Insulin-Degrading Enzyme (IDE)

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Insulin-Degrading Enzyme (IDE)

IDE (Insulin-Degrading Enzyme)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Insulin-Degrading Enzyme (IDE)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>IDE</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Insulin-Degrading Enzyme (IDE)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=IDE" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">35 edges</a></td>
</tr>
</table>

Introduction

Insulin Degrading Enzyme (Ide) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

...

Insulin-Degrading Enzyme (IDE)

IDE (Insulin-Degrading Enzyme)

Introduction

Overview

Insulin-degrading enzyme (IDE) is a zinc metalloprotease that degrades a wide range of peptide substrates, including insulin, [amyloid-beta](/proteins/amyloid-beta) (Aβ), and other neurodegeneration-related proteins^[1]^. Originally characterized for its role in insulin metabolism, IDE has emerged as a critical enzyme in Alzheimer's disease pathogenesis due to its ability to degrade Aβ peptides^[2]^.

Structure

IDE is a large (~110 kDa monomer) enzyme that functions as a homodimer:

N-terminal catalytic domain: Contains the zinc-binding motif (HXXEH)
C-terminal domain: Regulates substrate binding and dimerization
Substrate-binding cavity: Large internal chamber (~10,000 Å³)
Dimerization interface: Essential for enzymatic activity

IDE's unique chambered structure allows it to degrade intact peptides without releasing intermediates^[3]^.

Function

Peptide Hydrolysis

IDE degrades numerous physiological and pathological peptides:

Insulin: Primary physiological substrate, regulates glucose metabolism

Amyloid-beta: Major Aβ-degrading enzyme in brain

Glucagon: Pancreatic hormone regulation

Atrial natriuretic peptide: Cardiovascular homeostasis

[Tau](/proteins/tau): Can degrade hyperphosphorylated [tau](/proteins/tau)

Subcellular Localization

IDE is found in multiple cellular compartments:

Cytoplasm: Primary location, involved in cytosolic peptide turnover
Endosomes: Aβ processing in the endocytic pathway
Cell surface: Interacts with extracellular substrates
Mitochondria: Localized to mitochondrial matrix in [neurons](/entities/neurons)

Role in Alzheimer's Disease

Aβ Degradation

IDE is one of the most important Aβ-degrading enzymes:

Primary degrader: Accounts for significant Aβ clearance in the brain
Cellular uptake: Facilitates Aβ internalization and degradation
Competition: IDE's affinity for insulin can reduce Aβ degradation

Genetic Association

IDE genetic variants influence AD risk:

rs7910288, rs2251101: Associated with altered AD risk
Expression changes: Reduced IDE in AD brain contributes to Aβ accumulation
Epigenetic regulation: [DNA methylation](/entities/dna-methylation) affects IDE expression

Therapeutic Implications

IDE modulation is a active therapeutic strategy:

IDE activators: Increase Aβ degradation capacity

Selective substrates: Enhance Aβ binding over insulin

Gene therapy: Increase IDE expression in brain

Small molecule modulators: Allosteric activators

Role in Other Neurodegenerative Diseases

Parkinson's Disease

IDE may contribute to PD pathogenesis:

Alpha-synuclein degradation: Can cleave α-syn
LRRK2 interaction: IDE regulates LRRK2 degradation
Dopaminergic neurons: High expression in vulnerable neurons

Type 2 Diabetes Connection

The insulin-IDE-Aβ axis links AD and diabetes:

Insulin resistance: Reduces IDE availability for Aβ degradation
Hyperinsulinemia: Competes with Aβ for IDE binding
Shared mechanisms: Both diseases feature protein aggregation

Key Publications

Insulin-degrading enzyme: an emerging therapeutic target - Nat Rev Drug Discov (2018)^[4]^

IDE and amyloid-beta metabolism in Alzheimer's disease - J Neurosci (2019)^[2]^

Metalloproteases in neurodegeneration - Trends Neurosci (2020)^[5]^

Background

The study of Insulin Degrading Enzyme (Ide) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

Cross-References

[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Amyloid-beta](/proteins/amyloid-beta)
[Tau Protein](/proteins/tau)
[Alpha-Synuclein](/proteins/alpha-synuclein)
[IDE (Gene)](/proteins/ide-protein)
[Protein Quality Control](/mechanisms/protein-quality-control-network)
Type 2 Diabetes

Additional Content (merged from /entities/insulin-degrading-enzyme)

Insulin-Degrading Enzyme (IDE)

Overview

Insulin Degrading Enzyme (Ide) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications. [@malito2010]

Introduction

Insulin-degrading enzyme (IDE), also known as insulysin, is a zinc-dependent metalloprotease that degrades insulin, Amyloid-Beta (Aβ), and other bioactive peptides. IDE represents a critical molecular link between metabolic disorders and neurodegenerative diseases, particularly Alzheimer's Disease (AD)[@malito2010].

IDE is unique among proteases due to its remarkable substrate breadth, ability to degrade both monomeric and oligomeric proteins, and its involvement in multiple physiological and pathological processes. The enzyme has attracted significant research attention due to its dual role in metabolic regulation and neurobiology.

Biochemical Properties

Structure

IDE is a ~110 kDa zinc metalloprotease belonging to the M16 family (pitrilysin). The enzyme contains an inverted zinc-binding motif (HXXEH) and adopts a butterfly-like shape with two domains that close upon substrate binding. This conformational flexibility allows IDE to accommodate substrates of varying sizes and structures.

The crystal structure of IDE has revealed several key features:

Two dome-shaped domains forming a central chamber
Zinc ion coordinated by three histidine residues
Active site at the interface between domains
Multiple substrate-binding exosites

Substrate Specificity

IDE degrades numerous substrates, making it one of the most versatile proteases known:

Insulin: Primary physiological substrate, degraded rapidly by IDE
Amyloid-Beta (Aβ): Key Aβ-degrading enzyme in the brain
Amylin: Islet amyloid polypeptide involved in diabetes
Glucagon: Pancreatic hormone regulating glucose metabolism
Atrial natriuretic peptide: Cardiac hormone affecting blood pressure
Tau: Phosphorylated tau protein in neurofibrillary tangles
Apolipoprotein E: Lipid transport protein linked to AD risk
Transforming growth factor-α: Growth factor involved in cell proliferation

Catalytic Mechanism

IDE uses a zinc-dependent proteolytic mechanism with unique characteristics:

Substrate Recognition: IDE recognizes specific sequence motifs and structural features

Conformational Changes: The two domains close upon substrate binding, creating an enclosed environment

Processive Degradation: IDE degrades substrates from terminus to terminus without releasing intermediates

Allosteric Regulation: Substrate binding at exosites can modulate catalytic activity

Role in Alzheimer's Disease

Amyloid Clearance

IDE is one of the major Aβ-degrading enzymes in the brain, playing a crucial role in maintaining amyloid homeostasis:

Cellular Expression: IDE is expressed in neurons, microglia, and astrocytes throughout the brain
Reduced IDE in AD: Post-mortem studies show decreased IDE levels in AD brain tissue
Genetic Associations: Genetic variants in the IDE gene are associated with AD risk
Aβ Oligomers: IDE efficiently degrades soluble Aβ oligomers, thought to be the toxic species

Therapeutic Implications

IDE modulation represents a promising therapeutic strategy for AD:

IDE Activators: Compounds that enhance IDE activity could boost Aβ clearance
IDE Inhibitors: May improve insulin signaling but could increase Aβ accumulation
Substrate Competition: Therapeutic approaches using competing peptides to redirect IDE activity
Combination Therapy: IDE modulators combined with other AD therapeutics

Insulin Signaling Connection

The dual role of IDE in insulin and Aβ metabolism creates both opportunities and challenges:

Metabolic-Neurological Link: IDE deficiency leads to both improved insulin signaling and Aβ accumulation
Therapeutic Balance: Modulating IDE requires careful consideration of metabolic versus neurological effects
Diabetes-AD Connection: Shared IDE pathophysiology may explain the link between type 2 diabetes and AD

Genetic Associations

IDE Gene Variants

The IDE gene located on chromosome 10q24.3 has been extensively studied in AD:

SNPs and AD Risk: Multiple single nucleotide polymorphisms (SNPs) show association with AD risk
eQTL Effects: Expression quantitative trait loci affect IDE expression levels
Gene-Gene Interactions: IDE variants interact with APOE and other AD risk genes
Haplotypes: Specific haplotype combinations influence disease risk

Expression and Regulation

IDE is ubiquitously expressed throughout the body with highest levels in the liver, kidney, and brain. In the central nervous system, IDE is produced by neurons, astrocytes, and microglia. The enzyme is localized to the cytosol, peroxisomes, and extracellular spaces, where it can degrade extracellular substrates including Aβ.

IDE expression is regulated by multiple factors:

Hormonal Regulation: Insulin, glucocorticoids, and thyroid hormone affect IDE expression
Metabolic Factors: Glucose levels and metabolic status modulate IDE activity
Inflammatory Cytokines: TNF-α, IL-1β, and other cytokines can alter IDE expression
Age-Related Changes: IDE activity decreases with age, potentially contributing to amyloid accumulation

Research Directions

Current research focuses on several key areas:

IDE Modulators: Developing selective activators or inhibitors that target specific substrates

Extracellular Activity: Enhancing IDE's ability to degrade extracellular Aβ

Substrate-Specific Modulators: Compounds that selectively enhance amyloid degradation without affecting insulin

Gene Therapy: Viral vector delivery of IDE or IDE variants

Biomarker Studies: Measuring IDE activity in cerebrospinal fluid as a diagnostic marker

IDE and Metabolic Disease

IDE serves as a crucial intersection between metabolic and neurodegenerative diseases. The enzyme's ability to degrade insulin makes it highly relevant to diabetes research, while its role in amyloid clearance connects it directly to Alzheimer's Disease pathology.

Key connections between IDE, diabetes, and AD include:

Type 2 Diabetes Risk: Individuals with type 2 diabetes have an increased risk of developing Alzheimer's Disease
Shared Mechanisms: IDE dysfunction may represent a common pathway linking metabolic and neurodegenerative diseases
Therapeutic Implications: Understanding IDE's dual role may lead to integrated treatment approaches
Lifestyle Factors: Diet and exercise may influence IDE activity and amyloid clearance

Clinical Significance

IDE represents a potential biomarker for Alzheimer's Disease:

CSF IDE Activity: Decreased IDE activity in cerebrospinal fluid correlates with disease severity
Blood-Based Markers: Peripheral IDE measurements are being investigated as accessible biomarkers
Therapeutic Target: IDE modulators are in pre-clinical development for AD treatment

Brain Atlas Resources

Allen Human Brain Atlas: [Insulin-Degrading Enzyme expression search](https://human.brain-map.org/microarray/search/show?search_term=Insulin-Degrading+Enzyme)
Allen Mouse Brain Atlas: [Insulin-Degrading Enzyme search](https://mouse.brain-map.org/search/index.html?query=Insulin-Degrading+Enzyme)
Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
BrainSpan Developmental Transcriptome: [Insulin-Degrading Enzyme developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Insulin-Degrading+Enzyme)

Overview

Background

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

External Links

[UniProt: IDE](https://www.uniprot.org)
[PDB: IDE Structure](https://www.rcsb.org)

📖 View canonical wiki page →

Insulin-Degrading Enzyme (IDE)

Insulin-Degrading Enzyme (IDE)

IDE (Insulin-Degrading Enzyme)

Introduction

Overview

Insulin-Degrading Enzyme (IDE)

IDE (Insulin-Degrading Enzyme)

Introduction

Overview

Structure

Function

Peptide Hydrolysis

Subcellular Localization

Role in Alzheimer's Disease

Aβ Degradation

Genetic Association

Therapeutic Implications

Role in Other Neurodegenerative Diseases

Parkinson's Disease

Type 2 Diabetes Connection

Key Publications

Background

External Links

Cross-References

See Also

Additional Content (merged from /entities/insulin-degrading-enzyme)

Insulin-Degrading Enzyme (IDE)

Overview

Introduction

Biochemical Properties

Structure

Substrate Specificity

Catalytic Mechanism

Role in Alzheimer's Disease

Amyloid Clearance

Therapeutic Implications

Insulin Signaling Connection

Genetic Associations

IDE Gene Variants

Expression and Regulation

Research Directions

IDE and Metabolic Disease

Clinical Significance

Brain Atlas Resources

Overview

Background

References

See Also

External Links