Family M2

Family

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

Summary for family M2

Family type peptidase	M02.001 - angiotensin-converting enzyme peptidase unit 1 (Homo sapiens), MEROPS Accession MER0004967 (peptidase unit: 30-583)
Content of family	Peptidase 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 type	Metallo
Active site residues	H390 E391 H394 E418
Active site	Family 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 specificities	The 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).
Inhibitors	Like 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 structure	The 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).
Clan	MA
Subclan	MA(E)
Basis of clan assignment	Active 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 functions	Peptidyl-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 relevance	Because 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 M2	Sequences:	1390
	Identifiers:	9
	Identifiers with PDB entries:	4
Downloadable files	Sequence library (FastA format)
	Sequence alignment (FastA format)
	Phylogenetic tree (Newick format)

Other databases	INTERPRO	IPR001548
	PANTHER	PTHR10514
	PFAM	PF01401
	SCOP	55505

Peptidases and Homologues	MEROPS ID	Structure
angiotensin-converting enzyme peptidase unit 1	M02.001	Yes
peptidyl-dipeptidase Acer	M02.002	-
peptidyl-dipeptidase Ance	M02.003	Yes
angiotensin-converting enzyme peptidase unit 2	M02.004	Yes
peptidyl-dipeptidase A (Theromyzon-type)	M02.005	-
angiotensin-converting enzyme-2	M02.006	Yes
peptidyl-dipeptidase A (Crassostrea-type)	M02.007	-
Mername-AA152 protein	M02.971	-
Mername-AA153 protein	M02.972	-
Family M02 non-peptidase homologues	non-peptidase homologue	-
Family M02 unassigned peptidases	unassigned	-