Summary for peptidase M02.006: angiotensin-converting enzyme-2

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

 

Names
MEROPS Nameangiotensin-converting enzyme-2
Other namesACE2, ACEH
Name and HistoryAngiotensin-converting enzyme 2 is a carboxypeptidase which processes peptides involved in control of blood pressure. Angiotensin II is converted to the vasodilatory angiotensin(1-7); des-Arg9-bradykinin, the natural ligand for the bradykinin B1 receptor, is inactivated; apelin-13, another vasoactive peptide, is inactivated (Tipnis et al., 2000, Donoghue et al., 2000, Vickers et al., 2002).
Domain architecture
MEROPS Classification
Classification Clan MA >> Subclan MA(E) >> Family M2 >> Subfamily (none) >> M02.006
Holotypeangiotensin-converting enzyme-2 (Homo sapiens), Uniprot accession Q9BYF1 (peptidase unit: 17-618), MERNUM MER0011061
History Identifier created: MEROPS 5.3 (4 December 2000)
Activity
Catalytic typeMetallo
PeplistIncluded in the Peplist with identifier PL00135
NC-IUBMBSubclass 3.4 (Peptidases) >> Sub-subclass 3.4.17 (Metallocarboxypeptidases) >> Peptidase 3.4.17.23
EnzymologyBRENDA database
Proteolytic eventsCutDB database (3 cleavages)
Activity statushuman: active (Turner & Hooper, 2004)
mouse: active (by similarity)
SpecificityA consensus sequence around a scissile bond has been established as Pro-Xaa(1-3)-Pro+(hydrophobic/basic) (Guy et al., 2003). The carboxypeptidase specificity is determined by Arg272 (human numbering) which effectively removes the S2' binding pocket (in ACE the equivalent residue is glutamine) (Towler et al., 2004). Activity is chloride ion dependent (Guy et al., 2003).
pH optimum6.5 (Tipnis et al., 2000)
Special inhibitorThe phosphinic-peptide inhibitor 416F2 mimics the enzyme transition state (Mores et al., 2008).
StructureThere is a single peptidase domain and a collectrin-like transmembrane domain. The tertiary structure has been solved (Towler et al., 2004).
LocationACE2 is membrane bound to the surface of cells and is widely located in tissues (Hamming et al., 2004). A soluble form found in the plasma and urine but with an unknown physiological function is generated by ADAM17 and shedding of the ACE2 ectodomain is inhibited by calmodulin (Lambert et al., 2005).
PhysiologyGenetic data show that this peptidase is an essential regulator of heart function at least in rodents and Drosophila (Crackower et al., 2002).
Human angiotensin-converting enzyme 2 is a functional receptor for SARS coronavirus (Li et al., 2005).
KnockoutKnockout of the ACE2 gene in mouse resulted in a major defect in cardiac contractility and an upregulation of hypoxnia-inducible genes in the heart (Crackower et al., 2002).
Pharmaceutical relevanceA potential drug target because of its role in control of blood pressure, the synthetic inhibitor MLN-4760, based on the cleavage site in angiotensin I, was unsuccessfully developed as an anti-obesity drug and is now being examined as an anti-inflammatory (Dales et al., 2002, <%Byrnes et al., 2009[PubMed:19517214]%>). ACE2 activators have also been developed, including xanthenone, which reduces the blood pressure of hypertensive rats (Hernandez Prada et al., 2008).
Pathways KEGGProtein digestion and absorption
KEGGRenin-angiotensin system
Other databases TREEFAMhttp://www.treefam.org/family/TF312861
Cleavage site specificity Explanations of how to interpret the following cleavage site sequence logo and specificity matrix can be found here.
Cleavage patterng/p/-/PScissile bondfrl/-/-/- (based on 14 cleavages)
weblogo
Specificity matrix
 
Amino acid P4 P3 P2 P1 P1' P2' P3' P4'
Gly 4 0 0 0 0 0 0 0
Pro 0 5 1 10 0 0 0 0
Ala 1 0 2 0 0 0 0 0
Val 0 1 0 0 0 0 0 0
Leu 0 1 0 1 2 0 0 0
Ile 0 1 0 1 1 0 0 0
Met 0 0 2 0 0 0 0 0
Phe 2 2 1 1 5 0 0 0
Tyr 1 0 1 0 0 0 0 0
Trp 0 0 0 0 0 0 0 0
Ser 0 1 2 0 0 0 0 0
Thr 0 0 0 0 0 0 0 0
Cys 0 0 0 0 0 0 0 0
Asn 0 1 0 0 0 0 0 0
Gln 0 0 1 0 0 0 0 0
Asp 0 1 0 0 0 0 0 0
Glu 1 0 1 0 0 0 0 0
Lys 1 0 2 0 1 0 0 0
Arg 2 0 0 0 3 0 0 0
His 1 0 1 1 0 0 0 0
Human genetics
Gene symbol Locus Megabases Ensembl Entrez gene Gene Cards OMIM
ACE2 Xp22 ENSG00000130234 59272 ACE2 300335
Mouse genetics
Gene symbol Position Megabases Ensembl Entrez gene MGI
Ace2 X:F5 ENSMUSG00000015405 70008 MGI:1917258