Family M2


Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

Summary for family M2

Family type peptidaseM02.001 - angiotensin-converting enzyme peptidase unit 1 (Homo sapiens), MEROPS Accession MER0004967 (peptidase unit: 30-583)
Content of familyPeptidase family M2 contains metallo-exopeptidases.
History Identifier created: Biochem.J. 290:205-218 (1993)
Family M2 contains angiotensin-converting enzyme (ACE), and until recently this was the only known member of the family. Arguably, angiotensin-converting enzyme is better termed peptidyl-dipeptidase A because it has a number of important functions in addition to the processing of angiotensin, but "ACE" is what it is usually called. Quite recently in vertebrate evolution, about 400 million years ago, the ACE gene underwent an internal duplication, and the resulting separate but fused peptidase units are treated in MEROPS as separate peptidases M02.001 and M02.004 within the compound peptidase XM02-001. Use of an alternative initiation site leads to expression of a small form of the enzyme containing only one peptidase unit in mammalian testis, and similarly forms of the enzyme reflecting the situation prior to the gene duplication are known from a number of invertebrates. Vertebrates also contain the separate angiotensin-converting enzyme 2 (M02.006).
Catalytic typeMetallo
Active site residuesH390 E391 H394 E418 
Active siteFamily M2 is assigned to clan MA, subclan MA(E), because its peptidases contain catalytic residues in the HEXXH motif acting in conjunction with a C-terminally-located glutamate residue. The two His residues in the HEXXH motif, together with the C-terminal Glu, ligate the essential zinc atom, and the Glu in the HEXXH motif has a catalytic function (Williams et al., 1994).
Activities and specificitiesThe peptidases in family M2 are exopeptidases acting near the C-terminus of oligopeptides. Peptidyl-dipeptidase A hydrolyses C-terminal dipeptides, and occasionally tripeptides (Araujo et al., 2000), whereas angiotensin-converting enzyme 2 is a carboxypeptidase (Guy et al., 2003). Both enzymes show a strict requirement for chloride ion in their action on at least some substrates (Araujo et al., 2000).
InhibitorsLike most metallopeptidases, those in family M2 are inhibited by metal-chelating agents. Potent, selective inhibitors of peptidyl-dipeptidase A have been synthesised for use as drugs (Menard et al., 2001).
Molecular structureThe crystal structure of testicular peptidyl-dipeptidase A shows a fold reminiscent of those of neurolysin (M03.002) and carboxypeptidase Pfu (M32.002) (Natesh et al., 2003).
Basis of clan assignmentActive site residues for members of this family and thermolysin, the type example for clan MA, occur in the motif HEXXH
Distribution of family Bacteria details  
Archaea -  
Protozoa details  
Fungi -  
Plants -  
Animals details  
Viruses -  
Biological functionsPeptidyl-dipeptidase A is of great importance in the regulation of blood pressure, cleaving the C-terminal His-Leu dipeptide from angiotensin I to produce the potent vasopressor octapeptide, angiotensin II.
Pharmaceutical and biotech relevanceBecause peptidyl-dipeptidase A generates angiotensin II, inhibitors have the effect of lowering blood pressure, and are widely used as drugs. Angiotensin-converting enzyme 2 may also be considered a potential drug target (Huang et al., 2003).
Statistics for family M2Sequences:1411
Identifiers with PDB entries:4
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
angiotensin-converting enzyme peptidase unit 1M02.001Yes
peptidyl-dipeptidase AcerM02.002-
peptidyl-dipeptidase AnceM02.003Yes
angiotensin-converting enzyme peptidase unit 2M02.004Yes
peptidyl-dipeptidase A (Theromyzon-type)M02.005-
angiotensin-converting enzyme-2M02.006Yes
peptidyl-dipeptidase A (Crassostrea-type)M02.007-
Mername-AA152 proteinM02.971-
Mername-AA153 proteinM02.972-
family M2 non-peptidase homologuesnon-peptidase homologue-
family M2 unassigned peptidasesunassigned-