approved drugs that act on C326?
No. All reported C326‑targeting approaches are experimental, limited to laboratory studies and animal models. No compound has yet received regulatory approval for clinical use.
What are the potential risks of targeting C326?
Because C326 is present in multiple proteins, agents that covalently modify it could affect off‑target cysteines, leading to unintended protein dysfunction. Redox‑modulating agents also have systemic effects, and safety data in humans are currently lacking.
How have researchers studied the role of C326?
Researchers use site‑directed mutagenesis (e.g., C326S), biochemical assays to detect S‑nitrosylation or sulfhydration, structural techniques (crystallography, cryo‑EM), and in vivo models such as NOD mice for diabetes or xenograft tumors to assess functional outcomes of C326 modification.
What is C326?
C326 denotes a cysteine residue at position 326 found in several human proteins, including the m6A methyltransferase METTL3, the glycolytic enzyme PKM2, the iron exporter ferroportin, and the E3 ligase FBXO22. Across recent studies, this thiol side chain serves as a reactive hotspot for post‑translational modifications such as S‑nitrosylation, sulfhydration, and covalent binding by small‑molecule degraders, thereby influencing protein stability, enzymatic activity, and cellular signaling pathways.