3.4.24.11: neprilysin
This is an abbreviated version!
For detailed information about neprilysin, go to the full flat file.
Word Map on EC 3.4.24.11
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3.4.24.11
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angiotensin
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natriuretic
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alzheimer
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angiotensin-converting
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phosphoramidon
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atrial
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amyloid
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thiorphan
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cardiovascular
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hypertension
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bradykinin
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neuropeptides
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aminopeptidase
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ejection
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airway
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anp
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ventricular
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blocker
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captopril
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endothelins
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opioids
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metallopeptidase
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tachykinins
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renin-angiotensin
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hf
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valsartan
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enalapril
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renin-angiotensin-aldosterone
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neurokinin
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vasoactive
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endothelin-converting
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hfref
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naloxone
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insulin-degrading
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bestatin
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kinin
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diuretic
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3.4.15.1
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lily
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aceis
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met-enkephalin
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bronchoconstriction
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angioedema
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amastatin
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angiotensin-1-7
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kininase
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lisinopril
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nt-probnp
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medicine
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bronchoconstrictors
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pharmacology
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analysis
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molecular biology
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angiotensin-receptor
- 3.4.24.11
- angiotensin
-
natriuretic
- alzheimer
-
angiotensin-converting
- phosphoramidon
- atrial
-
amyloid
- thiorphan
- cardiovascular
- hypertension
- bradykinin
- neuropeptides
- aminopeptidase
-
ejection
- airway
- anp
- ventricular
-
blocker
- captopril
- endothelins
-
opioids
- metallopeptidase
- tachykinins
-
renin-angiotensin
- hf
- valsartan
- enalapril
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renin-angiotensin-aldosterone
- neurokinin
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vasoactive
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endothelin-converting
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hfref
- naloxone
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insulin-degrading
- bestatin
- kinin
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diuretic
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3.4.15.1
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lily
-
aceis
- met-enkephalin
-
bronchoconstriction
- angioedema
- amastatin
-
angiotensin-1-7
-
kininase
- lisinopril
-
nt-probnp
- medicine
-
bronchoconstrictors
- pharmacology
- analysis
- molecular biology
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angiotensin-receptor
Reaction
preferential cleavage of polypeptides between hydrophobic residues, particularly with Phe or Tyr at P1' =
Synonyms
Abeta-degrading enzyme, acute lymphoblastic leukemia antigen, antigen, CALLA (common acute lymphoblastic leukemia-associated), atriopeptidase, CALLA, CALLA (common acute lymphoblastic leukemia-associated) antigens, CALLA antigen, CALLA glycoproteins, CD10, CD10/neutral endopeptidase, CD10/neutral endopeptidase 24.11, common acute lymphoblastic leukemia antigen, common acute lymphoblastic leukemia-associated antigens, Common acute lymphocytic leukemia antigen, endopeptidase CD10, Endopeptidase-2, endopeptidase-24.11, enkephalinase, EP24.11, glycoprotein, CALLA, kidney-brush-border neutral endopeptidase, kidney-brush-border neutral peptidase, kidney-brush-border neutral proteinase, membrane metallo-endopeptidase, membrane metalloendopeptidase, MME, NEP, NEP 24.11, NEP, enkephalinase, neutrophil cluster-differentiation antigen 10, common acute lymphoblastic leukemia antigen, NEP-1, NEP/CD10, NEP2, NEP4A, NEP4B, neprilypsin, neprilysin, neprilysin 4, neutral endopeptidase, neutral endopeptidase 24.11, neutral endopeptidase 24.11/CD10, neutral metallendopeptidase, NL-1, peptidase, endo-, peptidase, membrane metalloendo-, SEP, skin fibroblast elastase
ECTree
3.4.24.11 neprilysinAdvanced search results
results (
results (Engineering
Engineering on EC 3.4.24.11 - neprilysin
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PROTEIN VARIANTS 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
E12A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
E403C
site-directed mutagenesis, homodimerization mutant, reduced localization in lipid rafts
E4A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
E584V
F3A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
F563I
site-directed mutagenesis, active site mutant which displays an increase in preference towards cleaving leucine5-enkephalin relative to insulin B chain, reduced activity with glutaryl-Ala-Ala-Phe-MNA compared to the wild-type enzyme
F563L
site-directed mutagenesis, active site mutant which exhibits different cleavage site preferences with insulin B chain and amyloid beta1-40 as substrates compared to the wild-type enzyme, similar activity with glutaryl-Ala-Ala-Phe-MNA as the wild-type enzyme
F563M
site-directed mutagenesis, active site mutant which exhibits reduced activity with glutaryl-Ala-Ala-Phe-MNA compared to the wild-type enzyme
F563V
site-directed mutagenesis, active site mutant which exhibits reduced activity with glutaryl-Ala-Ala-Phe-MNA compared to the wild-type enzyme
G399V
site-directed mutagenesis, the mutant shows increased catalytic efficiency on Ab1-40 with 6fold increased catalytic efficiency compared to the wild-type enzyme. The G399V mutation also significantly reduces the catalytic efficiency on angiotensin, bradykinin and neurotensin compared to the wild-type enzyme
G399V/G714K
G714K
site-directed mutagenesis, the mutant shows increased catalytic efficiency on Ab1-40 with 6fold increased catalytic efficiency compared to the wild-type enzyme
K15A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
K19A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
L10A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
L2A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
S20A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
S546A
site-directed mutagenesis, active site mutant with highly reduced activity compared to the wild-type enzyme
S546E
site-directed mutagenesis, active site mutant, that is less discriminating than wild-type neprilysin and exhibits different cleavage site preferences with insulin B chain and amyloid beta1-40 as substrates, reduced activity with glutaryl-Ala-Ala-Phe-MNA compared to the wild-type enzyme
S546T
site-directed mutagenesis, active site mutant with highly reduced activity compared to the wild-type enzyme
T13A
site-directed mutagenesis, the mutant cannot be stimulated by myotoxin II-derived peptides from Bothrops acer
R102M
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about 2fold increased Km-value for Leu5,Arg6-enkephalin, no inhibition by Phe-Gly
H583F
H587F
additional information
E584V
site-directed mutagenesis, catalytically inactive mutant, negative control
E584V
site-directed mutagenesis, inactive mutant, has no effects on prothrombin time (PT) and activated partial thromboplastin time (APTT) in rats and monkeys
G399V/G714K
site-directed mutagenesis, the enzyme variant displays an approximately 20fold improved activity on amyloid beta 1-40 and up to a 3200fold reduction in activity on other peptides, and the mutant enzyme produces a markedly altered series of amyloid beta cleavage products compared to the wild-type enzyme
G399V/G714K
site-directed mutagenesis, the engineered NEP, HSA-NEPv G399V/G714K, has a potential as therapeutic for Alzheimer disease but in pre-clinical safety testing, this variant increases prothrombin time (PT) and activated partial thromboplastin time (APTT) measured in cynomolgus monkeys and rats dosed with a human serum albumin fusion with an engineered variant of NEP as well as in control plasma spiked with wild-type or mutant enzyme. Wild-type HSA-NEP and mutant HSA-NEPv impair coagulation, increasing PT and APTT in plasma samples and abolishing fibrin formation from fibrinogen. This effect is mediated through cleavage of the N-termini of the Aalpha- and Bbeta-chains of fibrinogen thereby significantly impairing initiation of fibrin formation by thrombin. The effects on PT and APTT are broadly similar in male and female rats although the effect on APTT is less clear cut in females
additional information
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expression of neprilysin on the surface of leukocytes in mouse model of Alzheimer's disease reduces soluble brain amyloid beta peptide levels by 30% and lowers the accumulation of amyloid beta peptides by 50-60% when transplantation is performed at both young and early adult age. Peripheral neprilysin expression reduces amyloid-dependent performance deficits as measured by the Morris water maze test. Neprilysin expression results in the catabolism of amyloid beta to small, innocuous peptide fragments
additional information
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in both neprilysin and amyloid precursor protein transgenic mice, neprilysin overexpression reduces soluble amyloid beta levels by 50% and effectively prevents early amyloid beta deposition in the neocortex and hippocampus. However, it does not reduce levels of amyloid beta trimers and amyloid beta*56 or improve deficits in spatial learning and memory. Neprilysin-dependent degradation of amyloid beta may affect plaques more than oligomers and these structures may form through distinct assembly mechanisms
additional information
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in transgenic Drosophila melanogaster expressing human neprilysin and amyloid beta42, neprilysin efficiently suppresses the formation of intraneuronal amyloid beta42 deposits and amyloid beta42-induced neuron loss. Neuronal neprilysin overexpression reduces cAMP-responsive element-binding protein-mediated transcription, causes age-dependent axon degeneration, and shortens the life span of the flies. The mRNA levels of endogenous fly neprilysin genes and phosphoramidon-sensitive neprilysin activity decline during aging in fly brains
additional information
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overexpression neprilysin at low levels in transgenic mouse affects primarily the levels of neuropeptide Y compared with other neuropeptides. Neprilysin cleaves neuropeptide Y in C-terminal fragments, whereas silcencing neprilysin reduces neuropeptide Y processing. Infusion of the most abundant neuropeptide Y fragments 21-36 and 31-36 into the brain of amyloid precursor protein transgenic mice ameliorates the neurodegenerative pathology in this model. The amidated neuropeptide Y fragments protect human neuronal cultures from the neurotoxic effects of amyloid beta
additional information
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overexpression of human neprilysin for 4 months in young amyloid precursor protein//DeltaPS1 double-transgenic mice results in reduction in amyloid beta peptide levels, attenuation of amyloid load, oxidative stress, and inflammation, and improved spatial orientation. The overall reduction in amyloidosis and associated pathogenetic changes in the brain results in decreased memory impairment by about 50%
additional information
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sustained expression of a lentiviral vector carrying the neprilysin gene in amyloid precursor protein transgenic mice for up to 6 months lowers not only the amyloid plaque load but also reduces the levels of intracellular amyloid beta immunoreactivity. This is associated with improved behavioral performance in the water maze test and ameliorates the dendritic and synaptic pathology in the amyloid precursor protein transgenic mice
additional information
generation of a soluble version of the ectodomain of neprilysin with improved activity and specificity towards amyloid beta peptide as a potential therapeutic for Alzheimer's disease
additional information
it is possible to alter the cleavage site specificity of neprilysin opening the way for the development of substrate specific or substrate exclusive forms of the enzyme with enhanced therapeutic potential
additional information
viral expression of NEP in primary neurons leads to effective clearance of amylod-beta in vitro
additional information
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after chronic constriction injury of the right sciatic nerve, neprilysin knock-out mice are more sensitive to heat, to mechanical stimuli, and to cold than wild type mice. Tissue injury without nerve injury produced no differences between genotypes. After chronic constriction injury, neprilysin knock-out mice show increased hind paw edema but lower skin temperatures than wild type mice. Substance P and endothelin 1 are increased in sciatic nerves. Tissue calcitonin gene related peptide content does not differ between the genotypes
additional information
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double-mutated mice carrying a targeted depletion of one allele of Mme, the gene encoding neprilysin, and over-expressing human amyloid precursor protein APP, exhibit a reinforced amyloid pathology in comparison with their APP transgenic littermates. In contrast to their parental lines, these mice are impaired in the Morris water maze learning and memory paradigm and show facilitated extinction in the conditioned taste aversion test
additional information
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in neprilysin null mice, loss of neprilysin has no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance are found. After chronic hypoxia, neprilysin-null mice exhibit exaggerate pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia is also detected. Adaptive right ventricular hypertrophy is less than anticipated. Hypoxic wild-type pulmonary vessels display close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries have increased proliferation compared with controls, which is decreased by neprilysin replacement
