Editing Angiotensin-converting enzyme (section)

== Mechanism ==
ACE is a zinc [[metalloproteinase]].<ref>{{cite journal |vauthors=Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, Llorens-Cortes C, Hazra S, Murray AG, Vederas JC, Oudit GY |display-authors=6 |title=Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System |journal=Hypertension |volume=68 |issue=2 |pages=365–377 |date=August 2016 |pmid=27217402 |doi=10.1161/HYPERTENSIONAHA.115.06892 |s2cid=829514|doi-access=free }}</ref> The zinc center catalyses the peptide hydrolysis. Reflecting the critical role of zinc, ACE can be inhibited by metal[[Chelating agent|-chelating agents.]]<ref>{{cite journal |vauthors=Bünning P, Riordan JF |title=The functional role of zinc in angiotensin converting enzyme: implications for the enzyme mechanism |journal=Journal of Inorganic Biochemistry |volume=24 |issue=3 |pages=183–198 |date=July 1985 |pmid=2995578 |doi=10.1016/0162-0134(85)85002-9}}</ref>

[[File:ACE in complex with inhibitor lisinopril.png|thumb|center|400px|ACE in complex with inhibitor lisinopril, zinc cation shown in grey, chloride anions in yellow. Based on PyMOL rendering of PDB [http://www.rcsb.org/pdb/explore/explore.do?structureId=1o86 1o86]. The picture shows that lisinopril is a competitive inhibitor, since it and angiotensin I are similar structurally.  Both bind to the active site of ACE.  The structure of the ACE-lisinopril complex was confirmed by [[X-ray crystallography]].<ref name="Natesh_2003"/>]]

The E384 residue is mechanistically critical. As a general base, it deprotonates the [[metal aquo complex|zinc-bound water]], producing a nucleophilic Zn-OH center. The resulting ammonium group then serves as a general acid to cleave the C-N bond.<ref name="Zhang_2013">{{cite journal | vauthors = Zhang C, Wu S, Xu D | title = Catalytic mechanism of angiotensin-converting enzyme and effects of the chloride ion | journal = The Journal of Physical Chemistry B | volume = 117 | issue = 22 | pages = 6635–6645 | date = June 2013 | pmid = 23672666 | doi = 10.1021/jp400974n }}</ref>

The function of the chloride ion is very complex and is highly debated. The anion activation by chloride is a characteristic feature of ACE.<ref name="Bünning_1983">{{cite journal | vauthors = Bünning P | title = The catalytic mechanism of angiotensin converting enzyme | journal = Clinical and Experimental Hypertension, Part A | volume = 5 | issue = 7–8 | pages = 1263–1275 | year = 1983 | pmid = 6315268 | doi = 10.3109/10641968309048856 }}</ref> It was experimentally determined that the activation of hydrolysis by chloride is highly dependent on the substrate. While it increases hydrolysis rates for e.g. Hip-His-Leu it inhibits hydrolysis of other substrates like Hip-Ala-Pro.<ref name="Zhang_2013" /> Under physiological conditions the enzyme reaches about 60% of its maximal activity toward angiotensin I while it reaches its full activity toward bradykinin. It is therefore assumed that the function of the anion activation in ACE provides high substrate specificity.<ref name="Bünning_1983" /> Other theories say that the chloride might simply stabilize the overall structure of the enzyme.<ref name="Zhang_2013" />