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Information on EC 3.4.24.B14 - neprilysin-2
for references in articles please use BRENDA:EC3.4.24.B14preliminary BRENDA-supplied EC number
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EC Tree
3.4.24.B14 neprilysin-2Specify your search results
Word Map
- 3.4.24.B14
- neprilysins
- alzheimer
- endopeptidases
-
amyloid
- thiorphan
- phosphoramidon
- metalloproteases
- neuropeptides
-
3.4.24.11
-
zinc-dependent
- medicine
The enzyme appears in viruses and cellular organisms
Synonyms
mmel1, neprilysin-2, neprilysin 2, mmel2, neplp, nl1 protein, nep-like endopeptidase, membrane metallo-endopeptidase-like protein, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
NEP-like endopeptidase
NEP2
neprilysin 2
neprilysin-2
SEP
soluble-secreted endopeptidase
NEP2
NEP2 exists as two alternatively spliced isoforms, NEP2 and NEP2DELTA
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
proteolytic degradation of proteins
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CAS REGISTRY NUMBER
COMMENTARY
252986-92-8
-
82707-54-8
not distinguished from EC 3.4.24.11
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3-methoxysuccinyl-Gly-Leu-Phe-Met-7-amido-4-methylcoumarin + H2O
3-methoxysuccinyl-Gly-Leu + Phe-Met-7-amido-4-methylcoumarin
-
-
-
?
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 + H2O
Arg-Pro-Lys-Pro-Gln-Gln + Phe-Phe-Gly + Leu-Met-NH2
i.e. substance P(1-11), Arg-Pro-Lys-Pro-Gln-Gln-/-Phe-Phe-Gly-/-Leu-Met-NH2. Hydrolysis of substance P and derivatives occurs predominantly at the Gly9-/-Leu10 bond in the case of neprilysin and neprilysin 2. In addition neprilysin 2 cleaves at the Gln6-Phe7 bond
-
-
?
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg + H2O
Arg-Pro-Pro-Gly-Phe-Ser-Pro + Phe-Arg
i.e. bradykinin
-
-
?
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu + H2O
Asp-Arg-Val-Tyr-Ile-His-Pro + Phe-His-Leu
i.e. angiotensin
-
-
?
Asp-Tyr(sulfated)-Met-Gly-Trp-Met-Asp-Phe-NH2 + H2O
Asp-Tyr(sulfated)-Met-Gly + Trp-Met-Asp-Phe-NH2
i.e. cholecystokinin-8(sulfated). In cholecystokinins and derivatives, clear differences between neprilysin (EC 3.4.24.11) and neprilysin 2 can be observed: NEP2 does not attack the Asp7-/-Phe8-NH2 bond, a preferential cleavage site for neprilysin (EC 3.4.24.11, NEP) but cleaves the Gly4-/-Trp5 amide bond
-
-
?
Asp-Tyr-Met-Gly-Trp-Met + H2O
Asp-Tyr-Met-Gly + Trp-Met
i.e. cholecystokinin-(1-6)
-
-
?
Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2 + H2O
Asp-Tyr-Met-Gly + Trp-Met-Asp-Phe-NH2
i.e. cholecystokinin-8(non-sulfated)
-
-
?
Drosophila tachykinin-6 + H2O
QQR + Phe + ADFNSKFVAVR-amide
-
17% activity compared to Locusta tachykinin-1
-
-
?
Gly-Gly-Phe-Met + H2O
Gly-Gly + Phe-Met
i.e. Des-[Tyr1, Met5]enkephalin
-
-
?
Gly-Trp-Met-Asp-Phe-NH2 + H2O
Gly + Trp-Met-Asp-Phe-NH2
i.e. cholecystokinin-(4-8)
-
-
?
Phe-Gly-Leu-Met-NH2 + H2O
Phe-Gly + Leu-Met-NH2
i.e. substance P(8-11)
-
-
?
Phe-Phe-Gly-Leu-Met-NH2 + H2O
Phe-Phe-Gly + Leu-Met-NH2
i.e. substance P(7-11)
-
-
?
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide + H2O
succinyl-Ala-Ala + Phe-4-methylcoumarin 7-amide
-
-
-
-
?
succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
succinyl-Ala-Ala + Phe-7-amido-4-methylcoumarin
succinyl-Ala-Ala-Val-7-amido-4-methylcoumarin + H2O
succinyl-Ala-Ala + Val-7-amido-4-methylcoumarin
-
-
-
?
Tyr-Gly-Ala-Phe-Met + H2O
Tyr-Gly-Ala + Phe-Met
i.e. [L-Ala3,Met5]enkephalin
-
-
?
Tyr-Gly-Gly-Phe-Leu + H2O
Tyr-Gly-Gly + Phe-Leu
i.e. [Leu5]enkephalin
-
-
?
Tyr-Gly-Gly-Phe-Leu-NH2 + H2O
Tyr-Gly-Gly + Phe-Leu-NH2
i.e. [Leu5]enkephalin-NH2
-
-
?
Tyr-Gly-Gly-Phe-Met + H2O
Tyr-Gly-Gly + Phe-Met
i.e. [Met5]enkephalin. Regarding enkephalins and related opioid peptides, neprilysin (EC 3.4.24.11, NEP) and neprilysin 2 (NEP2) cleave the same Gly-/-Phe bond in all susceptible peptides, and hydrolysis by NEP2 and NEP is strongly reduced when the C-terminal carboxylate is amidated. Differences are: Ala instead of Gly in P1 significantly enhances hydrolysis by NEP2 but not NEP, whereas Leu instead of Met in P2' has an opposite influence (whereas affinity is enhanced) on NEP2. In contrast, neither affinity nor hydrolysis was significantly affected by the latter change in the case of NEP (EC 3.4.24.11)
-
-
?
Tyr-Gly-Gly-Phe-Met-NH2 + H2O
Tyr-Gly-Gly + Phe-Met-NH2
i.e. [Met5]enkephalin-NH2
-
-
?
Drosophila tachykinin-1 + H2O
APTSS + FIGMR-amide
-
3% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-1 + H2O
APTSS + FIGMR-amide
-
3% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-2 + H2O
APLAFYG + Leu-Arg-amide
-
33% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-2 + H2O
APLAFYG + Leu-Arg-amide
-
33% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-3 + H2O
APTG + FTGMR-amide
-
1% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-3 + H2O
APTG + FTGMR-amide
-
1% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-4 + H2O
APVNS + FVGMR-amide
-
8% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-4 + H2O
APVNS + FVGMR-amide
-
8% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-5 + H2O
APNG + FLGMR-amide
-
2% activity compared to Locusta tachykinin-1
-
-
?
Drosophila tachykinin-5 + H2O
APNG + FLGMR-amide
-
2% activity compared to Locusta tachykinin-1
-
-
?
gonadotropin-releasing hormone + H2O
?
cleavage site: pEHWSYG-/-LRPG-NH2
-
-
?
succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
succinyl-Ala-Ala + Phe-7-amido-4-methylcoumarin
-
-
-
-
?
succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
succinyl-Ala-Ala + Phe-7-amido-4-methylcoumarin
-
-
-
?
additional information
?
-
-
NEP2 plays a role in renal function and spermatogenesis
-
-
?
additional information
?
-
neprilysin-2 shows a much restriceted substrate specificity compared to neprilysin
-
-
?
additional information
?
-
-
neprilysin-2 shows a much restriceted substrate specificity compared to neprilysin
-
-
?
additional information
?
-
human neprilysin-2 has a more restricted substrate specificity compared to human neprilysin, EC 3.4.24.11, with less activity against several vasoactive peptides
-
-
?
additional information
?
-
-
does not cleave dansyl-D-Ala-Gly-p-nitro-Phe-Gly
-
-
?
additional information
?
-
in vivo in cells membrane-bound isoforms mNEP2-alpha and mNEP2-beta have similar activity against amyloid beta peptide Ab40 and Ab42 compared to neprilysin, EC 3.4.24.11
-
-
?
additional information
?
-
in vitro membrane-bound isoform mNEP2-alpha has slower and weaker amyloid beta peptide Ab40 degrading properties when compared to neprilysin, EC 3.4.24.11, and shows little to no effect on amyloid beta peptide Ab42. Membrane-bound isozymes mNEP2-beta and gamma have nearly undetectable activity against amyloid beta peptide
-
-
?
additional information
?
-
the following synthetic substrates are not hydrolysed by either isoform of NEP2: succinyl-Gly-Pro-7-amido-4-methylcoumarin, 3-methoxysuccinyl-Ala-Ala-Pro-Met-7-amido-4-methylcoumarin, 3-methoxysuccinyl-ASp-Tyr-Met-7-amido-4-methylcoumarin, benzyloxycarbony-Arg-7-amido-4-methylcoumarin, tert-butyloxycarbonyl-Val-Gly-Arg-7-amido-4-methylcoumarin, benzyloxycarbonyl-Arg-7-amido-4-methylcoumarin, tert-butyloxycarbonyl-Arg-Val-Arg-Arg-7-amido-4-methylcoumarin and tert-butyloxycarbonyl-Gly-Pro-Arg-7-amido-4-methylcoumarin
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
-
NEP2 plays a role in renal function and spermatogenesis
-
-
?
additional information
?
-
in vivo in cells membrane-bound isoforms mNEP2-alpha and mNEP2-beta have similar activity against amyloid beta peptide Ab40 and Ab42 compared to neprilysin, EC 3.4.24.11
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, wild-type enzyme
tunicamycin
-
inhibition of N-glycosylation by tunicamycin reduces the enzymatic activity of extracellular NEP2 to about 50% and the molecular size of intracellular NEP2
fasidotrilat
fasidotrilat interacts with the Arg661 of hNEP-2 with more consistent bidentate hydrogen bonding and with weaker His658 with monodentate hydrogen bonding. The extended conformation of the inhibitor in the hNEP2 pocket might be the reason for its weak interactions
phosphoramidon
approximately 8-fold more potent against neprilysin (EC 3.4.24.11) than neprilysin-2
phosphoramidon
the inhibitor induces a dramatic increase in amyloid-beta peptide levels
thiorphan
far more potent against neprilysin (EC 3.4.24.11) than neprilysin-2
thiorphan
the inhibitor induces a dramatic increase in amyloid-beta peptide levels
additional information
molecular docking studies, overview. For substrate and inhibitor binding, Arg661 and Zn694 are identified as the most conserved residues
-
additional information
-
molecular docking studies, overview. For substrate and inhibitor binding, Arg661 and Zn694 are identified as the most conserved residues
-
additional information
-
disruption of the Golgi apparatus with brefeldin A markedly reduces extracellular NEP2 activity in parallel with intracellular NEP2 protein level in HEK293 cells; nocodazole and cytochalasin B barely affect NEP2 activity
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Alzheimer Disease
Amyloid-beta and Alzheimer's disease: the role of neprilysin-2 in amyloid-beta clearance.
Arthritis, Rheumatoid
Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population.
Celiac Disease
Replication of GWAS Coding SNPs Implicates MMEL1 as a Potential Susceptibility Locus among Saudi Arabian Celiac Disease Patients.
Liver Cirrhosis
Genetic Risk Factors for Autoimmune Thyroid Disease might Affect the Susceptibility to and Modulate the Progression of Primary Biliary Cholangitis.
Liver Cirrhosis, Biliary
Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis.
Multiple Sclerosis
Investigating the association of polymorphisms of ANKRD55 and MMEL1 with susceptibility to multiple sclerosis in Iranian population.
Neuroblastoma
Molecular cloning, tissue distribution, and chromosomal localization of MMEL2, a gene coding for a novel human member of the neutral endopeptidase-24.11 family.
Osteochondrodysplasias
Molecular cloning, tissue distribution, and chromosomal localization of MMEL2, a gene coding for a novel human member of the neutral endopeptidase-24.11 family.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.023
3-methoxysuccinyl-Gly-Leu-Phe-Met-7-amido-4-methylcoumarin
37°C, membrane-bound form of NEP2
0.035
3-methoxysuccinyl-Gly-Leu-Phe-Met-7-amido-4-methylcoumarin
37°C, secreted soluble form of NEP2
0.04
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme L739G
0.044
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme L739G/S133G
0.045
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme R131M
0.062
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2. wild-type enzyme
0.185
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme S133G
1
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme N567G
0.027
succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin
37°C, membrane-bound form of NEP2
0.05
succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin
37°C, secreted soluble form of NEP2
0.04
succinyl-Ala-Ala-Val-7-amido-4-methylcoumarin
37°C, membrane-bound form of NEP2
0.1
succinyl-Ala-Ala-Val-7-amido-4-methylcoumarin
37°C, secreted soluble form of NEP2
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
11.5
3-methoxysuccinyl-Gly-Leu-Phe-Met-7-amido-4-methylcoumarin
37°C
0.52
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, wild-type enzyme
1.2
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme W774A
1.97
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme S133G
3.5
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme P764Y
5.23
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme N567G
7.8
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme W774F
8.7
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, wild-type enzyme
14.03
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, wild-type enzyme
17.3
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme R131M
19
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme L739G/S133G
30.7
succinyl-Ala-Ala-Phe-4-methylcoumarin 7-amide
-
37°C, pH 7.2, mutant enzyme L739G
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE