Summary for peptidase M13.001: neprilysin

Summary Gene structure Alignment Tree Sequences Sequence features Distribution Structure Literature Human EST Mouse EST Substrates Inhibitors Pharma

 

Names
MEROPS Nameneprilysin
Other namesatriopeptidase, CALLA, CD10, endopeptidase 24.11, enkephalinase, fibroblast metalloelastase, kidney-brush-border neutral peptidase, membrane metallopeptidase A, neutral endopeptidase, kidney-brush-border, NEP, MME g.p. (Homo sapiens)
Domain architecture
MEROPS Classification
Classification Clan MA >> Subclan MA(E) >> Family M13 >> Subfamily (none) >> M13.001
Holotypeneprilysin (Homo sapiens), Uniprot accession P08473 (peptidase unit: 52-750), MERNUM MER0001050
History Identifier created: Handbook of Proteolytic Enzymes (1998) Academic Press, London.
Activity
Catalytic typeMetallo
PeplistIncluded in the Peplist with identifier PL00201
NC-IUBMBSubclass 3.4 (Peptidases) >> Sub-subclass 3.4.24 (Metalloendopeptidases) >> Peptidase 3.4.24.11
EnzymologyBRENDA database
Proteolytic eventsCutDB database (55 cleavages)
Activity statushuman: active (Turner, 2004)
mouse: active (Marr et al., 2004)
PhysiologyAn ectoenzyme endopeptidase active in the degradation of enkephalins and other bioactive peptides. Also has Alzheimer"s alpha secretase activity, destroying the A beta peptide (Iwata et al., 2001).
KnockoutMice with targeted disruption of the gene show enhanced sensitivity to endotoxin shock (Lu et al., 1995). Deletion of the gene also results in an opioid-related increase in thermonociceptive threshold (Saria et al., 1997), and there is little compensation for the deficiency (Fischer et al., 2000). There was a modified ventilatory response to hypoxia (Grasemann et al., 1999). The severity of experimentally-induced colitis was markedly worse in the knockout mice than in controls, indicating that the enzyme maintains low levels of substance P in the extracellular fluid under basal conditions and terminates its proinflammatory effects (Sturiale et al., 1999). Neprilysin also terminates substance P-induced inflammation in allergic contact dermatitis (Scholzen et al., 2001). Work with knockout mice showed that neprilysin has alpha-secretase activity (Iwata et al., 2001), and down-regulation of neprilysin led to deposition of beta-amyloid (Iwata et al., 2002).
Pharmaceutical relevanceDrug target in hypertension and renal disease. However, neprilysin is an alpha-secretase for Alzheimer"s disease, contributing to the destruction of the harmful A beta-peptide, and artificially increasing the activity of neprilysin may be a useful approach to reducing A beta levels in the brain (Shirotani et al., 2001; Hama et al., 2001; Iwata et al., 2004; Marr et al., 2004).
Pathways KEGGAlzheimer's disease
KEGGProtein digestion and absorption
KEGGRenin-angiotensin system
Other databases TREEFAMhttp://www.treefam.org/family/TF315192
Cleavage site specificity Explanations of how to interpret the following cleavage site sequence logo and specificity matrix can be found here.
Cleavage pattern-/-/-/-Scissile bondfliy/-/-/- (based on 123 cleavages)
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Specificity matrix
 
Amino acid P4 P3 P2 P1 P1' P2' P3' P4'
Gly 9 9 15 24 2 15 13 7
Pro 9 8 9 12 0 1 6 4
Ala 4 4 7 6 3 3 5 2
Val 5 2 2 2 13 3 5 3
Leu 2 6 7 3 27 16 13 8
Ile 0 4 1 0 14 11 3 3
Met 3 4 4 3 3 9 1 5
Phe 6 8 6 9 36 7 1 6
Tyr 8 13 4 8 14 10 4 2
Trp 4 3 2 4 6 1 6 3
Ser 7 5 12 7 1 7 7 5
Thr 0 1 1 0 0 2 1 1
Cys 3 4 4 6 0 0 3 1
Asn 1 4 4 1 0 1 0 2
Gln 6 4 6 3 0 5 4 5
Asp 7 2 5 8 0 6 3 3
Glu 5 4 5 4 1 3 4 4
Lys 8 6 9 5 0 3 5 8
Arg 11 18 13 12 2 9 11 7
His 1 5 3 6 1 3 2 2
Human genetics
Gene symbol Locus Megabases Ensembl Entrez gene Gene Cards OMIM
MME 3q21-q27 ENSG00000114802 4311 MME 120520
Mouse genetics
Gene symbol Position Megabases Ensembl Entrez gene MGI
Mme 3:E1 ENSMUSG00000027820 17380 MGI:97004