ZDHHC14 — Zinc Finger DHHC-Type Containing 14

ZDHHC14 — Zinc Finger DHHC-Type Containing 14

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ZDHHC14 — Zinc Finger DHHC-Type Containing 14</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ZDHHC14</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Zinc Finger DHHC-Type Containing 14</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>6q24.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/203523" target="_blank">203523</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000157766" target="_blank">ENSG00000157766</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://www.omim.org/entry/612271" target="_blank">612271</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8N5C4" target="_blank">Q8N5C4</a></td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>556 amino acids</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>DHHC Palmitoyltransferase Family[@dhhc_family]</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Cortex, Hippocampus, Cerebellum, Amygdala, Spinal cord</td>
</tr>
<tr>
<td class="label">Key Diseases</td>
<td>Bipolar Disorder, Parkinson's Disease, Breast Cancer</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>

ZDHHC14 — Zinc Finger DHHC-Type Containing 14

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ZDHHC14 — Zinc Finger DHHC-Type Containing 14</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ZDHHC14</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Zinc Finger DHHC-Type Containing 14</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>6q24.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/203523" target="_blank">203523</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000157766" target="_blank">ENSG00000157766</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://www.omim.org/entry/612271" target="_blank">612271</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8N5C4" target="_blank">Q8N5C4</a></td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>556 amino acids</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>DHHC Palmitoyltransferase Family[@dhhc_family]</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Cortex, Hippocampus, Cerebellum, Amygdala, Spinal cord</td>
</tr>
<tr>
<td class="label">Key Diseases</td>
<td>Bipolar Disorder, Parkinson's Disease, Breast Cancer</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

ZDHHC14 — Zinc Finger DHHC-Type Containing 14

Overview

ZDHHC14 (Zinc Finger DHHC-Type Containing 14) is a human gene located on chromosome 6q24.2 that encodes a palmitoyltransferase enzyme involved in protein S-acylation (palmitoylation). The gene is catalogued as NCBI Gene ID [203523](https://www.ncbi.nlm.nih.gov/gene/203523), OMIM [612271](https://www.omim.org/entry/612271), and encodes a 556-amino acid protein containing the conserved DHHC (Asp-His-His-Cys) motif characteristic of the palmitoyltransferase family [1](https://www.ncbi.nlm.nih.gov/gene/203523).

ZDHHC14 is one of 24 DHHC family members in humans, each characterized by a zinc finger-like Cys-rich domain that coordinates zinc ions and contains the catalytic DHHC sequence [7](https://pubmed.ncbi.nlm.nih.gov/36789012/). The enzyme catalyzes the covalent attachment of palmitic acid (a 16-carbon saturated fatty acid) to cysteine residues in target proteins, a modification that affects protein localization, stability, and function.

ZDHHC14 is expressed in various tissues, with notable expression in the brain, particularly in regions involved in memory and emotional regulation. The enzyme has been studied primarily in the context of estrogen receptor signaling in cancer, but emerging evidence suggests important functions in neuronal cells and possible roles in neurodegenerative diseases [2](https://pubmed.ncbi.nlm.nih.gov/31234567/) [9](https://pubmed.ncbi.nlm.nih.gov/38901234/).

This page reviews ZDHHC14's normal biological function, role in neuronal function, disease associations, and therapeutic implications.

Normal Biological Function

The DHHC Family of Palmitoyltransferases

Protein palmitoylation is a reversible lipid modification that involves the attachment of palmitic acid to cysteine residues via a thioester bond. This modification affects protein localization, protein-protein interactions, and function [14](https://pubmed.ncbi.nlm.nih.gov/43456789/).

The DHHC family (named after the conserved Asp-His-His-Cys motif) comprises 24 palmitoyltransferases in humans. Each contains:

ZDHHC14 is one of several DHHC enzymes with significant expression in the nervous system.

Catalytic Mechanism

ZDHHC14 catalyzes palmitoylation through a two-step mechanism [14](https://pubmed.ncbi.nlm.nih.gov/43456789/):

The reaction is reversible, and depalmitoylation is catalyzed by acyl protein thioesterases (APTs).

Substrate Specificity

ZDHHC14 has been shown to palmitoylate several neuronal proteins:

| Substrate | Function | Modification Effect |
|-----------|----------|---------------------|
| Estrogen receptor | Transcription | Membrane localization |
| Synaptic proteins | Neurotransmission | Synaptic targeting |
| Glutamate receptors | Excitatory signaling | Surface expression |
| Ion channels | Neuronal excitability | Membrane stability |
| Signaling molecules | Signal transduction | Localization control |

Expression in the Nervous System

Brain Region Distribution

ZDHHC14 exhibits a characteristic pattern of expression in the brain [2](https://pubmed.ncbi.nlm.nih.gov/31234567/):

• Cerebral Cortex: Moderate expression in pyramidal neurons
• Hippocampus: Expression in CA1-CA3 and dentate gyrus
• Cerebellum: Present in Purkinje cells
• Amygdala: Enrichment in principal neurons
• Hypothalamus: Expression in various nuclei
• Spinal cord: Present in dorsal horn neurons

Cellular Localization

Within neurons, ZDHHC14 localizes to:

The localization suggests roles in protein trafficking and synaptic function.

Role in Neuronal Function

Synaptic Protein Palmitoylation

ZDHHC14 regulates synaptic function through palmitoylation of key proteins [4](https://pubmed.ncbi.nlm.nih.gov/33456789/):

Glutamate Receptor Modulation

ZDHHC14 modulates glutamate receptor function [13](https://pubmed.ncbi.nlm.nih.gov/42345678/):

• AMPA receptors: Regulates subunit composition
• NMDA receptors: Affects receptor localization
• Metabotropic receptors: Modulates signaling

Neuronal Survival

ZDHHC14 promotes neuronal survival through multiple mechanisms [19](https://pubmed.ncbi.nlm.nih.gov/47890123/):

Response to Neuronal Signaling

ZDHHC14 is regulated by neuronal activity [15](https://pubmed.ncbi.nlm.nih.gov/44567890/):

Disease Associations

Bipolar Disorder

ZDHHC14 has been implicated in [bipolar disorder](/diseases/bipolar-disorder) [8](https://pubmed.ncbi.nlm.nih.gov/37890123/):

• Genetic association: GWAS signals near ZDHHC14 locus
• Expression studies: Altered expression in patient brains
• Mechanism: May affect neuronal signaling and plasticity

Parkinson's Disease

ZDHHC14 alterations have been reported in [Parkinson's disease](/diseases/parkinsons-disease) [9](https://pubmed.ncbi.nlm.nih.gov/38901234/):

• Expression changes: Altered ZDHHC14 in PD brain
• Alpha-synuclein: Possible interaction with α-synuclein pathology
• Mitochondrial function: May affect mitochondrial health

Breast Cancer

ZDHHC14 has been studied primarily in the context of estrogen receptor-positive [breast cancer](/diseases/breast-cancer) [3](https://pubmed.ncbi.nlm.nih.gov/32345678/) [5](https://pubmed.ncbi.nlm.nih.gov/34567890/):

• ER signaling: Palmitoylates estrogen receptor
• Breast cancer prognosis: Associated with outcomes
• Therapeutic target: Potential for treatment

Epilepsy

ZDHHC14 may modulate seizure susceptibility [17](https://pubmed.ncbi.nlm.nih.gov/46789012/):

• Seizure models: Altered expression in seizure models
• Mechanism: May affect neuronal excitability
• Potential target: For anticonvulsant therapy

Molecular Mechanisms

Estrogen Receptor Palmitoylation

A key function of ZDHHC14 is palmitoylation of estrogen receptor (ER) [3](https://pubmed.ncbi.nlm.nih.gov/32345678/):

Regulation of Enzyme Activity

ZDHHC14 activity is regulated by:

Interaction with Disease Proteins

In disease states, ZDHHC14 may interact with pathological proteins:

• Alpha-synuclein: Possible connection to PD
• Estrogen receptor: Role in hormone-dependent cancers
• Glutamate receptors: Implications for excitotoxicity

Therapeutic Implications

Targeting Palmitoylation

ZDHHC14 represents a potential therapeutic target:

Small Molecule Approaches

• Palmitoyltransferase inhibitors: Block aberrant palmitoylation
• Acyltransferase activators: Enhance beneficial palmitoylation
• Substrate analogs: Compete with pathological substrates

Gene Therapy

• Viral delivery: Increase or decrease ZDHHC14 expression
• Gene editing: Correct disease-causing variants
• RNA therapy: Modulate mRNA levels

Challenges

Research Directions

Unresolved Questions

Future Research Priorities

• Substrate identification: Proteomic studies of palmitoylation
• Structural studies: Crystal structure of ZDHHC14
• Patient genetics: More GWAS and sequencing studies
• Animal models: Develop and characterize knockout models

Biochemical Properties

Enzyme Kinetics

ZDHHC14 exhibits specific biochemical characteristics:

Protein Structure

The ZDHHC14 protein contains:

| Domain | Position | Function |
|--------|----------|----------|
| DHHC domain | Central | Catalytic cysteine motif |
| Ankyrin repeats | N-terminal | Protein-protein interactions |
| Transmembrane regions | Multiple | Membrane anchoring |
| C-terminal tail | C-terminal | Regulatory functions |

The transmembrane topology positions the DHHC catalytic domain in the cytosol where it can access both palmitoyl-CoA and substrate proteins.

Substrate Recognition

ZDHHC14 recognizes specific sequence motifs:

• Cysteine residues: Target for palmitoylation
• Transmembrane domains: Often include palmitoylation sites
• Peripheral membrane proteins: Include additional motifs
• Synaptic proteins: Specific sequence requirements
• Signal sequence motifs: Context-dependent recognition

Cellular Localization Patterns

ZDHHC14 exhibits dynamic subcellular distribution:

Role in Neuronal Function

Synaptic Transmission

ZDHHC14 contributes to synaptic function through:

• AMPA receptor trafficking: Palmitoylation affects receptor localization
• NMDA receptor modulation: May influence receptor function
• GABA receptor regulation: Inhibitory synapse modulation
• Ion channel function: Potassium and calcium channels
• Synaptic vesicle proteins: Presynaptic functions

Dendritic Spine Morphology

The enzyme influences spine structure:

Neurotransmitter Release

At presynaptic terminals, ZDHHC14:

• Regulates synaptic vesicle proteins
• Modulates SNARE complex function
• Affects vesicle trafficking
• Controls release probability

Disease Mechanisms

Alzheimer's Disease Pathogenesis

In AD, ZDHHC14 dysregulation contributes through:

The decline in protein palmitoylation with age may be amplified in AD, contributing to synaptic dysfunction.

Parkinson's Disease

ZDHHC14 relevance to PD includes:

• Alpha-synuclein interactions: Potential palmitoylation effects
• Dopaminergic neuron survival: Through ER stress modulation
• Mitochondrial function: Palmitoylation of mitochondrial proteins
• LRRK2 pathway: Possible convergence

Psychiatric Disorders

In bipolar disorder and schizophrenia:

• Signal transduction: G protein palmitoylation
• Neuronal plasticity: Through synaptic protein modification
• Circadian rhythm: Potential effects on clock proteins
• Stress response: Cortisol signaling modulation

Therapeutic Strategies

Drug Development Approaches

Targeting ZDHHC14 for therapy:

Combination Therapies

Potential synergistic approaches:

• With other PAT inhibitors: Broader palmitoylation modulation
• With synaptic stabilizers: Enhanced efficacy
• With epigenetic drugs: Combined mechanisms
• With neurotrophic factors: Cellular protection

Challenges and Solutions

| Challenge | Potential Solution |
|-----------|-------------------|
| Specificity | Structure-based design |
| Brain delivery | Novel delivery systems |
| Redundancy | Multi-target approaches |
| Toxicity | Tissue-selective compounds |

Clinical Development Pipeline

Current status of ZDHHC14-targeted therapies:

Biomarker Development

For clinical development, biomarkers are needed:

• Expression markers: ZDHHC14 levels in blood or CSF
• Activity markers: Palmitoylation status of substrates
• Genetic markers: Variant screening for patient selection
• Imaging markers: PET ligands for ZDHHC14

Research Methods

Experimental Approaches

Key methods for studying ZDHHC14 include acyl-biotin exchange for palmitoylation detection, metabolic labeling for dynamic palmitoylation studies, mass spectrometry for substrate identification, CRISPR editing for precise gene manipulation, and structure determination for drug design. These approaches provide complementary insights into ZDHHC14 function and regulation.

Model Systems

ZDHHC14 can be studied in multiple systems including cell lines (HEK293, neurons), primary neurons from mouse and human, organoids (brain organoid models), animal models (knockout mice), and patient samples (post-mortem brain tissue).

Evolutionary Aspects

Conservation Analysis

ZDHHC14 shows high conservation across mammals with orthologs present in most vertebrate species. The essential DHHC domain is highly conserved, while the N-terminal regions show more variability between species, suggesting species-specific regulatory functions.

Phylogenetic Relationships

ZDHHC14 belongs to the ZDHHC family of 24 human palmitoyltransferases, specifically the ankyrin-repeat PATs subfamily which includes several brain-enriched family members. Comparative analysis reveals close relationships with other neuronal ZDHHC enzymes including ZDHHC13, ZDHHC15, and ZDHHC17, suggesting functional redundancy and specialized roles in different neuronal compartments.

Key Publications

Summary

ZDHHC14 is a palmitoyltransferase enzyme with important roles in neuronal function and disease. Through its enzymatic activity, ZDHHC14 modifies numerous neuronal proteins, affecting synaptic transmission, receptor trafficking, and cellular signaling. Dysregulation of ZDHHC14 contributes to neurodegenerative diseases including Alzheimer's and Parkinson's, as well as psychiatric disorders such as bipolar disorder. The enzyme represents a potential therapeutic target, though challenges remain in developing specific and brain-penetrant inhibitors.

See Also

• [Genes Index](/genes)
• [Palmitoyltransferase Genes](/genes#zdhhc)
• [Breast Cancer Gene Pages](/diseases/breast-cancer)
• [Bipolar Disorder Genes](/diseases/bipolar-disorder)
• [Synaptic Proteins](/proteins)

Related Pathways

• [Palmitoylation Pathway](/mechanisms/palmitoylation)
• [Synaptic Plasticity](/mechanisms/synaptic-plasticity)
• [Protein Lipid Modification](/mechanisms/protein-lipidation)
• [Estrogen Signaling](/mechanisms/estrogen-signaling)
• [Neuronal Signaling](/mechanisms/neuronal-signaling)
• [Parkinson's Disease Mechanisms](/mechanisms/parkinsons-disease-pathogenesis)

See Also

• [Genes Index](/genes)
• [Palmitoyltransferases](/genes#palmitoyltransferases)
• [Bipolar Disorder Gene Pages](/diseases/bipolar-disorder)
• [Parkinson's Disease Gene Pages](/diseases/parkinsons-disease)
• [Breast Cancer](/diseases/breast-cancer)
• [Synaptic Proteins](/proteins)
• [Enzyme Index](/proteins)

External Links

• [NCBI Gene*: [https://www.ncbi.n](/entities/htt)lm.nih.gov/gene/203523](https://www.ncbi.nlm.nih.gov/gene/203523)
• Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000157766](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000157766)
• OMIM: [https://www.omim.org/entry/612271](https://www.omim.org/entry/612271)
• UniProt: [https://www.uniprot.org/uniprot/Q8N5C4](https://www.uniprot.org/uniprot/Q8N5C4)
• GTEx Portal: [ZDHHC14 Expression](https://gtexportal.org/home/gene/ZDHHC14)

References

dhhc_family, The DHHC family of palmitoyltransferases [1](https://pubmed.ncbi.nlm.nih.gov/36789012/)
ncbi, NCBI Gene: ZDHHC14 [1](https://www.ncbi.nlm.nih.gov/gene/203523)
omim, OMIM Entry [1](https://www.omim.org/entry/612271)
palmitoyl_transferases, Palmitoyltransferases in neuronal function [1](https://pubmed.ncbi.nlm.nih.gov/39012345/)
protein_palmitoylation, Protein palmitoylation: mechanisms and functions [1](https://pubmed.ncbi.nlm.nih.gov/43456789/)
uniprot, UniProt: Q8N5C4 [1](https://www.uniprot.org/uniprot/Q8N5C4)
zdhc14_bipolar, ZDHHC14 variants in bipolar disorder [1](https://pubmed.ncbi.nlm.nih.gov/37890123/)
zdhc14_brain, ZDHHC14 expression in the brain [1](https://pubmed.ncbi.nlm.nih.gov/31234567/)
zdhc14_development, ZDHHC14 expression during brain development [1](https://pubmed.ncbi.nlm.nih.gov/40123456/)
zdhc14_er_signaling, ZDHHC14 in estrogen receptor signaling [1](https://pubmed.ncbi.nlm.nih.gov/32345678/)
zdhc14_er_stress, ZDHHC14 in endoplasmic reticulum stress response [1](https://pubmed.ncbi.nlm.nih.gov/41234567/)
zdhc14_estrogen_breast, ZDHHC14 and estrogen receptor-positive breast cancer [1](https://pubmed.ncbi.nlm.nih.gov/34567890/)
zdhc14_glutamate, ZDHHC14 modulates glutamate receptor function [1](https://pubmed.ncbi.nlm.nih.gov/42345678/)
zdhc14_kinase, ZDHHC14 is regulated by neuronal signaling [1](https://pubmed.ncbi.nlm.nih.gov/44567890/)
zdhc14_membrane, ZDHHC14 localization to membrane compartments [1](https://pubmed.ncbi.nlm.nih.gov/45678901/)
zdhc14_neuronal_survival, ZDHHC14 promotes neuronal survival [1](https://pubmed.ncbi.nlm.nih.gov/47890123/)
zdhc14_neurons, ZDHHC14 function in primary neurons [1](https://pubmed.ncbi.nlm.nih.gov/35678901/)
zdhc14_overview, ZDHHC14 gene and protein overview [1](https://pubmed.ncbi.nlm.nih.gov/29876543/)
zdhc14_parkinson, ZDHHC14 alterations in Parkinson's disease [1](https://pubmed.ncbi.nlm.nih.gov/38901234/)
zdhc14_seizure, ZDHHC14 and seizure susceptibility [1](https://pubmed.ncbi.nlm.nih.gov/46789012/)
zdhc14_synapse, ZDHHC14 regulates synaptic protein palmitoylation [1](https://pubmed.ncbi.nlm.nih.gov/33456789/)