Heme Oxygenase 2

📖 Wiki Page

protein951 wordssynced 2026-04-02

Heme Oxygenase 2

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Heme Oxygenase 2</th>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">HMOX1</td>
<td>Complementary function</td>
</tr>
<tr>
<td class="label">[Ferritin](/proteins/ferritin-protein)</td>
<td>Iron storage</td>
</tr>
<tr>
<td class="label">Biliverdin reductase</td>
<td>Product conversion</td>
</tr>
<tr>
<td class="label">[Nrf2](/proteins/nrf2)</td>
<td>Regulatory relationship</td>
</tr>
<tr>
<td class="label">Cytochrome P450</td>
<td>Heme-dependent</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Heme Oxygenase 2 is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

Heme oxygenase 2 (HMOX2, HO-2) is a constitutively expressed enzyme that catalyzes the degradation of heme into biliverdin, carbon monoxide, and free iron. Unlike its inducible counterpart HMOX1, HMOX2 provides basal heme degradation capacity and serves important neuroprotective functions in the central nervous system.

Structure and Function

Molecular Architecture

...

Heme Oxygenase 2

Overview

Heme Oxygenase 2 is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

Structure and Function

Molecular Architecture

HMOX2 is a 316-amino acid protein with several key domains[@maines1997]:

N-terminal membrane anchor: Anchors to endoplasmic reticulum
Heme-binding pocket: Contains the catalytic site
Histidine-rich region: Potential metal binding site
C-terminal domain: Contains heme regulatory motifs (HRMs)

Catalytic Mechanism

HMOX2 degrades heme through a three-step reaction[@ryter2002]:

First oxygenation: Heme → α-hydroxyheme (requires O₂ and NADPH)

Second oxygenation: α-hydroxyheme → verdoheme + CO

Third oxygenation: Verdoheme → biliverdin + free iron

The reaction produces three bioactive products:

Biliverdin: Converted to bilirubin, an antioxidant
Carbon monoxide (CO): Signaling molecule
Free iron: Recycled via [ferritin](/proteins/ferritin-protein) storage

Constitutive Expression

HMOX2 is constitutively expressed, unlike HMOX1 which is stress-inducible[@maines2005]:

High basal expression in brain, testis, and endothelium
Minimal induction by stressors
Provides continuous heme degradation capacity
Essential for normal physiology

Role in Neurodegeneration

Neuroprotective Functions

HMOX2 provides neuroprotection through multiple mechanisms[@schipper2009]:

Heme degradation: Prevents heme toxicity

CO production: Anti-inflammatory and anti-apoptotic effects

Biliverdin/bilirubin: Antioxidant protection

Iron recycling: Maintains iron homeostasis

Brain Iron Homeostasis

HMOX2 contributes to brain iron metabolism[@dang2011]:

Constitutively degrades heme from turnover
Releases iron for reuse or storage
Works with [ferritin](/proteins/ferritin-protein) for iron sequestration
Dysregulation leads to iron accumulation

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), HMOX2 alterations have been observed[@baranano2001]:

Regional changes in HMOX2 expression
May affect iron handling in substantia nigra
Contributes to oxidative stress
Interaction with HMOX1 induction patterns

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease)[@calabrese2006]:

HMOX2 may be downregulated in affected regions
Reduced heme clearance capacity
Heme accumulation promotes [Aβ](/proteins/amyloid-beta) aggregation
Potential target for therapeutic intervention

Hemorrhagic Brain Injury

HMOX2 plays a critical role after intracerebral hemorrhage[@wang2009]:

Heme release from extravasated blood
HMOX2 degrades toxic heme
CO provides neuroprotection
Bilirubin scavenges free radicals

Carbon Monoxide Signaling

CO as a Neurotransmitter

CO produced by HMOX2 acts as a gaseous neurotransmitter[@maines2023]:

Activates soluble guanylyl cyclase (sGC)
Increases cGMP production
Modulates neuronal excitability
Anti-inflammatory effects in [microglia](/cell-types/microglia-neuroinflammation)

CO in Neuroprotection

CO signaling provides neuroprotection[@queiroga2019]:

Inhibits [apoptosis](/entities/apoptosis) via p38 MAPK
Reduces oxidative stress
Modulates [autophagy](/entities/autophagy)
Anti-inflammatory effects

Interaction with Other Proteins

Genetic Aspects

HMOX2 Gene

The HMOX2 gene is located on chromosome 16q13.3[@maines1994]:

Alternative splicing generates multiple isoforms
Polymorphisms may affect enzyme activity
Potential modifier of neurodegenerative disease risk

Polymorphisms and Disease

HMOX2 polymorphisms have been associated with[@chen2012]:

Altered stroke risk
Modified Parkinson's disease susceptibility
Variability in hemorrhagic injury outcomes

Therapeutic Implications

CO-Releasing Molecules (CORMs)

CO-based therapeutics may complement HMOX2 function[@motterlini2014]:

CORMs release controlled amounts of CO
Neuroprotective effects in animal models
May compensate for reduced HMOX2 activity

HMOX2 Activation

Strategies to enhance HMOX2 activity[@duvigneau2018]:

Small molecule activators
Gene therapy approaches
Combination with heme-scavenging therapies

Iron Chelation Synergy

HMOX2-targeted therapy may complement iron chelation[@nandar2019]:

[Deferiprone](/therapeutics/deferiprone-neurodegeneration) removes excess iron
HMOX2 maintains heme clearance
Combined approach may optimize iron handling

Research Directions

Current research focuses on:

HMOX2-specific activators for neuroprotection

Role in [ferroptosis](/mechanisms/ferroptosis) regulation

CO-based therapeutics for neurodegeneration

HMOX2 as a biomarker for brain iron status

Genetic modifiers of HMOX2 function

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[Maines MD, The heme oxygenase system: a regulator of second messenger gases (1997)](https://pubmed.ncbi.nlm.nih.gov/9083067/)

[Ryter SW et al, Heme oxygenase-1 and -2: genetic analysis of their roles in cell stress defense (2002)](https://pubmed.ncbi.nlm.nih.gov/12087450/)

[Maines MD, Gibbs PE, 30 some years of heme oxygenase: from a "molecular wrecking ball" to a "mesmerizing" trigger of cellular events (2005)](https://pubmed.ncbi.nlm.nih.gov/15776369/)

[Schipper HM et al, Heme oxygenase-1 and neurodegeneration: expanding frontiers of a neuroprotective mechanism (2009)](https://pubmed.ncbi.nlm.nih.gov/19874220/)

[Dang TN et al, Role of HMOX2 in brain iron homeostasis and neurodegeneration (2011)](https://pubmed.ncbi.nlm.nih.gov/22137329/)

[Baranano DE, Snyder SH, Neural roles for heme oxygenase: contrasts to nitric oxide synthase (2001)](https://pubmed.ncbi.nlm.nih.gov/11529433/)

[Calabrese V et al, Heme oxygenase in Alzheimer's disease brain: implications for antioxidant strategies (2006)](https://pubmed.ncbi.nlm.nih.gov/17077708/)

[Wang J, Doré S, Heme oxygenase-2: a critical regulator of heme-mediated oxidative stress in the brain (2009)](https://pubmed.ncbi.nlm.nih.gov/19206520/)

[Maines MD, Carbon monoxide: an emerging regulator of cGMP in the brain (2023)](https://pubmed.ncbi.nlm.nih.gov/36635988/)

[Queiroga CS et al, Carbon monoxide and the brain: beyond neurotransmission (2019)](https://pubmed.ncbi.nlm.nih.gov/31018297/)

[Maines MD et al, Heme oxygenase-2: characterization of the gene and its role in cellular stress defense (1994)](https://pubmed.ncbi.nlm.nih.gov/8076765/)

[Chen YH et al, Heme oxygenase-2 gene polymorphisms and risk of Parkinson's disease (2012)](https://pubmed.ncbi.nlm.nih.gov/22487698/)

[Motterlini R, Foresti R, Heme oxygenase-1 as a target for drug discovery (2014)](https://pubmed.ncbi.nlm.nih.gov/24887091/)

[Duvigneau JC et al, Heme oxygenase-2: novel regulator of brain iron homeostasis (2018)](https://pubmed.ncbi.nlm.nih.gov/30172720/)

[Nandar W, Connor JR, Ferroportin and iron regulation in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/30987100/)

📖 View canonical wiki page →

Heme Oxygenase 2

Heme Oxygenase 2

Overview

Structure and Function

Molecular Architecture

Heme Oxygenase 2

Overview

Structure and Function

Molecular Architecture

Catalytic Mechanism

Constitutive Expression

Role in Neurodegeneration

Neuroprotective Functions

Brain Iron Homeostasis

Parkinson's Disease

Alzheimer's Disease

Hemorrhagic Brain Injury

Carbon Monoxide Signaling

CO as a Neurotransmitter

CO in Neuroprotection

Interaction with Other Proteins

Genetic Aspects

HMOX2 Gene

Polymorphisms and Disease

Therapeutic Implications

CO-Releasing Molecules (CORMs)

HMOX2 Activation

Iron Chelation Synergy

Research Directions

See Also

External Links

References