Family M38


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

Summary for family M38

NamePeptidase family M38 (beta-aspartyl dipeptidase family)
Family type peptidaseM38.001 - isoaspartyl dipeptidase (metallo-type) (Escherichia coli), MEROPS Accession MER0001495 (peptidase unit: 10-359)
Content of familyFamily M38 contains an omega peptidase.
History Identifier created: Proteolysis in Cell Function, pp13-21, IOS Press, Amsterdam (1997)
Both aspartate and asparagine can undergo a spontaneous post-translational cyclization reaction, which in the case of aspartate produces an isoaspartate residue. This residue can then form bonds through its beta-carboxyl group rather than the alpha-carboxyl in a normal peptide bond. beta-Aspartyl dipeptidase (M38.001) releases the isoaspartate from a dipeptide.
Catalytic typeMetallo
Active site residuesH68 H70 K162 H201 H230 D285 
Active sitebeta-Aspartyl dipeptidase has two cocatalytic zinc ions, one of which is pentahedrally co-ordinated and the other tetrahedrally co-ordinated. The zinc ligands are four histidines, two of which occur in an HXH motif, an asparatate and a modified lysine residue (lysine NZ-carboxylate) which ligates both zinc ions (Thoden et al., 2003). The aspartate is thought to be the catalytic base (Jozic et al., 2003).
Activities and specificitiesAn N-terminal isoaspartate is released from a select few dipeptides, the best substrate being beta-AspLeu (Gary & Clarke, 2004). Normal aspartyl dipeptides are not substrates. A homologue from Aureobacterium esteraromaticum (M38.002) has an entirely different activity, releasing hydroxyproline from a HypPro dipeptide (Kabashima et al., 1999).
InhibitorsThe metal chelator EDTA is inhibitory. p-Hydroxymercuribenzoate (2 mM) also inhibits. The phosphinic inhibitor Asp-Psi[PO(2)CH(2)]-LeuOH was used to form the complex by which the tertiary structure was determined (Jozic et al., 2003).
Molecular structureThe tertiary structure of beta-aspartyl dipeptidase has been determined (Thoden et al., 2003; Jozic et al., 2003) and shows that the native protein exists as a homo-octamer. The fold of each monomer is similar to that for peptidases from family M19, and consequently family M38 is included in clan MJ. beta-Aspartyl dipeptidase is homologous to a number of other amidases such as dihydro-orotase and subunits of urease. Many of these homologues have cocatalytic nickel ions, rather than zinc.
Basis of clan assignmentType family of clan MJ.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi -  
Plants details  
Animals details  
Viruses details  
Biological functionsThe beta-aspartyl dipeptidase is a cytosolic enzyme and is a product of the iadA gene in Escherichia coli. Its function is the release of isoaspartate residues from peptides which accumulate during the stationery phase of bacterial growth and may be toxic. However, isoaspartates do not accumulate in iadA knockouts, probably because another enzyme is capable of releasing them from peptides (Gary & Clarke, 1995).
Isoaspartates can also be metabolized by L-asparaginase (T02.002, Kelo et al., 2002), which also hydrolyses asparagine, though kinetic analysis suggests that the isoaspartyl dipeptidase activity is the major activity (Borek et al., 2004. The structure of L-asparaginase has been determined, showing that it is a N-terminal nucleophile hydrolase, unrelated to enzymes in family M38 (Prahl et al., 2004), which processes itself by cleavage of a normal peptide bond (Hejazi et al., 2002.
Statistics for family M38Sequences:24227
Identifiers with PDB entries:12
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Other databases CATH
PFAM PF00962
PFAM PF01979
PFAM PF04909
PFAM PF07969
PFAM PF12890
PFAM PF13147
PFAM PF13594
SCOP 51560
Peptidases and Homologues MEROPS ID Structure
isoaspartyl dipeptidase (metallo-type)M38.001Yes
Pro-Hyp dipeptidaseM38.002-
dihydropyrimidinase related protein-1M38.974Yes
dihydropyrimidinase related protein-2M38.975Yes
dihydropyrimidinase related protein-3M38.976Yes
dihydropyrimidinase related protein-4M38.977-
dihydropyrimidinase related protein-5M38.978Yes
hypothetical protein like 5730457F11RIKM38.979-
probable imidazolonepropionaseM38.980Yes
guanine deaminaseM38.981Yes
N-acetylglucosamine-6-phosphate deacetylase (Bacillus subtilis)M38.983Yes
PyrC protein (Escherichia coli)M38.A02-
family M38 non-peptidase homologuesnon-peptidase homologueYes
family M38 unassigned peptidasesunassignedYes