Details of Drug-Metabolizing Enzyme (DME)

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

• DME Name: Prolyl endopeptidase (PREP)
• Synonyms: Post-proline cleaving enzyme; Prolylendopeptidase; Prolylendo-peptidase; PE; PEP; PREP
• Gene Name: PREP
• UniProt ID: PPCE_HUMAN
• INTEDE ID: DME0574
• Gene ID: 5550
• EC Number:
  EC: 3.4.21.26
  Hydrolases
  Peptidase
  Serine protease
  EC: 3.4.21.26
• Lineage:
  Species: Homo sapiens
  Kingdom: Metazoa
  Phylum: Chordata
  Class: Mammalia
  Order: Primates
  Family: Hominidae
  Genus: Homo
  Species: Homo sapiens
• Sequence:
  MLSLQYPDVYRDETAVQDYHGHKICDPYAWLEDPDSEQTKAFVEAQNKITVPFLEQCPIR
  GLYKERMTELYDYPKYSCHFKKGKRYFYFYNTGLQNQRVLYVQDSLEGEARVFLDPNILS
  DDGTVALRGYAFSEDGEYFAYGLSASGSDWVTIKFMKVDGAKELPDVLERVKFSCMAWTH
  DGKGMFYNSYPQQDGKSDGTETSTNLHQKLYYHVLGTDQSEDILCAEFPDEPKWMGGAEL
  SDDGRYVLLSIREGCDPVNRLWYCDLQQESSGIAGILKWVKLIDNFEGEYDYVTNEGTVF
  TFKTNRQSPNYRVINIDFRDPEESKWKVLVPEHEKDVLEWIACVRSNFLVLCYLHDVKNI
  LQLHDLTTGALLKTFPLDVGSIVGYSGQKKDTEIFYQFTSFLSPGIIYHCDLTKEELEPR
  VFREVTVKGIDASDYQTVQIFYPSKDGTKIPMFIVHKKGIKLDGSHPAFLYGYGGFNISI
  TPNYSVSRLIFVRHMGGILAVANIRGGGEYGETWHKGGILANKQNCFDDFQCAAEYLIKE
  GYTSPKRLTINGGSNGGLLVAACANQRPDLFGCVIAQVGVMDMLKFHKYTIGHAWTTDYG
  CSDSKQHFEWLVKYSPLHNVKLPEADDIQYPSMLLLTADHDDRVVPLHSLKFIATLQYIV
  GRSRKQSNPLLIHVDTKAGHGAGKPTAKVIEEVSDMFAFIARCLNVDWIP
• Function: This enzyme cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.
• KEGG Pathway: Renin-angiotensin system (hsa04614)

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
Gonadorelin	DMAQ469	Amenorrhea	GA20.0	Approved	[11]

1 Clinical Trial Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BRADYKININ	DM4R6UV	N. A.	N. A.	Phase 1	[12]

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	6.45E-14	3.15E-01	9.10E-01
Alopecia	ED70	Skin from scalp	3.55E-05	-2.39E-01	-7.04E-01
Alzheimer's disease	8A20	Entorhinal cortex	2.28E-05	-3.02E-01	-5.90E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	3.04E-01	1.36E-01	5.23E-01
Aortic stenosis	BB70	Calcified aortic valve	5.89E-01	1.87E-01	3.28E-01
Apnea	7A40	Hyperplastic tonsil	6.14E-02	-3.63E-01	-6.25E-01
Arthropathy	FA00-FA5Z	Peripheral blood	1.32E-02	-1.79E-01	-1.31E+00
Asthma	CA23	Nasal and bronchial airway	3.81E-07	3.90E-01	5.99E-01
Atopic dermatitis	EA80	Skin	3.63E-01	1.40E-01	3.45E-01
Autism	6A02	Whole blood	4.12E-01	3.79E-02	1.29E-01
Autoimmune uveitis	9A96	Peripheral monocyte	6.05E-01	8.69E-03	3.40E-02
Autosomal dominant monocytopenia	4B04	Whole blood	7.32E-01	-1.20E-01	-4.06E-01
Bacterial infection of gingival	1C1H	Gingival tissue	9.83E-03	-8.22E-02	-3.07E-01
Batten disease	5C56.1	Whole blood	3.11E-01	-8.62E-02	-8.40E-01
Behcet's disease	4A62	Peripheral blood	7.41E-01	-2.07E-01	-6.55E-01
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	6.58E-01	-5.09E-01	-9.17E-01
Bladder cancer	2C94	Bladder tissue	9.50E-04	-3.40E-01	-2.25E+00
Breast cancer	2C60-2C6Z	Breast tissue	2.09E-07	1.97E-01	2.49E-01
Cardioembolic stroke	8B11.20	Whole blood	3.47E-01	6.03E-02	2.93E-01
Cervical cancer	2C77	Cervical tissue	3.03E-02	-2.91E-01	-8.59E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	7.55E-01	-1.33E-01	-1.33E-01
Chronic hepatitis C	1E51.1	Whole blood	4.99E-01	-5.54E-02	-2.65E-01
Chronic obstructive pulmonary disease	CA22	Lung tissue	1.46E-01	-8.43E-02	-3.65E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	3.52E-03	-2.54E-01	-7.03E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	1.25E-02	2.75E-01	1.39E+00
Colon cancer	2B90	Colon tissue	1.01E-10	1.96E-01	6.28E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	4.11E-01	3.49E-02	5.60E-02
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	8.28E-01	1.76E-01	3.18E-01
Endometriosis	GA10	Endometrium tissue	3.22E-05	-7.67E-01	-2.18E+00
Familial hypercholesterolemia	5C80.00	Peripheral blood	4.15E-01	-2.44E-02	-1.21E-01
Familial hypercholesterolemia	5C80.00	Whole blood	8.76E-04	3.46E-01	1.14E+00
Gastric cancer	2B72	Gastric tissue	4.27E-02	1.39E+00	2.33E+00
Glioblastopma	2A00.00	Nervous tissue	2.85E-01	-8.06E-02	-1.15E-01
Glioma	2A00.0Y-2A00.0Z	Brain stem tissue	3.27E-01	4.00E-01	1.14E+00
Glioma	2A00.0Y-2A00.0Z	White matter tissue	1.34E-05	8.51E-01	2.08E+00
Head and neck cancer	2D42	Head and neck tissue	3.77E-25	4.75E-01	1.64E+00
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	5.90E-01	4.46E-02	5.86E-02
Huntington's disease	8A01.10	Whole blood	9.42E-01	-1.67E-01	-4.82E-01
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	8.56E-01	9.33E-02	6.87E-01
Immunodeficiency	4A00-4A20	Peripheral blood	1.29E-01	3.61E-02	2.13E-01
Influenza	1E30	Whole blood	1.26E-03	-9.38E-01	-5.22E+00
Interstitial cystitis	GC00.3	Bladder tissue	1.18E-03	-3.65E-01	-2.65E+00
Intracranial aneurysm	8B01.0	Intracranial artery	1.48E-02	2.56E-01	6.66E-01
Irritable bowel syndrome	DD91.0	Rectal colon tissue	7.96E-01	2.97E-02	1.40E-01
Ischemic stroke	8B11	Peripheral blood	5.85E-03	-2.43E-01	-1.31E+00
Juvenile idiopathic arthritis	FA24	Peripheral blood	2.78E-01	2.03E-02	8.93E-02
Lateral sclerosis	8B60.4	Skin	6.64E-01	-4.19E-02	-2.60E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	4.04E-01	-1.54E-01	-3.59E-01
Liver cancer	2C12.0	Liver tissue	2.89E-03	9.61E-02	2.29E-01
Liver failure	DB99.7-DB99.8	Liver tissue	6.48E-05	-4.87E-01	-3.14E+00
Lung cancer	2C25	Lung tissue	4.07E-27	3.01E-01	9.19E-01
Lupus erythematosus	4A40	Whole blood	4.16E-01	5.06E-02	1.17E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	8.10E-01	-9.01E-02	-1.62E-01
Major depressive disorder	6A70-6A7Z	Whole blood	2.71E-01	2.45E-03	1.02E-02
Melanoma	2C30	Skin	9.07E-03	2.89E-01	5.52E-01
Multiple myeloma	2A83.1	Peripheral blood	8.54E-01	3.50E-02	1.09E-01
Multiple myeloma	2A83.1	Bone marrow	1.02E-06	4.64E-01	3.49E+00
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	7.49E-01	1.79E-02	6.27E-02
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	1.20E-01	7.82E-02	2.08E-01
Myelofibrosis	2A20.2	Whole blood	4.56E-01	-1.59E-03	-1.36E-02
Myocardial infarction	BA41-BA50	Peripheral blood	2.43E-02	-4.01E-01	-6.12E-01
Myopathy	8C70.6	Muscle tissue	1.75E-02	-2.36E-01	-1.43E+00
Neonatal sepsis	KA60	Whole blood	5.44E-04	-2.03E-01	-7.16E-01
Neuroectodermal tumour	2A00.11	Brain stem tissue	5.52E-09	1.91E+00	4.98E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	2.48E-01	3.31E-01	1.16E+00
Obesity related type 2 diabetes	5A11	Omental adipose tissue	9.46E-01	-2.22E-02	-1.58E-01
Olive pollen allergy	CA08.00	Peripheral blood	6.62E-01	-1.74E-01	-5.99E-01
Oral cancer	2B6E	Oral tissue	1.94E-03	4.81E-01	6.26E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	8.63E-01	2.10E-01	1.93E-01
Osteoporosis	FB83.1	Bone marrow	3.55E-01	-1.76E-01	-1.09E+00
Ovarian cancer	2C73	Ovarian tissue	5.45E-04	4.20E-01	1.15E+00
Pancreatic cancer	2C10	Pancreas	2.26E-04	3.75E-01	1.17E+00
Parkinson's disease	8A00.0	Substantia nigra tissue	5.70E-01	-9.02E-02	-3.28E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	4.92E-01	8.52E-02	5.27E-01
Pituitary cancer	2D12	Pituitary tissue	9.75E-01	-1.84E-01	-2.88E-01
Pituitary gonadotrope tumour	2D12	Pituitary tissue	9.60E-02	-3.51E-01	-7.92E-01
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	5.59E-01	8.49E-03	4.20E-02
Polycythemia vera	2A20.4	Whole blood	7.94E-04	-9.41E-02	-6.95E-01
Pompe disease	5C51.3	Biceps muscle	4.15E-04	-7.11E-01	-1.82E+00
Preterm birth	KA21.4Z	Myometrium	8.39E-01	-9.57E-03	-2.11E-02
Prostate cancer	2C82	Prostate	1.77E-04	8.42E-01	1.22E+00
Psoriasis	EA90	Skin	4.57E-12	4.12E-01	9.26E-01
Rectal cancer	2B92	Rectal colon tissue	7.45E-01	-3.19E-02	-2.69E-01
Renal cancer	2C90-2C91	Kidney	1.35E-03	7.94E-01	1.46E+00
Retinoblastoma	2D02.2	Uvea	6.30E-04	7.46E-01	3.04E+00
Rheumatoid arthritis	FA20	Synovial tissue	6.97E-01	3.09E-01	2.70E-01
Rhinovirus infection	CA42.1	Nasal epithelium tissue	3.81E-01	1.61E-02	8.75E-02
Schizophrenia	6A20	Prefrontal cortex	4.11E-01	-9.65E-02	-1.57E-01
Schizophrenia	6A20	Superior temporal cortex	8.56E-01	-1.01E-01	-3.12E-01
Scleroderma	4A42.Z	Whole blood	3.53E-02	8.78E-02	7.56E-01
Seizure	8A60-8A6Z	Whole blood	9.60E-01	2.29E-01	8.95E-01
Sensitive skin	EK0Z	Skin	4.72E-01	1.75E-01	9.79E-01
Sepsis with septic shock	1G41	Whole blood	2.32E-22	-2.98E-01	-9.77E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	1.22E-01	-3.31E-01	-1.18E+00
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	4.87E-02	-1.34E-01	-2.07E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	4.13E-01	3.96E-02	1.16E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	3.09E-02	2.56E-01	3.48E+00
Skin cancer	2C30-2C3Z	Skin	3.83E-13	3.29E-01	7.80E-01
Thrombocythemia	3B63	Whole blood	4.80E-01	4.59E-02	4.24E-01
Thrombocytopenia	3B64	Whole blood	3.00E-01	-1.69E-02	-3.18E-02
Thyroid cancer	2D10	Thyroid	7.50E-16	2.31E-01	9.05E-01
Tibial muscular dystrophy	8C75	Muscle tissue	3.70E-03	-3.26E-01	-1.04E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	2.89E-03	-1.26E+00	-3.58E+00
Type 2 diabetes	5A11	Liver tissue	4.66E-01	1.08E-01	4.76E-01
Ureter cancer	2C92	Urothelium	9.39E-01	2.14E-02	1.01E-01
Uterine cancer	2C78	Endometrium tissue	1.18E-01	-1.16E-01	-1.84E-01
Vitiligo	ED63.0	Skin	8.60E-02	2.18E-01	1.12E+00

The Drug Therapeutic Target (DTT) Role of This DME

• DME DTT Name: Prolyl endopeptidase (PREP) DTT Info
• DME DTT Type: Clinical trial

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALV-003	DMXSFA0	Coeliac disease	DA95	Phase 2	[1]
BAICALEIN	DM4C7E6	Influenza virus infection	1E30-1E32	Phase 2	[2]
ONO-1603	DMKIZAL	Cognitive impairment	6D71	Phase 2	[3]
S-17092-1	DMYR1K8	Cognitive impairment	6D71	Phase 1	[4]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
JTP-4819	DMI0UJS	Cognitive impairment	6D71	Discontinued in Phase 2	[5]
Z-321	DMLO2QY	Parkinson disease	8A00.0	Discontinued in Phase 1	[6]
BAICALIN	DMY1TLZ	Human immunodeficiency virus infection	1C62	Terminated	[7]
Y-29794	DMLAVES	N. A.	N. A.	Terminated	[7]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-Hydroxy-1-Thio-Glycerol	DMIOTQ8	Discovery agent	N.A.	Investigative	[8]
ARI-3531	DMEO82V	Discovery agent	N.A.	Investigative	[9]
Double Oxidized Cysteine	DM6TU84	Discovery agent	N.A.	Investigative	[8]
Monothioglycerol	DMENSOZ	Discovery agent	N.A.	Investigative	[8]
Z-Pro-Prolinal	DM43O2U	Discovery agent	N.A.	Investigative	[10]

References

• [1] The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol. 2010 Mar;134(3):289-95.
• [2] Baicalin, a prodrug able to reach the CNS, is a prolyl oligopeptidase inhibitor. Bioorg Med Chem. 2008 Aug 1;16(15):7516-24.
• [3] ONO-1603, a potential antidementia drug, shows neuroprotective effects and increases m3-muscarinic receptor mRNA levels in differentiating rat cerebellar granule neurons. Neurosci Lett. 1996 Aug 23;214(2-3):151-4.
• [4] Effect of S 17092, a novel prolyl endopeptidase inhibitor, on substance P and alpha-melanocyte-stimulating hormone breakdown in the rat brain. J Neurochem. 2003 Mar;84(5):919-29.
• [5] A novel prolyl endopeptidase inhibitor, JTP-4819, with potential for treating Alzheimer's disease. Behav Brain Res. 1997 Feb;83(1-2):147-51.
• [6] Z-321, a prolyl endopeptidase inhibitor, augments the potentiation of synaptic transmission in rat hippocampal slices. Behav Brain Res. 1997 Feb;83(1-2):213-6.
• [7] Inhibitors of prolyl oligopeptidases for the therapy of human diseases: defining diseases and inhibitors. J Med Chem. 2010 May 13;53(9):3423-38.
• [8] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [9] Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase. J Med Chem. 2013 May 9;56(9):3467-77.
• [10] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [11] Ion-exchange chromatography: basic principles and application to the partial purification of soluble mammalian prolyl oligopeptidase. Methods Mol Biol. 2011;681:215-28.
• [12] Bradykinin release and inactivation in brain of rats submitted to an experimental model of Alzheimer's disease. Peptides. 2006 Dec;27(12):3363-9.