IDE

Summary

IDE (insulin degrading enzyme, HGNC:5381) is a protein-coding gene on chromosome 10q23.33, encoding Insulin-degrading enzyme (P14735). Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling.

This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein’s function are associated with Alzheimer’s disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.

Source: NCBI Gene 3416 — RefSeq curated summary.

At a glance

• GWAS associations: 22
• Clinical variants (ClinVar): 131 total
• GTEx eGene: eQTL in 13 tissues, sQTL in 2 (q < 0.05)
• ChEMBL bioactivity: 6 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.08 (LoF-tolerant), LOEUF 0.64 (unconstrained)
• MANE Select transcript: NM_004969
• Notable: 131 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5381
Approved symbol	IDE
Name	insulin degrading enzyme
Location	10q23.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000119912
Ensembl biotype	protein_coding
OMIM	146680
Entrez	3416

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 20 protein_coding, 14 retained_intron, 14 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000265986

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 1, TSL 5: 1

ENST00000265986, ENST00000371581, ENST00000436178, ENST00000463640, ENST00000478361, ENST00000492362, ENST00000496903, ENST00000650060, ENST00000676540, ENST00000676626, ENST00000676816, ENST00000676987, ENST00000677079, ENST00000677096, ENST00000677193, ENST00000677196, ENST00000677434, ENST00000677569, ENST00000677953, ENST00000677978, ENST00000678026, ENST00000678082, ENST00000678097, ENST00000678248, ENST00000678410, ENST00000678458, ENST00000678673, ENST00000678715, ENST00000678824, ENST00000678844, ENST00000678977, ENST00000679069, ENST00000679089, ENST00000679174, ENST00000679222, ENST00000679232, ENST00000679304, ENST00000679312, ENST00000857320, ENST00000857321, ENST00000926841, ENST00000926842, ENST00000926843, ENST00000971392, ENST00000992064, ENST00001050041, ENST00001050043, ENST00001108135, ENST00001114005, ENST00001124379, ENST00001137353

RefSeq mRNA: 8 — MANE Select: NM_004969 NM_001165946, NM_001322793, NM_001322794, NM_001322795, NM_001322796, NM_001322797, NM_001410974, NM_004969

CCDS: CCDS53554, CCDS7421, CCDS91299, CCDS91300, CCDS91301

Canonical transcript exons

ENST00000265986 — 25 exons

Exon	Start	End
ENSE00001893153	92451684	92454539
ENSE00003463361	92463731	92464003
ENSE00003472980	92474841	92474961
ENSE00003480719	92508113	92508205
ENSE00003493344	92506442	92506522
ENSE00003496205	92534578	92534785
ENSE00003513908	92483255	92483337
ENSE00003516983	92470254	92470345
ENSE00003530878	92507575	92507666
ENSE00003556979	92468879	92468990
ENSE00003573870	92487196	92487318
ENSE00003576643	92456359	92456431
ENSE00003582944	92465676	92465843
ENSE00003587497	92510050	92510162
ENSE00003604775	92479277	92479421
ENSE00003622232	92508728	92508890
ENSE00003626360	92461191	92461252
ENSE00003629955	92490493	92490595
ENSE00003635720	92504794	92504897
ENSE00003646142	92531748	92531917
ENSE00003650499	92514920	92515042
ENSE00003655965	92475884	92475994
ENSE00003668022	92455576	92455643
ENSE00003669674	92537366	92537550
ENSE00003891074	92573922	92574093

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 97.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.8854 / max 159.4089, expressed in 1807 samples.

Highest expression (Bgee): upper leg skin, secondary oocyte, gluteal muscle, skeletal muscle tissue of rectus abdominis, penis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

IDE is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

15 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	3.9e-07	+0.29	10:92624101:T:G
Muscle Skeletal	eqtl	6.5e-05	+0.20	10:92573485:G:A
Nerve Tibial	eqtl	1.5e-03	+0.11	10:92500211:C:T
Colon Transverse	eqtl	2.5e-03	-0.31	10:92649100:G:T
Cells EBV-transformed lymphocytes	eqtl	2.7e-03	+0.23	10:92458541:G:A
Skin Sun Exposed Lower leg	eqtl	3.3e-03	-0.07	10:93339600:T:G
Cells Cultured fibroblasts	sqtl	8.2e-03	+0.78	10:92523612:A:T
Kidney Cortex	eqtl	2.0e-02	-1.58	10:92422486:A:G
Heart Left Ventricle	eqtl	2.0e-02	-0.16	10:92531009:A:G
Adipose Subcutaneous	eqtl	2.5e-02	+0.28	10:91952030:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.9e-02	-0.22	10:92608531:CG:C
Artery Aorta	eqtl	3.6e-02	+0.43	10:92806788:GGTTGTGTGT:G
Pancreas	eqtl	3.7e-02	-0.19	10:92515052:A:G
Brain Spinal cord cervical c-1	eqtl	4.4e-02	+1.86	10:91921166:T:C
Stomach	sqtl	4.5e-02	-0.35	10:93228606:T:C

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
110667	20.7841	1805
110666	1.9540	1250
110662	0.0438	3
110664	0.0416	17
110665	0.0342	4
110663	0.0238	3
205943	0.0039	2

Top tissues by expression

showing 100 of 294 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	97.28	gold quality
secondary oocyte	CL:0000655	96.50	gold quality
gluteal muscle	UBERON:0002000	96.09	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.71	gold quality
penis	UBERON:0000989	94.48	gold quality
triceps brachii	UBERON:0001509	94.22	gold quality
skin of leg	UBERON:0001511	93.86	gold quality
heart right ventricle	UBERON:0002080	93.67	gold quality
biceps brachii	UBERON:0001507	93.60	gold quality
zone of skin	UBERON:0000014	93.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.31	gold quality
oocyte	CL:0000023	93.10	gold quality
mammalian vulva	UBERON:0000997	92.91	gold quality
skin of abdomen	UBERON:0001416	92.80	gold quality
upper arm skin	UBERON:0004263	92.27	gold quality
nipple	UBERON:0002030	92.04	gold quality
pigmented layer of retina	UBERON:0001782	91.84	gold quality
gastrocnemius	UBERON:0001388	91.15	gold quality
muscle of leg	UBERON:0001383	91.00	gold quality
skeletal muscle tissue	UBERON:0001134	90.98	gold quality
calcaneal tendon	UBERON:0003701	90.85	gold quality
adrenal tissue	UBERON:0018303	90.82	gold quality
esophagus squamous epithelium	UBERON:0006920	90.79	gold quality
muscle organ	UBERON:0001630	90.57	gold quality
skeletal muscle organ	UBERON:0014892	90.56	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.26	gold quality
corpus epididymis	UBERON:0004359	90.26	gold quality
diaphragm	UBERON:0001103	89.40	silver quality
tendon	UBERON:0000043	89.26	gold quality
gingival epithelium	UBERON:0001949	89.23	gold quality
eye	UBERON:0000970	89.18	gold quality
squamous epithelium	UBERON:0006914	89.13	gold quality
epithelium of esophagus	UBERON:0001976	89.12	gold quality
visceral pleura	UBERON:0002401	89.02	gold quality
choroid plexus epithelium	UBERON:0003911	88.97	gold quality
hair follicle	UBERON:0002073	88.87	gold quality
vastus lateralis	UBERON:0001379	88.58	silver quality
palpebral conjunctiva	UBERON:0001812	88.46	gold quality
oviduct epithelium	UBERON:0004804	88.38	gold quality
epithelium of bronchus	UBERON:0002031	88.35	gold quality
gingiva	UBERON:0001828	88.25	gold quality
bronchial epithelial cell	CL:0002328	88.23	gold quality
colonic epithelium	UBERON:0000397	88.21	gold quality
muscle tissue	UBERON:0002385	88.15	gold quality
bronchus	UBERON:0002185	88.13	gold quality
bone marrow cell	CL:0002092	88.05	gold quality
pleura	UBERON:0000977	87.94	gold quality
seminal vesicle	UBERON:0000998	87.93	gold quality
quadriceps femoris	UBERON:0001377	87.93	gold quality
tonsil	UBERON:0002372	87.67	gold quality
epithelium of nasopharynx	UBERON:0001951	87.58	gold quality
endothelial cell	CL:0000115	87.57	gold quality
skin of hip	UBERON:0001554	87.57	gold quality
parietal pleura	UBERON:0002400	87.36	gold quality
deltoid	UBERON:0001476	87.16	gold quality
cauda epididymis	UBERON:0004360	86.88	gold quality
periodontal ligament	UBERON:0008266	86.74	gold quality
body of pancreas	UBERON:0001150	86.58	gold quality
endometrium	UBERON:0001295	86.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.50	gold quality
stromal cell of endometrium	CL:0002255	86.37	gold quality
body of tongue	UBERON:0011876	86.37	gold quality
nasal cavity mucosa	UBERON:0001826	86.23	gold quality
tibia	UBERON:0000979	86.20	gold quality
islet of Langerhans	UBERON:0000006	85.95	gold quality
cervix epithelium	UBERON:0004801	85.95	gold quality
tendon of biceps brachii	UBERON:0008188	85.95	gold quality
pancreas	UBERON:0001264	85.88	gold quality
rectum	UBERON:0001052	85.59	gold quality
cardiac ventricle	UBERON:0002082	85.44	gold quality
caput epididymis	UBERON:0004358	85.31	gold quality
heart left ventricle	UBERON:0002084	85.24	gold quality
tongue	UBERON:0001723	85.08	gold quality
adrenal gland	UBERON:0002369	85.07	gold quality
right adrenal gland cortex	UBERON:0035827	84.92	gold quality
liver	UBERON:0002107	84.91	gold quality
germinal epithelium of ovary	UBERON:0001304	84.82	gold quality
heart	UBERON:0000948	84.79	gold quality
fallopian tube	UBERON:0003889	84.77	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.75	silver quality
smooth muscle tissue	UBERON:0001135	84.74	gold quality
urinary bladder	UBERON:0001255	84.74	gold quality
right adrenal gland	UBERON:0001233	84.69	gold quality
left adrenal gland	UBERON:0001234	84.69	gold quality
colonic mucosa	UBERON:0000317	84.64	gold quality
prostate gland	UBERON:0002367	84.59	gold quality
tibialis anterior	UBERON:0001385	84.52	silver quality
uterine cervix	UBERON:0000002	84.51	gold quality
trabecular bone tissue	UBERON:0002483	84.38	gold quality
oral cavity	UBERON:0000167	84.36	gold quality
nasal cavity epithelium	UBERON:0005384	84.32	silver quality
adrenal cortex	UBERON:0001235	84.20	gold quality
esophagus mucosa	UBERON:0002469	84.20	gold quality
uterus	UBERON:0000995	84.19	gold quality
middle temporal gyrus	UBERON:0002771	84.17	gold quality
esophagus	UBERON:0001043	84.16	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.15	gold quality
cervix squamous epithelium	UBERON:0006922	84.14	silver quality
superior surface of tongue	UBERON:0007371	84.08	gold quality
mucosa of urinary bladder	UBERON:0001259	84.02	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.24

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Testis	tissue	24.1	medium
Superior colliculi	tissue	22.0
Skin 1	tissue	21.9	medium
Frontal cortex	tissue	21.8
Spinal cord	tissue	21.6
Thalamus	tissue	21.3
Medulla oblongata	tissue	21.1
Midbrain	tissue	20.9
Pons	tissue	19.7
Cerebral cortex	tissue	19.2	medium
Putamen	tissue	19.2
Substantia nigra	tissue	19.2
Caudate putamen	tissue	19.2
Somatosensory cortex	tissue	19.2
Motor cortex	tissue	18.6
Occipital cortex	tissue	18.1
Cerebellum	tissue	17.7	medium
Periaqueductal gray	tissue	17.5
Hippocampal formation	tissue	17.2
Entorhinal cortex	tissue	17.1
Retrosplenial and cingulate cortex	tissue	17.0
Corpus callosum	tissue	16.8
Hypothalamus	tissue	16.6
Temporal cortex	tissue	16.6
Retrosplenial cortex	tissue	16.5
Ventral forebrain	tissue	16.4
Prefrontal cortex	tissue	16.3
Septum	tissue	16.3
Amygdala	tissue	15.7
Insular cortex	tissue	15.6
Olfactory bulb	tissue	14.9
Basal ganglia	tissue	14.4	medium
Retina	tissue	9.6
Epididymis	tissue	9.2	medium
Parathyroid gland	tissue	9.0	low
Tongue	tissue	9.0
Skeletal muscle	tissue	8.3	high
Choroid plexus	tissue	7.2
Vagina	tissue	5.6	not detected
Liver	tissue	5.0	low
Heart muscle	tissue	4.5	high
Thyroid gland	tissue	4.5	low
Esophagus	tissue	4.4	low
Breast	tissue	4.3	medium
Seminal vesicle	tissue	4.0	medium
Urinary bladder	tissue	4.0	low
Tonsil	tissue	3.9	medium
Cervix	tissue	3.6	low
Salivary gland	tissue	3.6	medium
Rectum	tissue	3.6	medium
Prostate	tissue	3.6	not detected
Stomach 1	tissue	3.5	high
Smooth muscle	tissue	3.5	high
Adrenal gland	tissue	3.5	medium
Small intestine	tissue	3.4	high
Colon	tissue	3.3	medium
Bone marrow	tissue	3.3	not detected
Duodenum	tissue	3.2	medium
Pituitary gland	tissue	3.1
Lymph node	tissue	3.1	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Ventral spinal cord (21.6), Dorsal spinal cord (19.0), Dorsal hippocampus (17.2), White matter (16.8), Subiculum (16.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CNBP, IL13, IL4, NRF1, PPARG, PPARGC1A, STAT3, TBP, TGFB1, TNF

miRNA regulators (miRDB)

Targeting IDE by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 147 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6825-5P	99.96	69.81	3431

Functional genomics

gnomAD constraint: pLI 0.0768, LOEUF 0.638, missense Z 2.15 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000265986 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
10:92,454,447–92,510,088	660 / 894.7	0.74	no
10:92,510,089–92,574,019	321 / 339.3	0.95	no

Literature-anchored findings (GeneRIF, showing 40)

• Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). (PMID:11809755)
• IDE knockout mice show significantly elevated levels of blood insulin, brain beta-amyloid, and brain amyloid-precursor protein intracellular domain, providing key in vivo evidence that IDE degrades both extracellular and intracellular peptides. (PMID:12634421)
• analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans (PMID:12716770)
• when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells and this mechanism may contribute to insulin resistance (PMID:12746301)
• Polymorphism in this enzyme are associated with NIDDM in men. (PMID:12765971)
• IDE gene polymorphisms do not confer susceptibility to early- or late-onset AD at least in a Japanese population. (PMID:14755451)
• Biochemical characteristics of insulin degradation in wound fluid were consistent with characteristics of insulin-degrading enzyme. Reduction in insulin-degrading activity in wound fluid is potential therapeutic target. (PMID:14764804)
• This study provides strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate Alzheimer’s disease phenotypes and risk for AD. (PMID:15024728)
• genomic region in the proximity of IDE that may contribute to Alzheimer and Parkinson disease in a similar manner. (PMID:15088150)
• IDE gene promoter region variants are associated with AD in subjects without an epsilon4 allele (PMID:15181249)
• Polymorphism in/near IDE contributes to a large proportion of variance in plasma insulin levels and correlated traits. (PMID:15277398)
• The C allele of single-nucleotide polymorphism IDE2 associated with Alzheimer disease. There may be a possible synergic interaction between IDE & APOE epsilon4. (PMID:15277615)
• IDE is targeted to mitochondria via alternative initiation of translation. (PMID:15285718)
• a defect in Abeta proteolysis by IDE contributes to the accumulation of this peptide in the cortical microvasculature (PMID:15489232)
• To test the hypothesis that insulin might upregulate IDE via a negative feedback control mechanism, we used both in vitro and in vivo strategies to determine the impact of insulin signaling on IDE levels. (PMID:15590928)
• Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients. (PMID:15718037)
• This study systematically characterizes IDE mRNAs, identifies a novel, catalytically inefficient splice form and compares its subcellular distribution, kinetic properties and ability to degrade amyloid beta protein to the known isoform. (PMID:15850385)
• Common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians. (PMID:16380485)
• Beta-amyloid degradation is largely the result of the action of IDE, as it is blocked by insulin in the medium, a competitive substrate of IDE. IDE could be an important therapeutic target to decrease the amount of Abeta in the cerebrovasculature. (PMID:16511862)
• IDE-N is the catalytic domain and IDE-C facilitates substrate recognition as well as plays a key role in the oligomerization of IDE. (PMID:16574064)
• Different reconstructed insulin-degrading enzyme haplotypes were associated with Alzheimers disease and lower cognitive ability. (PMID:16675064)
• The combined genotype data from 1269 late-onset AD cases and 980 controls yielded a significant association to IDE_9 located in the 3’-end of the IDE gene after conservative multiple testing Bonferroni correction (p = 0.005). (PMID:16876916)
• protein structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon) (PMID:17051221)
• cellular receptor for infection by varicella-zoster virus. Interacts with VZV glycoprotein E. (PMID:17055432)
• First demonstration of IDE in normal and neoplastic human mammary tissues, providing an experimental starting point towards exploring a potential role of IDE in the control of tumor progression. (PMID:17143514)
• This study suggests IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimer’s. (PMID:17192720)
• the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression (PMID:17244626)
• SNPs rs4646953 & rs4646955 are associated with Alzheimer disease in Finnish patients, conferring an approximately two-fold increased risk. (PMID:17496198)
• Variations in IDE may contribute to diabetes susceptibility in the Korean population. (PMID:17913278)
• The single nucleotide polymorphism rs2209972 in the human IDE gene is associated with metabolic features of polycystic ovary syndrome women in a Chinese population. (PMID:17953957)
• This shows that IDE is involved in cellular insulin metabolism and provides further evidence that insulin inhibits protein degradation via an interaction with IDE. (PMID:17964527)
• Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race. (PMID:17971426)
• Importance of the distribution of the enzyme in brain and pituitary is discussed in relation to its main known substrataes. (PMID:18226493)
• the catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide (PMID:18411275)
• Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans. (PMID:18448515)
• predict that alkylation of C812 and C819 disrupts substrate binding, whereas alkylation of C178 interferes with the apposition of active-site domains and subtly repositions zinc-binding residues (PMID:18621727)
• IDE protein was expressed in all the tissues assessed and all the tumor cell lines except for Raji and HL-60. (PMID:18783335)
• Insulin-degrading enzyme protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. (PMID:18813847)
• kinetics and regulation of human IDE with short peptides (PMID:18986166)
• present study provides evidence that IDE promoter polymorphisms that significantly decrease IDE expression levels are associated with development of sporadic lzheimer disease (PMID:18996360)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ide	ENSDARG00000075570
mus_musculus	Ide	ENSMUSG00000056999
rattus_norvegicus	Ide	ENSRNOG00000016833
drosophila_melanogaster	Ide	FBGN0001247
caenorhabditis_elegans		WBGENE00013492
caenorhabditis_elegans		WBGENE00015360
caenorhabditis_elegans		WBGENE00018426

Paralogs (6): UQCRC1 (ENSG00000010256), NRDC (ENSG00000078618), PMPCB (ENSG00000105819), PITRM1 (ENSG00000107959), UQCRC2 (ENSG00000140740), PMPCA (ENSG00000165688)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96412) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 22 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cranium morphology	1
abnormal maxilla morphology	1
small seminiferous tubules	1
decreased body weight	1
hyperglycemia	1
abnormal hair texture	1
increased circulating insulin level	1
increased heart weight	1
decreased circulating alanine transaminase level	1
amyloid beta deposits	1
oxidative stress	1
decreased testis weight	1
decreased circulating cholesterol level	1
impaired glucose tolerance	1
abnormal incisor morphology	1
teratozoospermia	1
decreased circulating aspartate transaminase level	1
increased circulating amylase level	1
necrospermia	1
decreased total body fat amount	1
abnormal mitochondrial ATP synthesis coupled electron transport	1
increased testis apoptosis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q24K02	98.8%	Diamond
Pongo abelii	Q5R4H6	98.6%	Diamond
Arabidopsis thaliana	F4J3D9	80.5%	Diamond
Lathyrus oleraceus	Q40983	74.6%	Diamond
Dictyostelium discoideum	Q4W6B5	68.0%	Diamond
Saccharomyces cerevisiae S288C	Q06010	39.8%	Diamond
Bacillus subtilis subsp. subtilis str. 168	Q04805	39.0%	Diamond
Schizosaccharomyces pombe 972h-	O14077	38.3%	Diamond
Pseudomonas aeruginosa PAO1	Q9I2D2	36.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
KIF11	protein-coding	3832
CPEB3	protein-coding	22849
MARCHF5	protein-coding	54708

Protein

Protein identifiers

Insulin-degrading enzyme — P14735 (reviewed: P14735)

Alternative names: Abeta-degrading protease, Insulin protease, Insulysin

All UniProt accessions (16): A0A3B3ISG5, A0A7I2V2P6, A0A7I2V2S1, A0A7I2V373, A0A7I2V3E3, A0A7I2V3K9, A0A7I2V4A4, A0A7I2V4Q3, A0A7I2V610, A0A7I2V612, A0A7I2V634, A0A7I2YQS6, A0A7I2YQV5, B3KSB8, P14735, R4GN65

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling. Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin. Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP. Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia. Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP. Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients. Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I. (Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV).

Subunit / interactions. Homodimer. Can also form homotetramers. (Microbial infection) Interacts (via N-terminus) with varicella-zoster virus (VZV) envelope glycoprotein E (via N-terminus); the membrane-associated isoform may function as an entry receptor for this virus.

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Secreted.

Tissue specificity. Detected in brain and in cerebrospinal fluid (at protein level).

Post-translational modifications. The N-terminus is blocked.

Activity regulation. Activated by small peptides. Activated by ATP and GTP, and to a lesser extent by CTP, TTP and PPPi. Inhibited by bacitracin. In vitro modification of Cys residues impairs enzyme activity.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The SlyX motif may be involved in the non-conventional secretion of the protein.

Miscellaneous. ATP-binding induces a conformation change.

Similarity. Belongs to the peptidase M16 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P14735-1	1	yes
P14735-2	2

RefSeq proteins (8): NP_001159418, NP_001309722, NP_001309723, NP_001309724, NP_001309725, NP_001309726, NP_001397903, NP_004960* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001431	Pept_M16_Zn_BS	Binding_site
IPR007863	Peptidase_M16_C	Domain
IPR011249	Metalloenz_LuxS/M16	Homologous_superfamily
IPR011765	Pept_M16_N	Domain
IPR032632	Peptidase_M16_M	Domain
IPR050626	Peptidase_M16	Family
IPR054734	PqqF-like_C_4	Domain

Pfam: PF00675, PF05193, PF16187, PF22456

Enzyme classification (BRENDA)

• EC 3.4.24.56 — insulysin (BRENDA: 12 organisms, 277 substrates, 293 inhibitors, 87 Km, 99 kcat entries)

Substrate kinetics (BRENDA)

35 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ABZ-GGFLRKHGQ-EDDNP	0.0066–21.3	25
INSULIN	—	15
2-AMINOBENZOYL-GGFLRKHGQ-(N-(2,4-DINITROPHENYL)E	0.014–0.204	7
ABZ-GGFLRKHGQEDDNP	0.0059–0.0254	3
(7-METHOXYCOUMARIN-4-YL)ACETYL-KLVFFAEDK(DNP)-OH	0.0056–0.0076	2
7-METHOXYCOUMARIN-4-YL-ACETYL-RPPGFSAFK-2,4-DINI	0.0047–0.0049	2
AMYLOID BETA-PEPTIDE1-40	0.025–0.027	2
AMYLOID BETA-PROTEIN	0.0012–0.0025	2
DABCYL-TYR-GLU-VAL-HIS-HIS-GLN-LYS-LEU-VAL-PHE-P	1.2–2.3	2
PROINSULIN	0.0002–0.0009	2
(7-METHOXYCOUMARIN-4-YL)ACETYL-RPPGFSAFK(2,4-DIN	0.0099	1
ABZ-GLY-GLY-LEU-ARG-LYS-HIS-GLY-GLN-EDDNP	0.0111	1
ABZ-SEKKDNYIIKGV-NITROY-OH	0.219	1
AMYLOID BETA	0.08	1
AMYLOID BETA-PEPTIDE 1-40	0.0028	1

UniProt features (134 total): helix 60, strand 36, mutagenesis site 13, binding site 7, sequence conflict 6, turn 6, modified residue 2, chain 1, short sequence motif 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

showing 30 of 62 structures by resolution:

PDB	Title	Method	Resolution (Å)
3CWW	Crystal Structure of IDE-bradykinin complex	X-RAY DIFFRACTION	1.96
2G47	Crystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-40)	X-RAY DIFFRACTION	2.1
2G56	crystal structure of human insulin-degrading enzyme in complex with insulin B chain	X-RAY DIFFRACTION	2.2
4PES	Crystal structure of insulin degrading enzyme complexed with inhibitor tert-butyl …	X-RAY DIFFRACTION	2.21
4PFC	Crystal structure of insulin degrading enzyme complexed with inhibitor	X-RAY DIFFRACTION	2.21
2G54	Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B …	X-RAY DIFFRACTION	2.25
3E4Z	Crystal structure of human insulin degrading enzyme in complex with insulin-like growth …	X-RAY DIFFRACTION	2.28
3E50	Crystal structure of human insulin degrading enzyme in complex with transforming growth …	X-RAY DIFFRACTION	2.3
4PF7	Crystal structure of insulin degrading enzyme complexed with inhibitor	X-RAY DIFFRACTION	2.33
3OFI	Crystal structure of human insulin-degrading enzyme in complex with ubiquitin	X-RAY DIFFRACTION	2.35
2G49	Crystal structure of human insulin-degrading enzyme in complex with glucagon	X-RAY DIFFRACTION	2.5
4PF9	Crystal structure of insulin degrading enzyme complexed with inhibitor	X-RAY DIFFRACTION	2.5
2WK3	Crystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-42)	X-RAY DIFFRACTION	2.59
2G48	crystal structure of human insulin-degrading enzyme in complex with amylin	X-RAY DIFFRACTION	2.6
2WBY	Crystal structure of human insulin-degrading enzyme in complex with insulin	X-RAY DIFFRACTION	2.6
3E4A	Human IDE-inhibitor complex at 2.6 angstrom resolution	X-RAY DIFFRACTION	2.6
7K1F	Crystal structure of human insulin degrading enzyme (IDE) in complex with compound …	X-RAY DIFFRACTION	2.6
4GSF	The structure analysis of cysteine free insulin degrading enzyme (ide) with …	X-RAY DIFFRACTION	2.7
4LTE	Structure of Cysteine-free Human Insulin Degrading Enzyme in Complex with Macrocyclic …	X-RAY DIFFRACTION	2.71
4NXO	Crystal Structure of Insulin Degrading Enzyme in complex with BDM44768	X-RAY DIFFRACTION	2.73
2JG4	Substrate-free IDE structure in its closed conformation	X-RAY DIFFRACTION	2.8
2WC0	crystal structure of human insulin degrading enzyme in complex with iodinated insulin	X-RAY DIFFRACTION	2.8
2YPU	human insulin degrading enzyme E111Q in complex with inhibitor compound 41367	X-RAY DIFFRACTION	2.8
7K1E	Crystal structure of human insulin degrading enzyme (IDE) in complex with compound …	X-RAY DIFFRACTION	2.8
4GSC	Structure analysis of insulin degrading enzyme with compound bdm41559 …	X-RAY DIFFRACTION	2.81
4RE9	Crystal structure of human insulin degrading enzyme (IDE) in complex with compound 71290	X-RAY DIFFRACTION	2.91
3HGZ	Crystal structure of human insulin-degrading enzyme in complex with amylin	X-RAY DIFFRACTION	2.91
6BYZ	Structure of Cysteine-free Human Insulin-Degrading Enzyme in complex with …	X-RAY DIFFRACTION	2.96
4GS8	Structure analysis of cysteine free insulin degrading enzyme (ide) with compound bdm43079 …	X-RAY DIFFRACTION	2.99
2JBU	Crystal structure of human insulin degrading enzyme complexed with co- purified peptides.	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14735-F1	94.06	0.93

Antibody-complex structures (SAbDab)

9 antibodies co-crystallized with this protein: 4IOF, 4M1C, 5CJO, 5UOE, 5WOB, 6B70, 6B7Z, 6BF7, 6BF9

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Metallopeptidases, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
111	proton acceptor

Ligand- & substrate-binding residues (7)

Position	Role
108	Zn(2+)
112	Zn(2+)
189	Zn(2+)
336–342	substrate
359–363	substrate
429	ATP
895–901	ATP

Post-translational modifications (2)

Type	Positions
N6-succinyllysine	192, 697

Mutagenesis-validated functional residues (13)

Position	Phenotype
111	loss of catalytic activity.
132	increases catalytic rate towards ins and amyloid; when associated with c-817.
184	increases catalytic rate towards ins and amyloid; when associated with c-828.
286	reduced enzyme activity.
366–369	reduced enzyme activity.
426	increases catalytic rate towards ins and amyloid; when associated with c-899.
496	strongly reduced enzyme activity.
530	strongly increased enzyme activity.
767	decreases dimerization. no effect on degradation of anp. retains the ability to degrade an aberrant form of anp, when in the presence of …
817	increases catalytic rate towards ins and amyloid; when associated with c-132.
828	increases catalytic rate towards ins and amyloid; when associated with c-184.
831	no effect on catalytic activity.
899	increases catalytic rate towards ins and amyloid; when associated with c-426.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-77387	Insulin receptor recycling	curated
R-HSA-5689880	Ub-specific processing proteases	curated
R-HSA-5688426	Deubiquitination	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-9033241	Peroxisomal protein import	electronic
R-HSA-597592	Post-translational protein modification	—
R-HSA-9609507	Protein localization	—
R-HSA-162582	Signal Transduction	—
R-HSA-74752	Signaling by Insulin receptor	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—

MSigDB gene sets: 303 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, ELVIDGE_HYPOXIA_DN, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_PROTEIN_BINDING, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEIN_BINDING, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOMF_METALLOPEPTIDASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE

GO Biological Process (18): proteolysis (GO:0006508), insulin receptor signaling pathway (GO:0008286), bradykinin catabolic process (GO:0010815), ubiquitin recycling (GO:0010992), antigen processing and presentation of endogenous peptide antigen via MHC class I (GO:0019885), protein catabolic process (GO:0030163), positive regulation of protein binding (GO:0032092), hormone catabolic process (GO:0042447), peptide catabolic process (GO:0043171), positive regulation of protein catabolic process (GO:0045732), negative regulation of proteolysis (GO:0045861), amyloid-beta metabolic process (GO:0050435), amyloid-beta clearance (GO:0097242), amyloid-beta clearance by cellular catabolic process (GO:0150094), insulin metabolic process (GO:1901142), insulin catabolic process (GO:1901143), regulation of aerobic respiration (GO:1903715), symbiont entry into host cell (GO:0046718)

GO Molecular Function (21): amyloid-beta binding (GO:0001540), virus receptor activity (GO:0001618), endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), ATP binding (GO:0005524), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), beta-endorphin binding (GO:0031626), peptide binding (GO:0042277), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), insulin binding (GO:0043559), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), peptide hormone binding (GO:0017046), metal ion binding (GO:0046872)

GO Cellular Component (13): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), peroxisome (GO:0005777), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), basolateral plasma membrane (GO:0016323), cytosolic proteasome complex (GO:0031597), extracellular exosome (GO:0070062), extracellular region (GO:0005576), plasma membrane (GO:0005886)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Deubiquitination	1
Signaling by Insulin receptor	1
Protein localization	1
Post-translational protein modification	1
Metabolism of proteins	1
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

showing 60 of 69 GO namespaces:

Category	Terms
catabolic process	4
binding	4
cellular anatomical structure	4
protein metabolic process	3
protein binding	3
protein catabolic process	2
peptidase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
cellular homeostasis	1
antigen processing and presentation of peptide antigen via MHC class I	1
antigen processing and presentation of endogenous peptide antigen	1
macromolecule catabolic process	1
regulation of protein binding	1
positive regulation of binding	1
hormone metabolic process	1
peptide metabolic process	1
positive regulation of catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
metabolic process	1
multicellular organismal process	1
amyloid-beta metabolic process	1
amyloid-beta clearance	1
insulin metabolic process	1
aerobic respiration	1
regulation of cellular respiration	1
viral life cycle	1
symbiont entry into host	1
peptide binding	1
symbiont entry into host cell	1
exogenous protein binding	1
endopeptidase activity	1
metallopeptidase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
transition metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
identical protein binding	1
protein dimerization activity	1
peptide hormone binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
hormone binding	1
intracellular anatomical structure	1
microbody	1
peroxisome	1
microbody lumen	1
plasma membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 30 of 54 annotations. The rest are phylogenetic / computational / electronic (IEA).

30 experimentally-supported GO terms:

GO term	NS	Evidence
amyloid-beta clearance	BP	mutant phenotype
amyloid-beta clearance by cellular catabolic process	BP	mutant phenotype
amyloid-beta metabolic process	BP	direct assay
antigen processing and presentation of endogenous peptide antigen via MHC class I	BP	mutant phenotype
bradykinin catabolic process	BP	direct assay
hormone catabolic process	BP	direct assay
insulin catabolic process	BP	direct assay
insulin metabolic process	BP	direct assay
peptide catabolic process	BP	direct assay
positive regulation of protein binding	BP	direct assay
protein catabolic process	BP	mutant phenotype
proteolysis	BP	direct assay
regulation of aerobic respiration	BP	genetic interaction
ubiquitin recycling	BP	direct assay
basolateral plasma membrane	CC	mutant phenotype
cell surface	CC	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
external side of plasma membrane	CC	direct assay
mitochondrion	CC	direct assay
nucleus	CC	direct assay
peroxisome	CC	direct assay
ATP binding	MF	direct assay
endopeptidase activity	MF	direct assay
identical protein binding	MF	physical interaction
insulin binding	MF	direct assay
metalloendopeptidase activity	MF	direct assay
peptide binding	MF	physical interaction
protein homodimerization activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,618 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IDE	MMEL1	Q495T6	948
IDE	MME	P08473	936
IDE	APP	P05067	862
IDE	ECE1	P42892	811
IDE	INS	P01308	801
IDE	BACE1	P56817	783
IDE	ECE2	P0DPD6	769
IDE	PSEN1	P49768	723
IDE	GCG	P01275	697
IDE	IAPP	P10997	692
IDE	PMPCA	Q10713	683
IDE	APOE	P02649	655
IDE	PSEN2	P49810	610
IDE	ADAM10	O14672	590
IDE	CTSB	P07858	585

IntAct

Human interaction partners of IDE in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 31 partners by confidence:

Partner	Interaction type	MIscore	Records
CCL3	direct interaction	0.620	3
SIRT4	association	0.620	1
CCL23	physical association	0.590	2
APP	physical association	0.560	3
DOHH	association	0.530	2
HYLS1	association	0.530	2
C8A	association	0.530	1
HLA-DPB1	association	0.530	1
MBP	physical association	0.500	1
CCL4	cleavage reaction	0.440	1
DLK2	physical association	0.400	1
H2AC4	physical association	0.400	1
LINC01600	physical association	0.400	1
SOX2	physical association	0.400	1
DCANP1	association	0.350	2
FAM136A	association	0.350	2
LIME1	association	0.350	2
SAXO4	association	0.350	2
ACVR2A	association	0.350	1
CACNB4	association	0.350	1
CD5	association	0.350	1
EPS8L1	association	0.350	1
FOXE1	association	0.350	1
GALP	association	0.350	1
IFIH1	association	0.350	1
NEFL	association	0.350	1
PAK5	association	0.350	1
PRKACG	association	0.350	1
PROK1	association	0.350	1
PROZ	association	0.350	1

BioGRID (273 interactions; top human partners by supporting records): HOXC9 (Affinity Capture-MS; 4 records), DOHH (Affinity Capture-MS; 3 records), HYLS1 (Affinity Capture-MS; 3 records), NES (Reconstituted Complex; 3 records), SIRT4 (Affinity Capture-Western; 3 records), UBC (Co-crystal Structure; 3 records), AR (Reconstituted Complex; 2 records), ARSG (Affinity Capture-MS; 2 records), C3orf62 (Affinity Capture-MS; 2 records), CCL23 (Affinity Capture-MS; 2 records), CLPP (Proximity Label-MS; 2 records), CTAGE5 (Affinity Capture-MS; 2 records), FAM19A3 (Affinity Capture-MS; 2 records), HLA-DPB1 (Affinity Capture-MS; 2 records), LEPREL2 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
IDE	“down-regulates quantity by destabilization”	INS	cleavage

Disease & clinical

Genetic variants

Variant evidence for IDE: 131 ClinVar records (0 pathogenic / likely pathogenic); 22 GWAS associations.

ClinVar

131 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	105
Likely benign	4
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 2,678):

Position(s)	Effect	Δscore	Sites
10:92454540–92454541	acceptor_loss	1.0000	5
10:92461190	donor_loss	1.0000
10:92461253–92461254	acceptor_loss	1.0000	4
10:92463729–92463730	donor_loss	1.0000	5
10:92463787	donor_gain	1.0000
10:92465667	donor_gain	1.0000
10:92465679	donor_gain	1.0000
10:92468877–92468878	donor_loss	1.0000	5
10:92468991–92468992	acceptor_loss	1.0000	6
10:92474839–92474840	donor_loss	1.0000	5

AlphaMissense

3,535 missense substitutions predicted likely pathogenic (of 6,761 scored), across 775 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M254	9	0.883	0.991
M371	9	0.836	0.985
H112	8	1.000	1.000
H108	8	0.999	1.000
D197	8	0.998	1.000
D60	8	0.997	1.000
N528	8	0.997	1.000
F115	8	0.996	1.000
D564	8	0.996	0.999
H336	8	0.994	0.999
H340	8	0.994	0.999
D602	8	0.993	0.999
D378	8	0.992	0.997
N193	8	0.991	0.999
N139	8	0.989	1.000
H786	8	0.989	0.997
D80	8	0.988	0.998
S345	8	0.988	1.000
D426	8	0.986	0.999
F151	8	0.983	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:146680 | disease phenotypes:

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	amber

GWAS associations

22 associations:

Study	Trait	p-value
GCST010118_155	Type 2 diabetes	1e-71
GCST007847_8	Type 2 diabetes	5e-39
GCST008362_69	Birth weight	4e-23
GCST003400_30	Type 2 diabetes	6e-20
GCST005047_39	Type 2 diabetes	2e-19
GCST002352_42	Type 2 diabetes	3e-19
GCST000712_21	Type 2 diabetes	1e-15
GCST005146_39	Birth weight	1e-14
GCST003400_32	Type 2 diabetes	2e-14
GCST003400_33	Type 2 diabetes	2e-14
GCST005047_19	Type 2 diabetes	7e-13
GCST005047_60	Type 2 diabetes	5e-12
GCST010244_259	Triglyceride levels	3e-10
GCST008916_68	Asthma	7e-10
GCST003632_1	Survival in sporadic amyotrophic lateral sclerosis	2e-9
GCST005413_11	Type 2 diabetes	3e-9
GCST009379_131	Type 2 diabetes	1e-8
GCST009379_130	Type 2 diabetes	4e-7
GCST004131_111	Inflammatory bowel disease	5e-7
GCST009379_132	Type 2 diabetes	5e-7
GCST001621_19	Airflow obstruction	3e-6
GCST008159_84	Waist-to-hip ratio adjusted for BMI	8e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0000714	survival time
EFO:0004344	birth weight
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293287 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 628,301 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

6 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL857	BIOTIN	4	590,540
CHEMBL1201195	CEFMETAZOLE	4	10,395
CHEMBL1219	RABEPRAZOLE	4	12,552
CHEMBL1200883	THONZONIUM BROMIDE	4	1,116
CHEMBL51085	EBSELEN	3	13,356
CHEMBL1237046	ROLITETRACYCLINE	2	342

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M16: Pitrilysin

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
NTE-1	Inhibition	8.4	pIC50
NTE-2	Inhibition	7.74	pIC50
quinoline 2	Inhibition	5.7	pIC50

Binding affinities (BindingDB)

60 measured of 98 human assays (102 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL2324206	KI	1.4 nM
CHEMBL2324220	KI	1.7 nM
CHEMBL4437643	IC50	4 nM
CHEMBL4211248	KD	22 nM
CHEMBL2324201	KI	26 nM
CHEMBL4556893	IC50	50 nM
(4Z,8S,11S,14R)-8-(3-amino-3-oxopropyl)-14-[(4-benzoylphenyl)methyl]-11-(cyclohexylmethyl)-3,6,9,12,15-pentaoxo-1,2,7,10,13,16,21-heptazacyclohexacos-4-ene-22-carboxylic acid	IC50	54 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
CHEMBL4527561	IC50	56 nM
(4Z,8S,11S,14R)-8-(3-amino-3-oxopropyl)-14-[(4-benzoylphenyl)methyl]-11-(cyclohexylmethyl)-N-ethyl-3,6,9,12,15-pentaoxo-1,2,7,10,13,16,21-heptazacyclopentacos-4-ene-22-carboxamide	IC50	60 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3E,7S,10R,20S)-7-(3-aminobut-3-enyl)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	60 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3R,6S,9S,12E)-9-(4-aminobutyl)-3-[(4-benzoylphenyl)methyl]-6-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentazacycloicos-12-ene-16-carboxamide	IC50	65 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
CHEMBL2324209	KI	73 nM
CHEMBL2324219	KI	78 nM
5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[2-[2-[2-[(4Z,8S,11S,14R)-8-(3-amino-3-oxopropyl)-14-[(4-benzoylphenyl)methyl]-11-(cyclohexylmethyl)-3,6,9,12,15-pentaoxo-1,2,7,10,13,16,21-heptazacyclohexacos-4-en-22-yl]-2-oxoethoxy]ethoxy]ethoxy]propyl]pentanamide	IC50	80 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
3-[(3R,6S,12E)-3-[(4-benzoylphenyl)methyl]-16-carbamoyl-6-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentazacycloicos-12-en-9-yl]propanoic acid	IC50	85 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
CHEMBL2324202	KI	103 nM
CHEMBL2324203	KI	107 nM
CHEMBL2324207	KI	171 nM
CHEMBL2324204	KI	228 nM
CHEMBL4241044	IC50	330 nM
CHEMBL2324205	KI	365 nM
CHEMBL2324213	KI	498 nM
CHEMBL3235414	IC50	600 nM
CHEMBL3235415	IC50	600 nM
(3E,7S,10R,20S)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-7-(cyclopropylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	1000 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
CHEMBL2324208	KI	1150 nM
CHEMBL3235413	IC50	1400 nM
(3E,7S,10R,20R)-13-[(4-benzoylphenyl)methyl]-7,10-bis(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	1500 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
CHEMBL3235412	IC50	2900 nM
CHEMBL5195657	EC50	5010 nM
CHEMBL2324218	KI	5280 nM
(3E,7S,10R,20R)-7-(3-aminobut-3-enyl)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	5600 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
CHEMBL5189585	EC50	6760 nM
CEFMETAZOLE	IC50	7000 nM
CHEMBL2324214	KI	7020 nM
CHEMBL5185555	EC50	7240 nM
CHEMBL2324212	KI	7750 nM
CHEMBL5198743	EC50	7940 nM
CHEMBL5198912	EC50	8130 nM
CHEMBL5203883	EC50	8130 nM
CHEBI:8768	IC50	8500 nM
(3E,7S,10R)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-7-[3-(diaminomethylideneamino)propyl]-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	10000 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
CHEMBL5201963	EC50	10000 nM
CHEMBL5186397	EC50	10200 nM
CHEMBL5169861	EC50	10200 nM
CHEMBL5194929	EC50	12300 nM
CHEMBL5179418	EC50	13200 nM
CHEMBL5170331	EC50	13800 nM
CHEMBL5193447	EC50	14100 nM
CHEMBL5204606	EC50	14500 nM

ChEMBL bioactivities

154 potent at pChembl≥5 of 263 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.85	Ki	1.4	nM	CHEMBL2324206
8.77	Ki	1.7	nM	CHEMBL2324220
8.53	Ki	2.96	nM	CHEMBL2324220
8.40	IC50	4	nM	CHEMBL4437643
7.85	IC50	14	nM	EBSELEN
7.66	Ki	21.7	nM	CHEMBL2324220
7.66	Kd	22	nM	CHEMBL4211248
7.64	Ki	23.1	nM	CHEMBL2324207
7.59	Ki	25.9	nM	CHEMBL2324201
7.42	Ki	37.9	nM	CHEMBL2324220
7.38	IC50	42	nM	EBSELEN
7.36	Ki	43.7	nM	CHEMBL2324206
7.30	Ki	49.8	nM	CHEMBL2324204
7.30	IC50	50	nM	CHEMBL4556893
7.27	IC50	54	nM	CHEMBL3980383
7.25	IC50	56	nM	CHEMBL4241044
7.25	IC50	56	nM	CHEMBL4527561
7.22	IC50	60	nM	CHEMBL3986116
7.22	IC50	60	nM	CHEMBL4108142
7.22	IC50	60	nM	CHEMBL4113567
7.22	IC50	60	nM	CHEMBL4109327
7.22	IC50	60	nM	CHEMBL4108344
7.22	IC50	60	nM	CHEMBL4241044
7.22	IC50	60	nM	CHEMBL6062354
7.19	IC50	65	nM	CHEMBL4110918
7.15	Ki	70.3	nM	CHEMBL2324201
7.13	Ki	73.3	nM	CHEMBL2324209
7.11	Ki	78	nM	CHEMBL2324219
7.10	IC50	80	nM	CHEMBL3893930
7.07	Ki	85.1	nM	CHEMBL2324205
7.07	IC50	85	nM	CHEMBL4108429
7.06	Ki	87	nM	CHEMBL2324203
7.00	IC50	100	nM	CHEMBL3235416
7.00	IC50	100	nM	CHEMBL3925351
6.99	Ki	103	nM	CHEMBL2324202
6.97	Ki	107	nM	CHEMBL2324203
6.82	IC50	150	nM	CHEMBL4115434
6.77	Ki	171	nM	CHEMBL2324207
6.64	Ki	228	nM	CHEMBL2324204
6.61	Ki	246	nM	CHEMBL2324207
6.56	Ki	275	nM	CHEMBL2324201
6.48	IC50	330	nM	CHEMBL4241044
6.44	Ki	365	nM	CHEMBL2324205
6.43	IC50	370	nM	CHEMBL4112829
6.39	Ki	410	nM	CHEMBL2324206
6.30	Ki	498	nM	CHEMBL2324213
6.30	IC50	500	nM	CHEMBL4109006
6.28	EC50	530	nM	CHEMBL3235416
6.24	IC50	570	nM	CHEMBL3972636
6.24	IC50	570.7	nM	CHEMBL3212590

PubChem BioAssay actives

61 with measured affinity, of 187 total; 35 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-[2-[[(4S)-4-acetamido-5-[[(2R)-1-[benzoyl-[(2R)-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-oxopentanoyl]amino]ethylamino]naphthalene-1-sulfonic acid	729332: Inhibition of human recombinant IDE-mediated fluorescein-Abeta-(1-40)-Lys-biotin degradation	ki	0.0014	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2R)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	1600071: Inhibition of human recombinant IDE expressed in CHO cells in presence of [125I]-insulin by HTRF assay	ki	0.0017	uM
methyl N-[(2S)-2-[4-[5-[4-[[(2S)-2-[(3S)-3-amino-2-oxopiperidin-1-yl]-2-cyclohexylacetyl]amino]phenyl]pentoxy]phenyl]-3-quinolin-3-ylpropyl]carbamate	1600074: Inhibition of recombinant IDE exosite (unknown origin) expressed in Escherichia coli using insulin as substrate incubated for 4 hrs by AlphaLisa assay	ic50	0.0040	uM
2-phenyl-1,2-benzoselenazol-3-one	1600086: Inhibition of human recombinant IDE expressed in Escherichia coli BL21 (DE3) cells using insulin as substrate preincubated for 10 mins followed by substrate addition and measured after 15 mins by fluorescence based assay	ic50	0.0140	uM
(4S)-4-acetamido-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(3R,12S,17S,20S,23S)-17-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[(2-amino-2-oxoethyl)amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]-20-(2-carboxyethyl)-2,8,11,14,19,22-hexaoxo-1,7,10,15,18,21-hexazatricyclo[21.3.0.03,7]hexacosan-12-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1386258: Binding affinity to IDE E111Q mutant (unknown origin) using N-terminal FITC-labeled compound after 2 hrs in absence of light at 298 K by fluorescence polarization assay	kd	0.0220	uM
2-[(2R,5R,8R,11R,14R,17R)-8-benzyl-11-[(2R)-butan-2-yl]-17-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamoyl]-14-(3-carbamimidamidopropyl)-5-(1H-imidazol-5-ylmethyl)-3,6,9,12,15,20-hexaoxo-1,4,7,10,13,16-hexazacycloicos-2-yl]acetic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0231	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2R,3S)-3-hydroxy-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0259	uM
(4R)-4-amino-5-[[(2R)-1-[[(2R)-5-(diaminomethylideneamino)-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0498	uM
(3R,6S,9S,12E,16S)-9-(4-aminobutyl)-3-[(4-benzoylphenyl)methyl]-6-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentazacycloicos-12-ene-16-carboxamide	1625401: Inhibition of IDE (unknown origin) assessed as cleavage of Mca-RPPGFSAFK(Dnp)-OH by fluorescence assay	ic50	0.0500	uM
4-fluoro-N-[[3-[(2R)-4-(hydroxyamino)-1-naphthalen-2-yl-4-oxobutan-2-yl]-1,2-dihydrotriazol-5-yl]methyl]benzamide	1559627: Inhibition of human recombinant IDE pre-incubated for 10 mins before Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp substrate addition and measured after 30 mins by fluorescence based assay	ic50	0.0560	uM
4-fluoro-N-[[1-[(2R)-4-(hydroxyamino)-1-naphthalen-2-yl-4-oxobutan-2-yl]triazol-4-yl]methyl]benzamide	1396210: Inhibition of human IDE using insulin as substrate preincubated for 10 mis followed by substrate addition and measured after 30 mins	ic50	0.0560	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0733	uM
(4S)-4-acetamido-5-[[(2S)-1-[[(4S,6S)-1-(diaminomethylideneamino)-8-(hydroxyamino)-6-(naphthalen-2-ylmethyl)-5,8-dioxooctan-4-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0780	uM
(4R)-4-amino-5-[[(2R)-1-[[(2R)-5-(diaminomethylideneamino)-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0851	uM
prop-2-enyl (2S)-5-(diaminomethylideneamino)-2-[[(2R)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoate	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0870	uM
2-[[2-[[(2S)-3-(1H-imidazol-5-yl)-1-(methylamino)-1-oxopropan-2-yl]amino]-2-oxoethyl]-(3-phenylpropyl)amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	0.1000	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2R,3R)-3-hydroxy-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.1030	uM
(2R,3R)-N-[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’,3-dihydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.4980	uM
2-[benzyl-[2-[[(2S)-3-(1H-imidazol-5-yl)-1-(methylamino)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	0.6000	uM
2-[[2-[[(2S)-3-(1H-imidazol-5-yl)-1-methoxy-1-oxopropan-2-yl]amino]-2-oxoethyl]-(3-phenylpropyl)amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	0.6000	uM
(2R)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’-hydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	1.1500	uM
2-[[2-[[(2S)-3-(1H-imidazol-5-yl)-1-methoxy-1-oxopropan-2-yl]amino]-2-oxoethyl]-(2-phenylethyl)amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	1.4000	uM
2-[benzyl-[2-[[(2S)-3-(1H-imidazol-5-yl)-1-methoxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	2.9000	uM
N-(3-imidazol-1-ylpropyl)-4-(1-thiophen-2-ylsulfonylindol-3-yl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	5.0119	uM
prop-2-enyl (2S)-5-(diaminomethylideneamino)-2-[[(2S)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoate	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	5.2800	uM
4-[1-(4-fluorophenyl)sulfonylindol-3-yl]-N-(3-imidazol-1-ylpropyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	6.7608	uM
(6R,7S)-7-[[2-(cyanomethylsulfanyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	1600069: Inhibition of human recombinant IDE expressed in Escherichia coli BL21 (DE3) cells using ATTO 655- Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins followed by substrate addition and measured after 30 mins by spectrophotometric analysis	ic50	7.0000	uM
(2R,3R)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’,3-dihydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	7.0200	uM
5-[1-(benzenesulfonyl)indol-3-yl]-N-(3-imidazol-1-ylpropyl)pentanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	7.2444	uM
(2R,3S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’,3-dihydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	7.7500	uM
4-[1-(2-fluorophenyl)sulfonylindol-3-yl]-N-(3-imidazol-1-ylpropyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	7.9433	uM
4-[1-(benzenesulfonyl)indol-3-yl]-N-(4-imidazol-1-ylbutyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	8.1283	uM
4-[1-(benzenesulfonyl)indol-2-yl]-N-(3-imidazol-1-ylpropyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	8.1283	uM
(2S)-2-[bis(1H-imidazol-5-ylmethyl)amino]-5-(3-naphthalen-2-yl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)pentanoic acid	1935861: Inhibition of recombinant human IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate measured after 45 mins by fluorescence assay	ic50	9.1000	uM
N-(3-imidazol-1-ylpropyl)-4-(1H-indol-3-yl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	10.0000	uM

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases expression	4
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression, increases expression	1
3,4-dihydroxyphenylpropionic acid	affects activity, affects binding	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
scopolin	affects activity, affects binding	1
2-chloro-5-nitrobenzanilide	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
thifluzamide	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
isopraeroside IV	affects activity, affects binding	1
Bortezomib	increases expression	1
Rosiglitazone	decreases reaction, increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Arsenic	decreases expression, increases abundance	1

ChEMBL screening assays

68 unique, capped per target: 66 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614462	Functional	PUBCHEM_BIOASSAY: Dose Response: Fluorescence polarization-based cell-based high throughput dose response assay for inhibitors of insulin-degrading enzyme (IDE). (Class of assay: confirmatory) [Related pubchem assays: 434962 (Primary screen	PubChem BioAssay data set
CHEMBL1794358	Binding	PUBCHEM_BIOASSAY: Counterscreen for IDE activators: Fluorescence polarization-based biochemical high throughput dose response assay for activators of recombinant IDE. (Class of assay: confirmatory) [Related pubchem assays (depositor defined	PubChem BioAssay data set

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1U4	Abcam HeLa IDE KO	Cancer cell line	Female
CVCL_SR99	HAP1 IDE (-) 1	Cancer cell line	Male
CVCL_SS00	HAP1 IDE (-) 2	Cancer cell line	Male
CVCL_SS01	HAP1 IDE (-) 3	Cancer cell line	Male
CVCL_SS02	HAP1 IDE (-) 4	Cancer cell line	Male
CVCL_YB06	EndoC-betaH1 IDE-KO	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for IDE across ~30M SureChEMBL compounds — explore on Sugi Predict.