Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5Q39P8)

• DOT Name: Neprilysin (MME)
• Synonyms: EC 3.4.24.11; Atriopeptidase; Common acute lymphocytic leukemia antigen; CALLA; Enkephalinase; Neutral endopeptidase 24.11; NEP; Neutral endopeptidase; Skin fibroblast elastase; SFE; CD antigen CD10
• Gene Name: MME
• Related Disease:
  Charcot-Marie-Tooth disease axonal type 2T
  Charcot-Marie-Tooth disease type 2T
  Congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization
  MME-related autosomal dominant Charcot Marie Tooth disease type 2
  Spinocerebellar ataxia 43
• UniProt ID: NEP_HUMAN
• PDB ID: 1DMT; 1R1H; 1R1I; 1R1J; 1Y8J; 2QPJ; 2YB9; 4CTH; 5JMY; 6GID; 6SH1; 6SH2; 6SUK; 6SVY; 6THP; 6XVP
• EC Number: 3.4.24.11
• Pfam ID: PF01431 ; PF05649
• Sequence:
  MGKSESQMDITDINTPKPKKKQRWTPLEISLSVLVLLLTIIAVTMIALYATYDDGICKSS
  DCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPETSSRYGNFDILRDELEVVLKD
  VLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDIYGWPVATENWEQKYGA
  SWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVIHIDQPRLGLPSRDYYECTGIYKE
  ACTAYVDFMISVARLIRQEERLPIDENQLALEMNKVMELEKEIANATAKPEDRNDPMLLY
  NKMTLAQIQNNFSLEINGKPFSWLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILT
  KYSARDLQNLMSWRFIMDLVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNME
  NAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERI
  GYPDDIVSNDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAA
  VVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKD
  GDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAYR
  AYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSPGNFRII
  GTLQNSAEFSEAFHCRKNSYMNPEKKCRVW
• Function: Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Catalyzes cleavage of bradykinin, substance P and neurotensin peptides. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF) and brain natriuretic factor (BNP(1-32)). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.
• KEGG Pathway:
  Renin-angiotensin system (hsa04614)
  Hematopoietic cell lineage (hsa04640)
  Protein digestion and absorption (hsa04974)
  Alzheimer disease (hsa05010)
• Reactome Pathway:
  Physiological factors (R-HSA-5578768)
  Neutrophil degranulation (R-HSA-6798695)
  Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease axonal type 2T	DISJU9TL	Definitive	Autosomal recessive	[1]
Charcot-Marie-Tooth disease type 2T	DISVWX62	Supportive	Autosomal recessive	[2]
Congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization	DISXRDA6	Supportive	Autosomal recessive	[3]
MME-related autosomal dominant Charcot Marie Tooth disease type 2	DIS7QIGL	Supportive	Autosomal dominant	[4]
Spinocerebellar ataxia 43	DISSMHTU	Supportive	Autosomal dominant	[5]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Neprilysin (MME) affects the response to substance of Mitomycin.	[34]
Vinblastine	DM5TVS3	Approved	Neprilysin (MME) affects the response to substance of Vinblastine.	[34]

27 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Neprilysin (MME).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neprilysin (MME).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neprilysin (MME).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neprilysin (MME).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neprilysin (MME).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Neprilysin (MME).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Neprilysin (MME).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neprilysin (MME).	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Neprilysin (MME).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Neprilysin (MME).	[15]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Neprilysin (MME).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Neprilysin (MME).	[11]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Neprilysin (MME).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Neprilysin (MME).	[18]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Neprilysin (MME).	[19]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Neprilysin (MME).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neprilysin (MME).	[21]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the activity of Neprilysin (MME).	[22]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Neprilysin (MME).	[23]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Neprilysin (MME).	[24]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Neprilysin (MME).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neprilysin (MME).	[27]
Zibotentan	DMIK6C9	Discontinued in Phase 3	Zibotentan decreases the expression of Neprilysin (MME).	[28]
Candoxatrilat	DMQIWZL	Discontinued in Phase 1	Candoxatrilat decreases the activity of Neprilysin (MME).	[29]
Omapatrilat	DMAGUY0	Terminated	Omapatrilat decreases the activity of Neprilysin (MME).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neprilysin (MME).	[31]
Thiorphan	DM86LFB	Investigative	Thiorphan decreases the activity of Neprilysin (MME).	[32]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neprilysin (MME).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neprilysin (MME).	[30]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
LBQ657	DMQ2DFN	Investigative	LBQ657 affects the binding of Neprilysin (MME).	[33]

References

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• [2] Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2. Ann Neurol. 2016 Apr;79(4):659-72. doi: 10.1002/ana.24612. Epub 2016 Mar 17.
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• [4] Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies. Am J Hum Genet. 2016 Sep 1;99(3):607-623. doi: 10.1016/j.ajhg.2016.07.008.
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• [19] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
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• [24] PMA and doxorubicin decrease viability, MTT activity and expression of CD10 marker on NALM-1 leukemic cells. Immunopharmacol Immunotoxicol. 2006;28(3):411-20.
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• [32] Neprilysin participates in skeletal muscle regeneration and is accumulated in abnormal muscle fibres of inclusion body myositis. J Neurochem. 2006 Feb;96(3):777-89.
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