HK2 Protein — Hexokinase 2

HK2 Protein — Hexokinase 2

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HK2 Protein — Hexokinase 2</th>
</tr>
<tr>
<td class="label">Gene</td>
<td><a href="/genes/hk2">HK2</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P19367" target="_blank">P19367</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2YHX" target="_blank">2YHX</a>, <a href="https://www.rcsb.org/structure/2YHZ" target="_blank">2YHZ</a></td>
</tr>
<tr>
<td class="label">Mol.

HK2 Protein — Hexokinase 2

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HK2 Protein — Hexokinase 2</th>
</tr>
<tr>
<td class="label">Gene</td>
<td><a href="/genes/hk2">HK2</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P19367" target="_blank">P19367</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2YHX" target="_blank">2YHX</a>, <a href="https://www.rcsb.org/structure/2YHZ" target="_blank">2YHZ</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>100 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Mitochondrial outer membrane (bound to VDAC)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Hexokinase family (HK1-4)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/alzheimers">Alzheimer's Disease</a>, <a href="/diseases/parkinsons-disease">Parkinson's Disease</a>, <a href="/diseases/neurons">Cancer</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/acute-kidney-injury" style="color:#ef9a9a">Acute Kidney Injury</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-a1b56d74" style="color:#ce93d8" title="Score: 0.44">Metabolic Switch Targeting for A1→A2 Rep...</a><br><a href="/hypothesis/h-38292315" style="color:#ce93d8" title="Score: 0.37">Metabolic Reprogramming via Microglial G...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">518 edges</a></td>
</tr>
</table>

HK2 Protein — Hexokinase 2

Introduction

[HK2](/genes/hk2) (Hexokinase 2) is a rate-limiting enzyme in glycolysis that catalyzes the phosphorylation of glucose to glucose-6-phosphate[@nature2010]. Unlike other hexokinases, HK2 binds to the mitochondrial outer membrane via the voltage-dependent anion channel (VDAC), positioning it at the interface between mitochondrial metabolism and cellular signaling[@dimauro2003]. This unique localization has made HK2 a focus of research in neurodegeneration, where mitochondrial dysfunction is a hallmark[@lin2006].

Overview

HK2 is one of four mammalian hexokinase isoforms (HK1, HK2, HK3, HK4/GCK). HK2 is unique among them for its high-affinity binding to mitochondria and its expression pattern, being primarily induced in tissues with high glycolytic demand[@schapira2006].

The mitochondrial-bound form of HK2:

• Directly couples glycolysis to oxidative phosphorylation
• Inhibits [apoptosis](/entities/apoptosis) by blocking VDAC
• Provides metabolic advantage to cells with high energy demands

Structure

HK2 features:

• N-terminal mitochondrial binding domain (~50 amino acids)
• Catalytic domains (two tandem hexokinase domains)
• Molecular weight approximately 100 kDa
• Binds VDAC1 at the mitochondrial outer membrane

Normal Function

Glycolysis

• Phosphorylates glucose to initiate glycolysis
• Traps glucose-6-phosphate inside cells
• Rate-limiting step in glucose metabolism

Metabolic Coupling

• Binds to VDAC to couple glycolysis to mitochondrial ATP production
• Directly accesses mitochondrial ATP for the first step of glycolysis
• Maintains efficient cellular energetics

Cell Survival

• Mitochondrial HK2 inhibits apoptosis
• Blocks cytochrome c release
• Protects against mitochondrial permeability transition

Role in Disease

Alzheimer's Disease

• HK2 binding to mitochondria is reduced in AD brains
• Contributes to bioenergetic deficits
• Loss of anti-apoptotic protection
• Linked to [amyloid-beta](/proteins/amyloid-beta) toxicity

Parkinson's Disease

• Altered HK2 expression in substantia nigra
• Contributes to mitochondrial dysfunction
• May affect dopaminergic neuron survival
• Linked to PINK1/Parkin pathway

Cancer

• HK2 is overexpressed in many cancers
• Warburg effect supports proliferation
• Anti-apoptotic function aids tumor survival

Therapeutic Targeting

HK2 is being investigated as a therapeutic target:

• 2-deoxyglucose (2-DG) inhibits HK2
• Lonidamine targets mitochondrial-bound HK2
• Gene therapy approaches to modulate HK2 expression

Key Publications

See Also

• [Mitochondrial Dynamics](/mechanisms/mitochondrial-dynamics)
• [Glucose Metabolism](/mechanisms/glucose-metabolism-neurodegeneration)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [VDAC Protein](/proteins/vdac-protein)

External Links

• [UniProt: hk2](https://www.uniprot.org/)
• [PubMed: hk2](https://pubmed.ncbi.nlm.nih.gov/?term=hk2+neurodegeneration)

References