DB code: T00422

CATH domain 1.10.1370.30 : Neurolysin; domain 3 Catalytic domain
3.30.70.- : Alpha-Beta Plaits
1.-.-.- :
E.C. 3.4.17.23
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq MEROPS Pfam
Q9BYF1 Angiotensin-converting enzyme 2
EC 3.4.17.23
Angiotensin-converting enzyme homolog
ACEH
Angiotensin-converting enzyme-related carboxypeptidase
ACE-related carboxypeptidase
EC 3.4.17.-
NP_068576.1 (Protein)
NM_021804.2 (DNA/RNA sequence)
M02.006 (Metallo)
PF01401 (Peptidase_M2)
[Graphical View]
Q56NL1 Angiotensin-converting enzyme 2
EC 3.4.17.23
ACE-related carboxypeptidase
EC 3.4.17.-
M02.006 (Metallo)
PF01401 (Peptidase_M2)
[Graphical View]

KEGG enzyme name
angiotensin-converting enzyme 2
ACE-2
ACE2
hACE2
angiotensin converting enzyme 2
angiotensin converting enzyme-2
Tmem27

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
Q56NL1 ACE2_PAGLA angiotensin II + H2O = angiotensin-(1-7) + L-phenylalanine angiotensin I + H2O = angiotensin-(1-9) + L-leucine Interacts with ITGB1 (By similarity). Interacts with the catalytically active form of TMPRSS2 (By similarity). Interacts with SLC6A19, this interaction is essential for expression and function of SLC6A19 in intestine (By similarity). (Microbial infection) Interacts with SARS-CoV S protein. [Processed angiotensin-converting enzyme 2] Secreted. Cell membrane, Single-pass type I membrane protein. Cytoplasm. Zn(2+) chloride
Q9BYF1 ACE2_HUMAN angiotensin II + H2O = angiotensin-(1-7) + L-phenylalanine angiotensin I + H2O = angiotensin-(1-9) + L-leucine [des-Arg(9)]-bradykinin + H2O = [des-Phe(8), des-Arg(9)]-bradykinin + L-phenylalanine H2O + neurotensin = L-leucine + neurotensin-(1-12) H2O + neurotensin-(1-8) = L-arginine + neurotensin-(1-7) H2O + kinetensin = kinetensin-(1-8) + L-leucine dynorphin A-(1-13) + H2O = dynorphin A-(1-12) + L-lysine apelin-13 + H2O = apelin-12 + L-phenylalanine [Pyr1]apelin-13 + H2O = [Pyr1]apelin-12 + L-phenylalanine apelin-17 + H2O = apelin-16 + L-phenylalanine beta-casomorphin-7 + H2O = beta-casomorphin-6 + L-isoleucine H2O + neocasomorphin = L-isoleucine + neocasomorphin-(1-5) Homodimer. Interacts with ITGB1. Interacts with the catalytically active form of TMPRSS2. Interacts with SLC6A19, this interaction is essential for expression and function of SLC6A19 in intestine (By similarity). (Microbial infection) Interacts with SARS coronavirus/SARS-CoV spike protein. (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein. (Microbial infection) Interacts with human coronavirus NL63/HCoV-NL63 spike glycoprotein. [Processed angiotensin-converting enzyme 2] Secreted. Cell membrane, Single-pass type I membrane protein. Cytoplasm. Zn(2+) chloride

KEGG Pathways
Map code Pathways E.C.
MAP04614 Renin-angiotensin system

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00038 C02135 C00001 C15850 C00079 I00195
E.C.
Compound Zinc Angiotensin II H2O Angiotensin (1-7) L-Phenylalanine Angiotensin II tetrahedral transition-state
Type heavy metal amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group,imine group,peptide/protein H2O amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group,imine group,peptide/protein amino acids,aromatic ring (only carbon atom)
ChEBI 29105
15377
58095
17295
PubChem 32051
962
22247451
6925665
6140
1r42A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
1r4lA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Transition-state-analogue:XX5
2ajfA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
2ajfB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3kbhA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3kbhB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3kbhC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3kbhD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
3sciA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3sciB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3scjA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3scjB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6m0jA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6vw1A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6vw1B Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6m17B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6m17D01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6m18B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6m18D01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3d0gA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3d0gB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3d0hA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3d0hB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3d0iA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3d0iB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3sckA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3sckB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3sclA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
3sclB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:_ZN Unbound Unbound Unbound Unbound
6m17B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
6m17D02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
6m18B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
6m18D02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1r42A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
1r4lA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
2ajfA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
2ajfB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3kbhA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3kbhB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3kbhC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3kbhD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3sciA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3sciB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3scjA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3scjB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6m0jA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6vw1A Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6vw1B Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6m17B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6m17D01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6m18B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6m18D01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3d0gA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3d0gB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3d0hA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3d0hB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3d0iA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3d0iB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3sckA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3sckB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3sclA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
3sclB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain HIS 345;GLU 375;HIS 505 HIS 374;HIS 378;GLU 402 (Zinc binding) PRO 346
6m17B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
6m17D02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
6m18B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
6m18D02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[2]
Fig.8, p.18004-18005

References
[1]
Resource
Comments
Medline ID
PubMed ID 11815627
Journal J Biol Chem
Year 2002
Volume 277
Pages 14838-43
Authors Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P
Title Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 14754895
Journal J Biol Chem
Year 2004
Volume 279
Pages 17996-8007
Authors Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW
Title ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis.
Related PDB 1r42 1r4l
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 16166518
Journal Science
Year 2005
Volume 309
Pages 1864-8
Authors Li F, Li W, Farzan M, Harrison SC
Title Structure of SARS coronavirus spike receptor-binding domain complexed with receptor.
Related PDB 2ajf
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 18448527
Journal J Virol
Year 2008
Volume 82
Pages 6984-91
Authors Li F
Title Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections.
Related PDB 3d0g 3d0h 3d0i
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 19901337
Journal Proc Natl Acad Sci U S A
Year 2009
Volume 106
Pages 19970-4
Authors Wu K, Li W, Peng G, Li F
Title Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor.
Related PDB 3kbh
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 22291007
Journal J Biol Chem
Year 2012
Volume 287
Pages 2558465
Authors Wu K, Peng G, Wilken M, Geraghty RJ, Li F
Title Mechanisms of host receptor adaptation by severe acute respiratory syndrome coronavirus.
Related PDB 3sci 3scj 3sck 3scl
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 32132184
Journal Science
Year 2020
Volume 367
Pages 1444-1448
Authors Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q
Title Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.
Related PDB 6m17 6m18
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 32225175
Journal Nature
Year 2020
Volume 581
Pages 221-224
Authors Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Geng Q, Auerbach A, Li F
Title Structural basis of receptor recognition by SARS-CoV-2.
Related PDB 6vw1
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 32225176
Journal Nature
Year 2020
Volume 581
Pages 215-220
Authors Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, Zhang Q, Shi X, Wang Q, Zhang L, Wang X
Title Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.
Related PDB 6m0j
Related UniProtKB

Comments
The active site of this enzyme is similar to thermolysin (EzCatDB; D00234), and astacin (EzCatDB; S00394) [2](PMID 14754895).
According to the literature [2](PMID 14754895), the proposed catalytic mechanism is as follows:
(1) Glu375 acts as a general base to deprotonate the zinc-bound water; The water attacks the carbonyl group of the scissile amide bond, to form a tetrahedral intermediate.
(2) His505 acts as a general acid to protonate to the leaving nitrogen atom of the P1’ residue.
(3) The nitrogen atom is stabilized by Pro346, His505 and/or His345.
(4) The amide C-N bond breaks; Glu375 acts as a general acid to protonate the emerging free nitrogen of the product amino acid.
(5) His505 acts as a general base to deprotonate the new emerging product carboxyl group, directly or through solvent.
According to the literature [2](PMID 14754895), Chloride binding sites:
(i) The (first) binding site is conserved with tACE, but ~21 angstrom away from the active site zinc ion, and ~16 angstrom away from dichlorobenzyl group of inhibitor, MLN-4760.
(ii) The second binding site, in which chloride ion is invisible, is not conserved. The chloride ion at this site may help to shift the open/closed conformational equilibrium in favor of the catalytic competent closed conformer.
ACE2 as the SARS coronavirus receptor
(iii) Interfering with the active site has no effect on viral spike protein binding to ACE2.
(iv) The large conformational change observed upon MLN-4760 binding to ACE2 could prove to be unfavorable for viral binding to its receptor.

Created Updated
2020-07-14 2021-01-06