F
IPR001548

Peptidase M2, peptidyl-dipeptidase A

InterPro entry
Short namePeptidase_M2

Description

This group of metallopeptidases belong to the MEROPS peptidase family M2 (clan MA(E)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA. The catalytic residues and zinc ligands have been identified, the zinc ion being ligated to two His residues within the motif HEXXH, showing that the enzyme belongs to the glu-zincin sub-group of metalloproteases
[4]
.

Peptidyl-dipeptidase A (angiotensin-converting enzyme or ACE,
3.4.15.1
) is a mammalian enzyme responsible for cleavage of dipeptides from the C-termini of proteins, notably converting decapeptide angiotensin I to the octapeptide angiotensin II
[4]
. The enzyme exists in two differentially transcribed forms, the most common of which is from lung endothelium; this contains two homologous domains that have arisen by gene duplication
[4]
. The testis-specific form contains only the C-terminal domain, arising from a duplicated promoter region present in intron 12 of the gene
[4]
. Both enzymatic forms are membrane proteins that are anchored by means of a C-terminal transmembrane domain. Both domains of the endothelial enzyme are active, but have differing kinetic constants
[4, 3]
. ACE is well-known as a key part of the renin-angiotensin system that regulates blood pressure and ACE inhibitors are important for the treatment of hypertension
[5, 6]
.

An ACE homologue, ACE2 (MEROPS identifier M02.006), has been identified in humans that differs from ACE; it preferentially removes carboxy-terminal hydrophobic or basic amino acids and appears to be important in cardiac function
[2, 1]
.

References

1.The emerging role of ACE2 in physiology and disease. Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, Timens W, Turner AJ, Navis G, van Goor H. J. Pathol. 212, 1-11, (2007). View articlePMID: 17464936

2.ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW. J. Biol. Chem. 279, 17996-8007, (2004). View articlePMID: 14754895

3.The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. Wei L, Alhenc-Gelas F, Corvol P, Clauser E. J. Biol. Chem. 266, 9002-8, (1991). View articlePMID: 1851160

4.Evolutionary families of metallopeptidases. Rawlings ND, Barrett AJ. Meth. Enzymol. 248, 183-228, (1995). View articlePMID: 7674922

5.The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380. Corradi HR, Chitapi I, Sewell BT, Georgiadis D, Dive V, Sturrock ED, Acharya KR. Biochemistry 46, 5473-8, (2007). View articlePMID: 17439247

6.Probing the basis of domain-dependent inhibition using novel ketone inhibitors of Angiotensin-converting enzyme. Watermeyer JM, Kroger WL, O'Neill HG, Sewell BT, Sturrock ED. Biochemistry 47, 5942-50, (2008). View articlePMID: 18457420

Further reading

7. Crystal structure of Drosophila angiotensin I-converting enzyme bound to captopril and lisinopril. Kim HM, Shin DR, Yoo OJ, Lee H, Lee JO. FEBS Lett. 538, 65-70, (2003). View articlePMID: 12633854

8. Toward a role for angiotensin-converting enzyme in insects. Isaac RE, Schoofs L, Williams TA, Corvol P, Veelaert D, Sajid M, Coates D. Ann. N. Y. Acad. Sci. 839, 288-92, (1998). View articlePMID: 9629165

9. Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Natesh R, Schwager SL, Sturrock ED, Acharya KR. Nature 421, 551-4, (2003). View articlePMID: 12540854

10. Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design. Corradi HR, Schwager SL, Nchinda AT, Sturrock ED, Acharya KR. J. Mol. Biol. 357, 964-74, (2006). View articlePMID: 16476442

11. Characterization of the first non-insect invertebrate functional angiotensin-converting enzyme (ACE): leech TtACE resembles the N-domain of mammalian ACE. Riviere G, Michaud A, Deloffre L, Vandenbulcke F, Levoye A, Breton C, Corvol P, Salzet M, Vieau D. Biochem J 382, 565-73, (2004). PMID: 15175004

12. The angiotensin-converting enzyme (ACE) gene family of Anopheles gambiae. Burnham S, Smith JA, Lee AJ, Isaac RE, Shirras AD. BMC Genomics 6, 172, (2005). View articlePMID: 16329762

13. [Structure and function of angiotensin converting enzyme and its inhibitors]. Zhao Y, Xu C. Sheng Wu Gong Cheng Xue Bao 24, 171-6, (2008). View articlePMID: 18464595

14. An essential role in molting and morphogenesis of Caenorhabditis elegans for ACN-1, a novel member of the angiotensin-converting enzyme family that lacks a metallopeptidase active site. Brooks DR, Appleford PJ, Murray L, Isaac RE. J Biol Chem 278, 52340-6, (2003). View articlePMID: 14559923

15. ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. Lubbe L, Cozier GE, Oosthuizen D, Acharya KR, Sturrock ED. Clin Sci (Lond) 134, 2851-2871, (2020). View articlePMID: 33146371

16. Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis. Rushworth CA, Guy JL, Turner AJ. FEBS J 275, 6033-42, (2008). View articlePMID: 19021774

17. Structural diversity of angiotensin-converting enzyme. Bingham RJ, Dive V, Phillips SE, Shirras AD, Isaac RE. FEBS J 273, 362-73, (2006). View articlePMID: 16403023

18. A new high-resolution crystal structure of the Drosophila melanogaster angiotensin converting enzyme homologue, AnCE. Harrison C, Acharya KR. FEBS Open Bio 5, 661-7, (2015). View articlePMID: 26380810

GO terms

Cross References

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