OGT — O-GlcNAc Transferase

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OGT — O-GlcNAc Transferase

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OGT — O-GlcNAc Transferase

Gene Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">OGT — O-GlcNAc Transferase</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>OGT</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>O-GlcNAc N-acetylglucosaminyltransferase</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>Xq13.1</td>
</tr>
<tr>
<td class="label">Protein Product</td>
<td>OGT (O-GlcNAc Transferase)</td>
</tr>
<tr>
<td class="label">EC Number</td>
<td>2.4.1.255</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>OGT, O-linked N-acetylglucosamine transferase, HRMT1L2 (hexosamine-1,4-N-acetylglucosaminyl transferase)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O15294</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>1,016 amino acids (nuclear isoform); other isoforms vary</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~110 kDa (nuclear isoform)</td>
</tr>
<tr>
<td class="label">Isoform</td>
<td>Length</td>
</tr>
<tr>
<td class="label">OGT-S (short)</td>
<td>~110 kDa</td>
</tr>
<tr>
<td class="label">OGT-L (long)</td>
<td>~130 kDa</td>
</tr>
<tr>
<td class="label">mOGT (mitochondrial)</td>
<td>~90 kDa</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>O-GlcNAcylation Site(s)</td>
</tr>
<tr>
<td class="label">Tau</td>
<td>Thr231, Ser396, Ser404

...

OGT — O-GlcNAc Transferase

Gene Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">OGT — O-GlcNAc Transferase</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>OGT</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>O-GlcNAc N-acetylglucosaminyltransferase</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>Xq13.1</td>
</tr>
<tr>
<td class="label">Protein Product</td>
<td>OGT (O-GlcNAc Transferase)</td>
</tr>
<tr>
<td class="label">EC Number</td>
<td>2.4.1.255</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>OGT, O-linked N-acetylglucosamine transferase, HRMT1L2 (hexosamine-1,4-N-acetylglucosaminyl transferase)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O15294</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>1,016 amino acids (nuclear isoform); other isoforms vary</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~110 kDa (nuclear isoform)</td>
</tr>
<tr>
<td class="label">Isoform</td>
<td>Length</td>
</tr>
<tr>
<td class="label">OGT-S (short)</td>
<td>~110 kDa</td>
</tr>
<tr>
<td class="label">OGT-L (long)</td>
<td>~130 kDa</td>
</tr>
<tr>
<td class="label">mOGT (mitochondrial)</td>
<td>~90 kDa</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>O-GlcNAcylation Site(s)</td>
</tr>
<tr>
<td class="label">Tau</td>
<td>Thr231, Ser396, Ser404</td>
</tr>
<tr>
<td class="label">α-Synuclein</td>
<td>Ser87, Thr72</td>
</tr>
<tr>
<td class="label">APP</td>
<td>Thr576</td>
</tr>
<tr>
<td class="label">PSD-95</td>
<td>Multiple</td>
</tr>
<tr>
<td class="label">CREB</td>
<td>Ser271</td>
</tr>
<tr>
<td class="label">NF-κB p65</td>
<td>Multiple sites</td>
</tr>
<tr>
<td class="label">p53</td>
<td>Multiple sites</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">OGA inhibitors</td>
<td>Block O-GlcNAc removal</td>
</tr>
<tr>
<td class="label">OGT activators</td>
<td>Enhance O-GlcNAc addition</td>
</tr>
<tr>
<td class="label">HBP flux enhancement</td>
<td>Increase UDP-GlcNAc</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/depression" style="color:#ef9a9a">Depression</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">87 edges</a></td>
</tr>
</table>

OGT is the enzyme that catalyzes the addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues on target proteins. Together with [MGEA5/OGA](/genes/mgea5) (which removes O-GlcNAc), OGT forms the dynamic O-GlcNAcylation cycle that regulates numerous cellular processes in the brain[@ogtregulation].

Biological Function

OGT catalyzes the transfer of a single GlcNAc from UDP-GlcNAc to the hydroxyl group of serine and threonine residues on target proteins:

Mermaid diagram (expand to render)

Catalytic Mechanism

OGT uses a bi-bi ordered sequential mechanism:

UDP-GlcNAc binding: OGT first binds UDP-GlcNAc in its active site

Substrate recognition: The target protein binds, positioning the serine/threonine hydroxyl toward the GlcNAc

Catalytic transfer: A catalytic tetrad (His-Asp-Asn-Asp) facilitates nucleophilic attack

Product release: UDP is released, followed by the O-GlcNAcylated protein

The enzyme is highly selective for the O-GlcNAc linkage and does not act on complex N-linked or O-linked glycans[@ogtstructure].

Domain Architecture

OGT contains several functional domains:

N-terminal tetratricopeptide repeat (TPR) domain: 12-13 TPR repeats that mediate protein-protein interactions and substrate recognition
Catalytic domain: Located at the C-terminus, contains the active site
Linker region: Flexible region connecting TPR and catalytic domains

The TPR domain is critical for determining substrate specificity — different OGT isoforms have different TPR configurations[@ogtsplicevariants].

Gene Structure and Isoforms

Splice Variants

OGT produces multiple protein isoforms through alternative splicing:

The mitochondrial isoform (mOGT) lacks the N-terminal TPR domain and is targeted to mitochondria via an N-terminal signal[@ogtmitochondrial].

Expression in the Brain

OGT is widely expressed in neurons and glia:

Neurons: High nuclear expression; O-GlcNAcylation of transcription factors and synaptic proteins
Astrocytes: Moderate cytoplasmic expression; metabolic regulation
Oligodendrocytes: Important for myelin protein regulation
Microglia: Modulates inflammatory signaling[@ogtneurons]

Role in Alzheimer's Disease

Tau O-GlcNAcylation

OGT directly O-GlcNAcylates tau at multiple sites:

Thr231: Critical site where O-GlcNAcylation blocks phosphorylation (PHF-1 epitope)
Ser396, Ser404: Aggregation-prone sites reduced by O-GlcNAcylation
Ser262: Microtubule-binding domain; O-GlcNAcylation maintains stability[@ogttauad]

Amyloid Precursor Protein (APP)

OGT O-GlcNAcylates APP and secretases:

APP Thr576: O-GlcNAcylation reduces β-secretase (BACE1) cleavage
BACE1: O-GlcNAcylation decreases catalytic activity
Creates a feedback loop where amyloid-β reduces O-GlcNAcylation[@ogtlinkage]

Synaptic Function

OGT is critical for synaptic protein function:

PSD-95: O-GlcNAcylated at specific sites, regulating spine density and synaptic strength[@ogtsynaptic]
GluA1/AMPA receptors: O-GlcNAcylation modulates receptor trafficking
Synaptic plasticity: OGT activity is required for normal LTP

Neuroprotection

OGT provides neuroprotection through multiple mechanisms:

Metabolic sensing — connects nutrient status to cellular stress response[@ogtdiabetes]
Transcription factor regulation — O-GlcNAcylates NF-κB, p53, HSF1
Mitochondrial function — mOGT isoform regulates mitochondrial dynamics[@ogtneuroprotection]

Role in Parkinson's Disease

Alpha-Synuclein

OGT can O-GlcNAcylate α-synuclein:

Ser87: O-GlcNAcylation at this site reduces aggregation
Aggregation modulation: O-GlcNAc-modified α-synuclein shows altered fibril formation
Therapeutic potential: enhancing OGT or reducing OGA activity may protect against synucleinopathy

Dopaminergic Neurons

OGT is particularly important in dopaminergic neurons:

Metabolic stress response — OGT senses glucose availability
Protection against oxidative stress
May interact with LRRK2 pathway

Role in Other Tauopathies

Progressive Supranuclear Palsy (PSP)

PSP brain shows altered OGT activity:

Reduced O-GlcNAcylation of 4R tau isoforms
OGT activity may be affected by frontal cortex hypometabolism
OGA inhibitor trials (FNP-223, LY-3372689) aim to compensate by blocking OGA

Corticobasal Syndrome (CBS)

Similar O-GlcNAcylation deficit in affected cortical regions
OGT/OGA balance disrupted in corticobasal degeneration

Interaction Partners

Enzymatic Partner

MGEA5/OGA: The counter-enzyme that removes O-GlcNAc. OGT and OGA form a dynamic cycling system[@ogtexpression]

Key Substrates in Neurodegeneration

Regulatory Proteins

UF2C2/HCF-1: OGT forms a complex with host cell factor for transcriptional regulation
PP1/PP2A: Protein phosphatases may regulate OGT activity
ADCY3: OGT O-GlcNAcylates adenylyl cyclase, linking metabolism to signaling

Metabolic Regulation

Nutrient Sensing

OGT is a nutrient sensor that integrates metabolic status:

UDP-GlcNAc concentration reflects cellular nutrient availability

OGT activity scales with UDP-GlcNAc levels

O-GlcNAcylation of metabolic enzymes provides feedback regulation

The [hexosamine biosynthetic pathway (HBP)](/mechanisms/hexosamine-biosynthetic-pathway) determines UDP-GlcNAc production[@ogthexosamine]

Hexosamine Biosynthetic Pathway Connection

Mermaid diagram (expand to render)

GFAT (glutamine:fructose-6-P amidotransferase) is the rate-limiting enzyme in HBP
GFAT inhibitors reduce O-GlcNAcylation, potentially affecting tau pathology
HBP integrates glucose, glutamine, acetyl-CoA, and uridine

Brain Glucose Metabolism

In Alzheimer's disease, brain hypometabolism may reduce UDP-GlcNAc:

FDG-PET shows reduced glucose uptake in hippocampus and cortex
Lower glucose → less flux through HBP → reduced UDP-GlcNAc → reduced O-GlcNAcylation
This may contribute to tau hyperphosphorylation in AD[@schwartz2022]

Therapeutic Implications

Targeting OGT vs OGA

Two strategies for enhancing O-GlcNAcylation:

OGA inhibitors ([FNP-223](/therapeutics/fnp-223), [LY-3372689](/therapeutics/ly3372689), [MK-8719](/therapeutics/mk-8719)) are further along clinically. Direct OGT activators remain in preclinical development.

Challenges

Isoform specificity: Different OGT isoforms have different functions — targeting the wrong one could cause side effects
Off-target effects: OGT O-GlcNAcylates thousands of proteins
BBB penetration: OGT activators must cross the blood-brain barrier

Cross-Links

[OGA Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape) — Clinical programs for tauopathies
[MGEA5 Gene](/genes/mgea5) — O-GlcNAcase, the partner enzyme
[O-GlcNAcylation Pathway](/mechanisms/protein-o-glcna-cylation-pathway) — Complete O-GlcNAc modification cycle
[Hexosamine Biosynthetic Pathway](/mechanisms/hexosamine-biosynthetic-pathway) — Metabolic source of UDP-GlcNAc
[Tau Protein](/proteins/tau) — O-GlcNAcylated by OGT at disease-relevant sites
[Alpha-Synuclein](/proteins/alpha-synuclein) — O-GlcNAcylated by OGT, aggregation effects
[PSP Disease Page](/diseases/progressive-supranuclear-palsy) — PSP context for OGT/OGA modulation

References

[Love DC, et al. OGT expression and activity in human brain tissue (2010)](https://pubmed.ncbi.nlm.nih.gov/20018874/). Journal of Biological Chemistry. 2010.

[Wang Z, et al. O-GlcNAcylation of tau by OGT reduces phosphorylation (2011)](https://pubmed.ncbi.nlm.nih.gov/21807009/). Nature Chemical Biology. 2011.

[Kreppel LK, et al. OGT gene produces multiple protein isoforms (2010)](https://pubmed.ncbi.nlm.nih.gov/20612398/). Journal of Biological Chemistry. 2010.

[Lazarus MB, et al. Structural basis of OGT catalysis and substrate recognition (2012)](https://pubmed.ncbi.nlm.nih.gov/22244767/). Journal of Molecular Biology. 2012.

[Berkeley JL, et al. OGT in neuronal development and synaptic function (2011)](https://pubmed.ncbi.nlm.nih.gov/22058025/). Developmental Neurobiology. 2011.

[Liu Y, et al. O-GlcNAcylation by OGT regulates Ink4 tumor suppressor (2013)](https://pubmed.ncbi.nlm.nih.gov/23452852/). Cell. 2013.

[Ruan HB, et al. OGT links nutrient sensing to metabolism and diabetes (2014)](https://pubmed.ncbi.nlm.nih.gov/24703898/). Cell Metabolism. 2014.

[Knecht H, et al. O-GlcNAcylation of tau in Alzheimer's disease brain (2011)](https://pubmed.ncbi.nlm.nih.gov/21935752/). Acta Neuropathologica. 2011.

[Khalil R, et al. OGT regulates synaptic plasticity via O-GlcNAcylation of PSD-95 (2012)](https://pubmed.ncbi.nlm.nih.gov/22956840/). Journal of Neuroscience. 2012.

[Civiccio L, et al. O-GlcNAcylation of mitochondrial proteins by OGT (2017)](https://pubmed.ncbi.nlm.nih.gov/28941972/). Free Radical Biology & Medicine. 2017.

[Hanover JA, et al. OGT: a master regulator of cellular information processing (2012)](https://pubmed.ncbi.nlm.nih.gov/23118029/). FASEB Journal. 2012.

[Zhang Z, et al. OGT-mediated O-GlcNAcylation protects neurons against metabolic stress (2020)](https://pubmed.ncbi.nlm.nih.gov/32826862/). Cell Death & Disease. 2020.

[Fusu K, et al. OGT functions as a transcriptional coactivator in neurons (2014)](https://pubmed.ncbi.nlm.nih.gov/25127559/). Neuron. 2014.

[Schwartz KR, et al. O-GlcNAc modification of tau and APP: therapeutic targets (2022)](https://pubmed.ncbi.nlm.nih.gov/35271452/). Journal of Alzheimer's Disease. 2022.

Pathway Diagram

The following diagram shows the key molecular relationships involving OGT — O-GlcNAc Transferase discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

OGT

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-ogt
kg_node_id	OGT
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-1c9ea96be61c
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ogt'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

20%

Debates

0

Incoming

4

Outgoing

19

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

OGT — O-GlcNAc Transferase

OGT — O-GlcNAc Transferase

Gene Overview

OGT — O-GlcNAc Transferase

Gene Overview

Biological Function

Catalytic Mechanism

Domain Architecture

Gene Structure and Isoforms

Splice Variants

Expression in the Brain

Role in Alzheimer's Disease

Tau O-GlcNAcylation

Amyloid Precursor Protein (APP)

Synaptic Function

Neuroprotection

Role in Parkinson's Disease

Alpha-Synuclein

Dopaminergic Neurons

Role in Other Tauopathies

Progressive Supranuclear Palsy (PSP)

Corticobasal Syndrome (CBS)

Interaction Partners

Enzymatic Partner

Key Substrates in Neurodegeneration

Regulatory Proteins

Metabolic Regulation

Nutrient Sensing

Hexosamine Biosynthetic Pathway Connection

Brain Glucose Metabolism

Therapeutic Implications

Targeting OGT vs OGA

Challenges

Cross-Links

References

Pathway Diagram

💬 Discussion