Family M79


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

Summary for family M79

NamePeptidase family M79 (prenyl protease 2 family)
Family type peptidaseM79.001 - RCE1 peptidase (Saccharomyces cerevisiae-type) (Saccharomyces cerevisiae), MEROPS Accession MER0004244 (peptidase unit: 1-315)
Content of familyPeptidase family M79 contains specialised endopeptidases that typically cleave a C-terminal tripeptide from an isoprenylated protein.
History Identifier created: MEROPS 9.3 (7 September 2010)
It should be noted that peptidases in family M48, prenyl-processing peptidase family I, catalyse a similar reaction to those in family M79. The specificities are overlapping (for example, peptidases from both families process the yeast a-mating factor), but they are not identical (Dolence et al., 2000; Trueblood et al., 2000). The sequence of events in the biosynthesis of the proteins that are processed by the prenyl-processing peptidases is (1) condensation of the thiol of a cysteine residue near the C-terminus with farnesyl pyrophosphate or geranylgeranyl pyrophosphate, (2) cleavage of the peptide bond C-terminal to the modified cysteine and liberation of an intact C-terminal tripeptide, and (3) methylation of the new C-terminal carboxyl group. Steps (1) and (3) are catalysed by non-peptidase enzymes.
Catalytic typeMetallo
Active siteResidues Glu156, Glu157, His194, His258 and Cys261 (numbering as in the MEROPS Alignment) are potential active site residues that are fully conserved in the Alignment of sequences for family M79 (Dolence et al., 2000) and indeed in a larger group of more distantly related proteins (Pei & Grishin, 2001). Recombinant forms of the yeast protein (M79.001) mutated to substitute alanine for His194, Glu156, His258 and Cys261 were catalytically inactive (Dolence et al., 2000). The importance of the cysteine, taken together with some inhibition data, led Dolence et al. (2000) to the conclusion that M79.001 is a cysteine peptidase. In contrast to this view, Pei & Grishin, 2001 noted that the cysteine was not conserved in their wider group of proteins (not all known to be peptidases), and concluded that the type II prenyl-processing peptidases are metallopeptidases. In further mutagenic sudies, Plummer et al. (2005) have found that Glu156, His194 and His258 are critical for activity, but Cys261 is not, and again support the tentative conclusion that family M79 is a family of metallopeptidases.
Activities and specificitiesThe specificity of the prenyl-processing peptidases is usually described as cleavage of the '-CaaX' motif, a representation of the C-terminal tetrapeptide of the substrate protein. This cleavage can alternatively be represented: -Cys(R)Xaa-Xaa-Xbb, in which Cys(R) is cysteine in which the thiol is substituted with a C15 (farnesyl) or C20 (geranylgeranyl) side chain, Xaa is normally a small, aliphatic residue, and Xbb is any amino acid. In vitro assays have been made with N-acetyl-S-farnesyl-L-CysVal-Ile-Met as substrate (Ma et al., 1993). A comparison with the prenyl-processing peptidases of family M48 has been made by Trueblood et al. (2000).
InhibitorsPeptidase M79.002 was not affected by EDTA (25 mM), 1,10-phenanthroline (1 mM) or compound E-64 (44 micromolar), but there was inhibition by some compounds that have non-specific thiol-reactivity, notably mercurials (Dolence et al., 2000). N-Boc-S-Farnesyl-L-cysteine aldehyde (2 micromolar) is an inhibitor (Ma et al., 1993) as is the corresponding chloromethane (Chen et al., 1996). The pseudo-peptide analogue of the substrate N-acetyl-S-farnesyl-L-CysVal-Ile-Met is a potent competitive inhibitor of Ki 85 nM (Chen et al., 1996).
Molecular structurePeptidase M79.001 is a membrane protein, and no structure is available for it. The number of predicted trans-membrane segments is either seven (Dolence et al., 2000) or eight (UniProt database). Crucially, the trans-membrane segment predicted by UniProt but not by Dolence and colleagues contains the residues Glu156 and Glu157 that are very likely to contribute to catalysis. Peptidases in several other families are believed to contain active site residues in transmembrane segments.
Basis of clan assignmentProtein fold and active site residues are not known for any members of this family.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi -  
Plants details  
Animals details  
Viruses details  
Biological functionsProteins that require processing by the prenyl peptidases include fungal mating factors, nuclear lamins, Ras and Ras-related GTP-binding proteins (G proteins), the subunits of trimeric G proteins, protein kinases, and at least one viral protein (Zhang & Casey, 1996).
Pharmaceutical and biotech relevanceThe metabolism of the oncogene products in particular may be of great importance in tumour biology, so there has been considerable interest in the processing peptidases in families M48 and M79. This being the case, it is remarkable that the catalytic type of the peptidases in M79 still remains to be established beyond doubt.
Statistics for family M79Sequences:9336
Identifiers with PDB entries:1
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Other databases INTERPRO IPR003675
PFAM PF02517
Peptidases and Homologues MEROPS ID Structure
RCE1 peptidase (Saccharomyces cerevisiae-type)M79.001-
RCE1 peptidase (Homo sapiens-type)M79.002-
fce-2 peptidaseM79.003-
microcystinase MlrAM79.004Yes
RCE1 peptidase (Sarcomastigophora-type)M79.005-
CAAX amino terminal peptidase (plant)M79.006-
At1g14270 (Arabidopsis thaliana)M79.A02-
At2g20725 (Arabidopsis thaliana)M79.A03-
At3g26085 (Arabidopsis thaliana)M79.A04-
ydiL g.p. (Bacillus subtilis)M79.A09-
PFI0660c g.p. (Plasmodium falciparum)M79.A10-
family M79 unassigned peptidasesunassigned-