Get   for     ? 
 Site search     ? 
Catalytic Site Atlas Version 2.2.12
Find Annotated Site: PDB code:
Swiss-Prot code:
EC number:
Help
CSA entry for 1o8a
Original Entry
Title:
Metalloprotease
Compound:
Angiotensin converting enzyme
Mutant:
No
UniProt/Swiss-Prot:
P22966-ACET_HUMAN
EC Class:
3.4.15.1
Other CSA Entries:
Overview of all sites for 1o8a
Homologues of 1o8a
Entries for UniProt/Swiss-Prot: P22966
Entries for EC: 3.4.15.1
Other Databases:
PDB entry: 1o8a
PDBsum entry: 1o8a
UniProt/Swiss-Prot: P22966
IntEnz entry: 3.4.15.1
Literature Report:
Introduction:
Angiotensin I-converting enzymes (ACEs) are zinc metalloproteases that cleave dipeptides from the C-termini of short peptide hormones. In humans, ACE has an important role in regulating blood pressure and heart maintenance by catalysing production of the hypertensive peptide angiotensin II and the destruction of the hypotensive peptide bradykinin. ACE has minimal sequence homology with other zinc proteases, but it does share the HExxH zinc-binding motif of the well-studied zinc metalloprotease theromolysin.


Mechanism:
The catalytic mechanism of ACE has been inferred from that of thermolysin. The nucleophilic water molecule is polarised by a Zn2+ ion and is deprotonated by Glu 384 as it attacks the peptide carbonyl. The zinc ion also coordinates the carbonyl and so activates it towards nucleophilic attack. Accumulation of negative charge on the carbonyl oxygen is stabilised by the zinc ion and a hydrogen bond from Tyr 523, His 353 and His 513. A hydrogen bond with the backbone carbonyl of Ala 354 stabilises the positive charge on the amide of the intermediate. Collapse of the tetrahedral intermediate with protonation of the departing amine group by Glu 384 completes the reaction.


Sites:

Click to Display Catalytic Site (Get help with this section)
Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 353 384Sidechain
ElectrostaticSubstrate
Stabilises transition state by hydrogen bonding to the carboxylate oxygen atom.
Evidence from paper Evidence concerns Evidence type
PubMed ID 14983080 Current protein Conservation of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ALAA 354 385Backbone carbonyl
ElectrostaticSubstrate
Stabilizes the positive charge on the amide of the intermediate by hydrogen bonding.
Evidence from paper Evidence concerns Evidence type
PubMed ID 14983080 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLUA 384 415Sidechain
Acid/baseSubstrate
Acid/baseWater
Activates a water molecule, and donates the proton to the scissile amide nitrogen.
Evidence from paper Evidence concerns Evidence type
PubMed ID 14983080 Current protein Conservation of residue
PubMed ID 14983080 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 513 544Sidechain
ElectrostaticSubstrate
Stabilises the intermediate by hydrogen bonding to the carboxylate oxygen atom.
Evidence from paper Evidence concerns Evidence type
PubMed ID 14983080 Current protein Mutagenesis of residue
PubMed ID 14983080 Current protein Conservation of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
TYRA 523 554Sidechain
ElectrostaticSubstrate
Stabilises the negative charge on the intermediate by hydrogen bonding to the carboxylate oxygen atom.
Evidence from paper Evidence concerns Evidence type
PubMed ID 14983080 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 14983080 Current protein Conservation of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ZNA 701 0
ElectrostaticSubstrate
ElectrostaticWater
Polarises the nucleophilic water molecule, allowing it to be deprotonated by Glu 384. Also, its positive charge helps to stabilise the negatively charged intermediate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 14983080 Current protein Residue is positioned appropriately (ligand position known)
Notes:



References:
1
Crystal structure of Drosophila angiotensin I-converting enzyme bound to captopril and lisinopril
H. M. Kim and D. R. Shin and O. J. Yoo and H. Lee and J. O. Lee
FEBS Lett. 538 (1-3) 65-70, (2003)
12633854
2
Structure-function discrimination of the N- and C- catalytic domains of human angiotensin-converting enzyme: implications for Cl- activation and peptide hydrolysis mechanisms
A. G. Tzakos and A. S. Galanis and G. A. Spyroulias and P. Cordopatis and E. Manessi-Zoupa and I. P. Gerothanassis
Protein Eng. 16 (12) 993-1003, (2003)
14983080
3
Structure-function discrimination of the N- and C- catalytic domains of human angiotensin-converting enzyme: implications for Cl- activation and peptide hydrolysis mechanisms.
A. G. Tzakos and A. S. Galanis and G. A. Spyroulias and P. Cordopatis and E. Manessi-Zoupa and I. P. Gerothanassis
Protein Eng 16, (12) 993-1003, (2003).
14983080
Which EBI biological databases are available and how do I access them? EBI Site Map