Details of Drug-Metabolizing Enzyme (DME)

General Information of Drug-Metabolizing Enzyme (DME) (ID: DE9OSW8)

• DME Name: Insulin-degrading enzyme (IDE)
• Synonyms: Abeta-degrading protease; Insulin protease; Insulinase; Insulysin; IDE
• Gene Name: IDE
• UniProt ID: IDE_HUMAN
• INTEDE ID: DME0494
• Gene ID: 3416
• EC Number:
  EC: 3.4.24.56
  Hydrolases
  Peptidase
  Metallopeptidase
  EC: 3.4.24.56
• Lineage:
  Species: Homo sapiens
  Kingdom: Metazoa
  Phylum: Chordata
  Class: Mammalia
  Order: Primates
  Family: Hominidae
  Genus: Homo
  Species: Homo sapiens
• Sequence:
  MRYRLAWLLHPALPSTFRSVLGARLPPPERLCGFQKKTYSKMNNPAIKRIGNHITKSPED
  KREYRGLELANGIKVLLISDPTTDKSSAALDVHIGSLSDPPNIAGLSHFCEHMLFLGTKK
  YPKENEYSQFLSEHAGSSNAFTSGEHTNYYFDVSHEHLEGALDRFAQFFLCPLFDESCKD
  REVNAVDSEHEKNVMNDAWRLFQLEKATGNPKHPFSKFGTGNKYTLETRPNQEGIDVRQE
  LLKFHSAYYSSNLMAVCVLGRESLDDLTNLVVKLFSEVENKNVPLPEFPEHPFQEEHLKQ
  LYKIVPIKDIRNLYVTFPIPDLQKYYKSNPGHYLGHLIGHEGPGSLLSELKSKGWVNTLV
  GGQKEGARGFMFFIINVDLTEEGLLHVEDIILHMFQYIQKLRAEGPQEWVFQECKDLNAV
  AFRFKDKERPRGYTSKIAGILHYYPLEEVLTAEYLLEEFRPDLIEMVLDKLRPENVRVAI
  VSKSFEGKTDRTEEWYGTQYKQEAIPDEVIKKWQNADLNGKFKLPTKNEFIPTNFEILPL
  EKEATPYPALIKDTAMSKLWFKQDDKFFLPKACLNFEFFSPFAYVDPLHCNMAYLYLELL
  KDSLNEYAYAAELAGLSYDLQNTIYGMYLSVKGYNDKQPILLKKIIEKMATFEIDEKRFE
  IIKEAYMRSLNNFRAEQPHQHAMYYLRLLMTEVAWTKDELKEALDDVTLPRLKAFIPQLL
  SRLHIEALLHGNITKQAALGIMQMVEDTLIEHAHTKPLLPSQLVRYREVQLPDRGWFVYQ
  QRNEVHNNCGIEIYYQTDMQSTSENMFLELFCQIISEPCFNTLRTKEQLGYIVFSGPRRA
  NGIQGLRFIIQSEKPPHYLESRVEAFLITMEKSIEDMTEEAFQKHIQALAIRRLDKPKKL
  SAECAKYWGEIISQQYNFDRDNTEVAYLKTLTKEDIIKFYKEMLAVDAPRRHKVSVHVLA
  REMDSCPVVGEFPCQNDINLSQAPALPQPEVIQNMTEFKRGLPLFPLVKPHINFMAAKL
• Function: This enzyme plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, glucagon, bradykinin, kallidin and other peptides. Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin. It plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia.
• KEGG Pathway: Alzheimer's disease (hsa05010)
• Reactome Pathway:
  Ub-specific processing proteases (R-HSA-5689880)
  Peroxisomal protein import (R-HSA-9033241)

Molecular Interaction Atlas (MIA) of This DME

1 Approved Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Insulin	DMB7CE0	Diabetic complication	5A2Y	Approved	[5]

Experimental Enzyme Kinetic Data of Drugs

Drug Name	Indication	Highest Status	Kinetic Data	REF
Insulin	Diabetic complication [5A2Y]	Approved	Km = 0.0000657 microM	[5]

Molecular Expression Atlas (MEA) of This DME

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2B33.1	Bone marrow	4.84E-01	1.41E-01	3.15E-01
Alopecia	ED70	Skin from scalp	2.06E-01	1.04E-01	2.61E-01
Alzheimer's disease	8A20	Entorhinal cortex	4.21E-01	-1.19E-02	-4.93E-02
Ankylosing spondylitis	FA92.0	Pheripheral blood	7.49E-01	-1.10E-01	-2.88E-01
Aortic stenosis	BB70	Calcified aortic valve	6.46E-01	9.22E-02	4.20E-01
Apnea	7A40	Hyperplastic tonsil	1.35E-02	-6.82E-01	-1.12E+00
Arthropathy	FA00-FA5Z	Peripheral blood	7.63E-01	-5.29E-02	-2.12E-01
Asthma	CA23	Nasal and bronchial airway	8.80E-01	3.03E-02	5.56E-02
Atopic dermatitis	EA80	Skin	2.12E-09	-1.71E+00	-7.05E+00
Autism	6A02	Whole blood	1.16E-01	-4.67E-02	-1.73E-01
Autoimmune uveitis	9A96	Peripheral monocyte	6.06E-01	-3.07E-02	-8.11E-02
Autosomal dominant monocytopenia	4B04	Whole blood	3.90E-01	-1.36E-01	-5.37E-01
Bacterial infection of gingival	1C1H	Gingival tissue	1.58E-07	-1.70E-01	-5.89E-01
Batten disease	5C56.1	Whole blood	8.94E-02	1.01E-01	6.07E-01
Behcet's disease	4A62	Peripheral blood	1.58E-01	1.66E-01	1.04E+00
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	8.89E-01	-4.18E-02	-1.89E-01
Bladder cancer	2C94	Bladder tissue	7.04E-04	-5.60E-01	-2.30E+00
Breast cancer	2C60-2C6Z	Breast tissue	1.99E-51	4.67E-01	1.28E+00
Cardioembolic stroke	8B11.20	Whole blood	5.96E-04	2.32E-01	9.29E-01
Cervical cancer	2C77	Cervical tissue	3.13E-02	-2.86E-01	-5.80E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	9.04E-01	-7.39E-02	-8.22E-02
Chronic hepatitis C	1E51.1	Whole blood	6.28E-03	-2.31E-01	-1.41E+00
Chronic obstructive pulmonary disease	CA22	Lung tissue	2.86E-02	1.78E-01	4.93E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	4.22E-01	-9.87E-02	-2.61E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	8.76E-01	-3.67E-02	-1.06E-01
Colon cancer	2B90	Colon tissue	4.01E-07	2.59E-01	5.08E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	6.26E-01	-1.77E-01	-5.11E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	3.02E-01	1.50E-01	2.50E-01
Endometriosis	GA10	Endometrium tissue	1.23E-02	-1.02E-01	-1.94E-01
Familial hypercholesterolemia	5C80.00	Peripheral blood	3.29E-01	5.24E-03	2.29E-02
Familial hypercholesterolemia	5C80.00	Whole blood	6.07E-06	7.31E-01	1.50E+00
Gastric cancer	2B72	Gastric tissue	1.94E-01	4.84E-01	9.66E-01
Glioblastopma	2A00.00	Nervous tissue	1.52E-08	1.17E-01	3.03E-01
Glioma	2A00.0Y-2A00.0Z	Brain stem tissue	7.76E-01	3.48E-02	1.81E-01
Glioma	2A00.0Y-2A00.0Z	White matter tissue	1.28E-02	6.69E-01	9.74E-01
Head and neck cancer	2D42	Head and neck tissue	2.52E-03	-2.98E-01	-7.68E-01
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	1.45E-01	-2.54E-02	-1.46E-01
Huntington's disease	8A01.10	Whole blood	9.15E-01	-1.48E-01	-4.40E-01
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	4.73E-01	-4.99E-02	-1.93E-01
Immunodeficiency	4A00-4A20	Peripheral blood	1.17E-01	3.31E-02	3.18E-01
Influenza	1E30	Whole blood	5.24E-02	-1.04E+00	-2.29E+00
Interstitial cystitis	GC00.3	Bladder tissue	1.80E-01	1.43E-01	7.16E-01
Intracranial aneurysm	8B01.0	Intracranial artery	3.33E-02	2.03E-01	5.92E-01
Irritable bowel syndrome	DD91.0	Rectal colon tissue	1.46E-01	7.89E-02	2.79E-01
Ischemic stroke	8B11	Peripheral blood	3.79E-01	-1.07E-02	-5.16E-02
Juvenile idiopathic arthritis	FA24	Peripheral blood	9.18E-03	1.02E-01	1.57E-01
Lateral sclerosis	8B60.4	Skin	3.36E-01	1.93E-01	6.19E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	6.04E-01	1.34E-01	5.88E-01
Liver cancer	2C12.0	Liver tissue	4.35E-01	6.55E-02	9.78E-02
Liver failure	DB99.7-DB99.8	Liver tissue	1.28E-01	-4.06E-01	-1.67E+00
Lung cancer	2C25	Lung tissue	3.65E-33	4.67E-01	1.27E+00
Lupus erythematosus	4A40	Whole blood	9.47E-05	3.17E-01	6.50E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	5.63E-01	-3.60E-02	-1.68E-01
Major depressive disorder	6A70-6A7Z	Whole blood	6.53E-01	8.67E-02	3.20E-01
Melanoma	2C30	Skin	7.86E-02	-7.41E-01	-9.31E-01
Multiple myeloma	2A83.1	Peripheral blood	7.57E-01	-3.57E-01	-6.47E-01
Multiple myeloma	2A83.1	Bone marrow	1.77E-01	1.45E-02	4.84E-02
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	3.29E-01	-4.73E-02	-1.66E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	1.97E-01	-8.13E-02	-3.48E-01
Myelofibrosis	2A20.2	Whole blood	3.34E-03	-9.95E-02	-1.77E+00
Myocardial infarction	BA41-BA50	Peripheral blood	8.04E-01	-3.08E-01	-2.72E-01
Myopathy	8C70.6	Muscle tissue	7.87E-01	-2.34E-01	-3.01E-01
Neonatal sepsis	KA60	Whole blood	4.42E-13	4.91E-01	1.06E+00
Neuroectodermal tumour	2A00.11	Brain stem tissue	8.28E-01	-1.39E-02	-4.02E-02
Non-alcoholic fatty liver disease	DB92	Liver tissue	9.18E-01	1.94E-04	5.16E-04
Obesity related type 2 diabetes	5A11	Omental adipose tissue	5.15E-01	1.26E-01	5.04E-01
Olive pollen allergy	CA08.00	Peripheral blood	8.80E-01	-3.34E-01	-3.28E-01
Oral cancer	2B6E	Oral tissue	5.58E-02	1.15E-01	1.93E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	2.07E-01	4.48E-01	1.03E+00
Osteoporosis	FB83.1	Bone marrow	1.67E-01	-1.77E-01	-5.55E-01
Ovarian cancer	2C73	Ovarian tissue	1.31E-03	1.38E+00	1.87E+00
Pancreatic cancer	2C10	Pancreas	3.53E-02	2.16E-01	5.78E-01
Parkinson's disease	8A00.0	Substantia nigra tissue	1.82E-01	-2.66E-02	-1.21E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	8.36E-03	1.92E-01	9.74E-01
Pituitary cancer	2D12	Pituitary tissue	5.27E-01	-1.24E-01	-4.72E-01
Pituitary gonadotrope tumour	2D12	Pituitary tissue	5.08E-01	-3.37E-02	-1.21E-01
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	4.47E-01	-1.50E-01	-7.41E-01
Polycythemia vera	2A20.4	Whole blood	2.91E-18	-1.68E-01	-2.38E+00
Pompe disease	5C51.3	Biceps muscle	2.19E-01	-1.42E-01	-5.80E-01
Preterm birth	KA21.4Z	Myometrium	4.01E-01	1.13E-03	2.25E-03
Prostate cancer	2C82	Prostate	6.09E-01	-1.54E-01	-2.85E-01
Psoriasis	EA90	Skin	5.33E-14	4.40E-01	8.42E-01
Rectal cancer	2B92	Rectal colon tissue	4.75E-04	5.03E-01	2.82E+00
Renal cancer	2C90-2C91	Kidney	7.87E-01	2.50E-02	5.76E-02
Retinoblastoma	2D02.2	Uvea	1.07E-03	-7.24E-01	-1.48E+00
Rheumatoid arthritis	FA20	Synovial tissue	7.26E-03	5.73E-01	1.26E+00
Rhinovirus infection	CA42.1	Nasal epithelium tissue	3.68E-01	1.03E-02	6.32E-02
Schizophrenia	6A20	Prefrontal cortex	2.46E-01	1.02E-01	1.59E-01
Schizophrenia	6A20	Superior temporal cortex	8.24E-01	-4.56E-02	-4.42E-01
Scleroderma	4A42.Z	Whole blood	8.31E-01	2.20E-02	1.98E-01
Seizure	8A60-8A6Z	Whole blood	1.96E-01	-1.77E-01	-4.91E-01
Sensitive skin	EK0Z	Skin	8.67E-01	-7.21E-02	-1.69E-01
Sepsis with septic shock	1G41	Whole blood	2.88E-05	1.71E-01	4.56E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	5.88E-01	-1.20E-01	-4.70E-01
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	1.53E-01	-1.18E-01	-4.33E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	7.25E-01	1.71E-01	9.61E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	6.03E-01	1.65E-01	2.61E-01
Skin cancer	2C30-2C3Z	Skin	5.72E-94	-2.17E+00	-3.46E+00
Thrombocythemia	3B63	Whole blood	8.36E-08	-1.26E-01	-1.78E+00
Thrombocytopenia	3B64	Whole blood	5.66E-01	-1.43E-01	-1.18E-01
Thyroid cancer	2D10	Thyroid	2.95E-01	3.03E-02	9.33E-02
Tibial muscular dystrophy	8C75	Muscle tissue	6.99E-05	-7.76E-01	-1.41E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	1.14E-01	-5.05E-01	-1.45E+00
Type 2 diabetes	5A11	Liver tissue	4.28E-01	1.00E-02	3.72E-02
Ureter cancer	2C92	Urothelium	2.77E-01	-2.80E-02	-1.88E-01
Uterine cancer	2C78	Endometrium tissue	1.38E-07	2.97E-01	5.41E-01
Vitiligo	ED63.0	Skin	9.99E-01	-3.77E-02	-1.05E-01

The Drug Therapeutic Target (DTT) Role of This DME

• DME DTT Name: Insulin-degrading enzyme (IDE) DTT Info
• DME DTT Type: Successful

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bacitracin	DM5OHYE	Blepharoconjunctivitis		Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PRO-001	DM5ZTE4	Retinitis pigmentosa	9B70	Phase 2	[2]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GNF-PF-4478	DMCDU8K	Discovery agent	N.A.	Investigative	[3]
NTE-1	DMFIE0U	Discovery agent	N.A.	Investigative	[4]
NTE-2	DM4DB0W	Discovery agent	N.A.	Investigative	[4]
quinoline 2	DM1QIPZ	Discovery agent	N.A.	Investigative	[4]

References

• [1] Brain insulin impairs amyloid-beta(1-40) clearance from the brain. J Neurosci. 2004 Oct 27;24(43):9632-7.
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2371).
• [3] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [4] Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo. J Biol Chem. 2015 Aug 14;290(33):20044-59.
• [5] Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry. 2005 May 3;44(17):6513-25.