Zinc peptidases M18, M20, M28, and M42; Zinc peptidases play vital roles in metabolic and signaling pathways throughout all kingdoms of life. This hierarchy contains zinc peptidases that correspond to the MH clan in the MEROPS database, which contains 4 families (M18, M20, M28, M42). The peptidase M20 family includes carboxypeptidases such as the glutamate carboxypeptidase from Pseudomonas, the thermostable carboxypeptidase Ss1 of broad specificity from archaea and yeast Gly-X carboxypeptidase. The dipeptidases include bacterial dipeptidase, peptidase V (PepV), a non-specific eukaryotic dipeptidase, and two Xaa-His dipeptidases (carnosinases). There is also the bacterial aminopeptidase, peptidase T (PepT) that acts only on tripeptide substrates and has therefore been termed a tripeptidase. Peptidase family M28 contains aminopeptidases and carboxypeptidases, and has co-catalytic zinc ions. However, several enzymes in this family utilize other first row transition metal ions such as cobalt and manganese. Each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Glutamate carboxypeptidase II and plasma glutamate carboxypeptidase hydrolyze dipeptides. Peptidase families M18 and M42 contain metallo-aminopeptidases. M18 is widely distributed in bacteria and eukaryotes. However, only yeast aminopeptidase I and mammalian aspartyl aminopeptidase have been characterized in detail. Some M42 (also known as glutamyl aminopeptidase) enzymes exhibit aminopeptidase specificity while others also have acylaminoacyl-peptidase activity (i.e. hydrolysis of acylated N-terminal residues).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 240 RETWQIIADTKEGDPNNIVMLGAHLDSVQEGPGINDNGSGVAALLSIAESIKQKSFKNKLRFAFWGAEESGMIGSNYYVS 319
Cdd:cd03876    61 RTTYNVIAETKGGDPNNVVMLGAHLDSVSAGPGINDNGSGSAALLEVALALAKFKVKNAVRFAWWTAEEFGLLGSKFYVN 140

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 320 NLSKEEASNIRFYYNYDMIASLQPYYIVY--SNSEAHKTG------AQYLYE-YLTEHGYPAEYAPFGSSSDYIGFLELG 390
Cdd:cd03876   141 NLSSEERSKIRLYLNFDMIASPNYGYFIYdgDGSAFNLTGppgsaeIERLFEaYFTSLGLPSTPTEFDGRSDYAPFIEAG 220

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2101147568 391 IPSSGIFTG----------------AGPPQDVCYHTACDDIKNINKEAFLVN 426
Cdd:cd03876   221 IPAGGLFTGaegikteeqaalwggtAGVAYDPCYHQACDTIDNINRTALLRN 272

M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family M28; Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved. It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30 kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 240 RETWQIIADTKEGDPNNIVMLGAHLDSVQEGPGINDNGSGVAALLSIAESIKQKSFKNKLRFAFWGAEESGMIGSNYYVS 319
Cdd:cd03876    61 RTTYNVIAETKGGDPNNVVMLGAHLDSVSAGPGINDNGSGSAALLEVALALAKFKVKNAVRFAWWTAEEFGLLGSKFYVN 140

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 320 NLSKEEASNIRFYYNYDMIASLQPYYIVY--SNSEAHKTG------AQYLYE-YLTEHGYPAEYAPFGSSSDYIGFLELG 390
Cdd:cd03876   141 NLSSEERSKIRLYLNFDMIASPNYGYFIYdgDGSAFNLTGppgsaeIERLFEaYFTSLGLPSTPTEFDGRSDYAPFIEAG 220

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2101147568 391 IPSSGIFTG----------------AGPPQDVCYHTACDDIKNINKEAFLVN 426
Cdd:cd03876   221 IPAGGLFTGaegikteeqaalwggtAGVAYDPCYHQACDTIDNINRTALLRN 272

Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein turnover, chaperones, Amino acid transport and metabolism];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 237 TEKRETWQIIADTK-EGDPNNIVMLGAHLDSV-QEGPGINDNGSGVAALLSIAESIKQKSFKNK--LRFAFWGAEESGMI 312
Cdd:COG2234    41 AAGGDSRNVIAEIPgTDPPDEVVVLGAHYDSVgSIGPGADDNASGVAALLELARALAALGPKPKrtIRFVAFGAEEQGLL 120

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 313 GSNYYVSNLsKEEASNIRFYYNYDMIASLQPYYIVY-----SNSEAHKTGAQYLYEYLTEHGYPAEY-APFGSSSDYIGF 386
Cdd:COG2234   121 GSRYYAENL-KAPLEKIVAVLNLDMIGRGGPRNYLYvdgdgGSPELADLLEAAAKAYLPGLGVDPPEeTGGYGRSDHAPF 199

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 2101147568 387 LELGIPSSGIFTGAgPPQDVCYHTACDDIKNINKEAF 423
Cdd:COG2234   200 AKAGIPALFLFTGA-EDYHPDYHTPSDTLDKIDLDAL 235

PA domain; The PA (Protease associated) domain is found as an insert domain in diverse proteases. The PA domain is also found in a plant vacuolar sorting receptor Swiss:O22925 and members of the RZF family Swiss:O43567. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 124 TAPLVLIPiddergsGCFEDQW--KGIDMKGKIALIKRGKCHFINKLKLAKDNGASAAVVFNDNPAQTAGSGSLGAENIG 201
Cdd:pfam02225   1 TGPLVLAP-------GCYAGDGipADFDVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPPGAGGNELYP 73

                          90
                  ....*....|....*...
gi 2101147568 202 KL--APVGVITYDRGNAW 217
Cdd:pfam02225  74 DGiyIPAVGVSRADGEAL 91

myxosortase-dependent M36 family metallopeptidase; Members of this bacterial protein family have an M36 family metallopeptidase domain, like fungalysin (see PF02128), and a C-terminal MYXO-CTERM domain (see TIGR03901), suggesting processing and surface-anchoring by the still-unknown putative transpeptidase, myxosortase. Members of this family include MXAN_3564 (mepA), part of the effector cargo of outer membrane vesicles that the species produces in large numbers during predation on other microbes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568  123 VTAPLVLIPidDERGS---GC--FEDQwkgIDMKGKIALIKRGKCHFINKLKLAKDNGASAAVVFNDNPAQTAGsgsLGA 197
Cdd:NF038112   517 VTGDVVLAP--DGTGSdtdGCtpFTNA---AEVAGKIALIDRGTCDFTVKALNAQNAGAIGVIIANNAAGAAPG---LGG 588

                           90       100
                   ....*....|....*....|....*..
gi 2101147568  198 ENIGKLAPVGVITYDRGNAWADRLKSG 224
Cdd:NF038112   589 TDPAVTIPALSITQADGNAWKAALANG 615

M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family M28; Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved. It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30 kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 240 RETWQIIADTKEGDPNNIVMLGAHLDSVQEGPGINDNGSGVAALLSIAESIKQKSFKNKLRFAFWGAEESGMIGSNYYVS 319
Cdd:cd03876    61 RTTYNVIAETKGGDPNNVVMLGAHLDSVSAGPGINDNGSGSAALLEVALALAKFKVKNAVRFAWWTAEEFGLLGSKFYVN 140

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 320 NLSKEEASNIRFYYNYDMIASLQPYYIVY--SNSEAHKTG------AQYLYE-YLTEHGYPAEYAPFGSSSDYIGFLELG 390
Cdd:cd03876   141 NLSSEERSKIRLYLNFDMIASPNYGYFIYdgDGSAFNLTGppgsaeIERLFEaYFTSLGLPSTPTEFDGRSDYAPFIEAG 220

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2101147568 391 IPSSGIFTG----------------AGPPQDVCYHTACDDIKNINKEAFLVN 426
Cdd:cd03876   221 IPAGGLFTGaegikteeqaalwggtAGVAYDPCYHQACDTIDNINRTALLRN 272

Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein turnover, chaperones, Amino acid transport and metabolism];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 237 TEKRETWQIIADTK-EGDPNNIVMLGAHLDSV-QEGPGINDNGSGVAALLSIAESIKQKSFKNK--LRFAFWGAEESGMI 312
Cdd:COG2234    41 AAGGDSRNVIAEIPgTDPPDEVVVLGAHYDSVgSIGPGADDNASGVAALLELARALAALGPKPKrtIRFVAFGAEEQGLL 120

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 313 GSNYYVSNLsKEEASNIRFYYNYDMIASLQPYYIVY-----SNSEAHKTGAQYLYEYLTEHGYPAEY-APFGSSSDYIGF 386
Cdd:COG2234   121 GSRYYAENL-KAPLEKIVAVLNLDMIGRGGPRNYLYvdgdgGSPELADLLEAAAKAYLPGLGVDPPEeTGGYGRSDHAPF 199

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 2101147568 387 LELGIPSSGIFTGAgPPQDVCYHTACDDIKNINKEAF 423
Cdd:COG2234   200 AKAGIPALFLFTGA-EDYHPDYHTPSDTLDKIDLDAL 235

M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also called aminopeptidase Y family) contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Plasma glutamate carboxypeptidase (PGCP) and glutamate carboxypeptidase II (NAALADase) hydrolyze dipeptides. Several members of the M28 peptidase family have PA domain inserts which may participate in substrate binding and/or in promoting conformational changes, which influence the stability and accessibility of the site to substrate. These include prostate-specific membrane antigen (PSMA), yeast aminopeptidase S (SGAP), human transferrin receptors (TfR1 and TfR2), plasma glutamate carboxypeptidase (PGCP) and several predicted aminopeptidases where relatively little is known about them. Also included in the M28 family are glutaminyl cyclases (QC), which are involved in N-terminal glutamine cyclization of many endocrine peptides. Nicastrin and nicalin belong to this family but lack the amino-acid conservation required for catalytically active aminopeptidases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 245 IIAD-TKEGDPNNIVMLGAHLDSVQEGPGINDNGSGVAALLSIAESIKQKSFKNK--LRFAFWGAEESGMIGSNYYVSNL 321
Cdd:cd02690     4 VIATiKGSDKPDEVILIGAHYDSVPLSPGANDNASGVAVLLELARVLSKLQLKPKrsIRFAFWDAEELGLLGSKYYAEQL 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 322 sKEEASNIRFYYNYDMIASLQPYYIVYSNSEAHKTGAQYLYEYLTEHGYPAEYAPFGSS-----SDYIGFLELGIPSSGI 396
Cdd:cd02690    84 -LSSLKNIRAALNLDMIGGAGPDLYLQTAPGNDALVEKLLRALAHELENVVYTVVYKEDggtggSDHRPFLARGIPAASL 162

                         170       180
                  ....*....|....*....|....*.
gi 2101147568 397 FTGAGPPQDvCYHTACDDIKNINKEA 422
Cdd:cd02690   163 IQSESYNFP-YYHTTQDTLENIDKDT 187

M28 Zn-peptidase, many containing a protease-associated (PA) domain insert; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. This subfamily is composed of uncharacterized proteins, many of which contain a protease-associated (PA) domain insert which may participate in substrate binding and/or promote conformational changes, influencing the stability and accessibility of the site to substrate. Some proteins in this subfamily are also associated with the PDZ domain, a widespread protein module that has been recruited to serve multiple functions during the course of evolution.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 254 PNNIVMLGAHLDSVQEG---------PGINDNGSGVAALLSIAESIK-QKSFKNKLRFAFWGAEESGMIGSNYYVSNLSK 323
Cdd:cd03877    14 PDETIVIGAHYDHLGIGggdsgdkiyNGADDNASGVAAVLELARYFAkQKTPKRSIVFAAFTAEEKGLLGSKYFAENPKF 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 324 EEAsNIRFYYNYDMIASLQPYYIVY------SNSE------AHKTGAQYLYEYLTEHGYPAeyapfgssSDYIGFLELGI 391
Cdd:cd03877    94 PLD-KIVAMLNLDMIGRLGRSKDVYligsgsSELEnllkkaNKAAGRVLSKDPLPEWGFFR--------SDHYPFAKAGV 164

                         170       180       190
                  ....*....|....*....|....*....|..
gi 2101147568 392 PSSGIFTGAGPpqdvCYHTACDDIKNINKEAF 423
Cdd:cd03877   165 PALYFFTGLHD----DYHKPSDDYEKIDYEGM 192

M28 Zn-peptidase containing a protease-associated (PA) domain insert; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. This subfamily is composed of uncharacterized proteins containing a protease-associated (PA) domain insert which may participate in substrate binding and/or promote conformational changes, influencing the stability and accessibility of the site to substrate.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 235 VITEKRETWQIIADTKEGD--PNNIVMLGAHLD-----SVQEGPGIN----DNGSGVAALLSIAESIK--QKSFKNKLRF 301
Cdd:cd05660    51 VSKIEYSTSHNVVAILPGSklPDEYIVLSAHWDhlgigPPIGGDEIYngavDNASGVAAVLELARVFAaqDQRPKRSIVF 130

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 302 AFWGAEESGMIGSNYYVSNLS---KEEASNIrfyyNYDMIASLQP----YYIVYSNSE--------AHKTGAQYLYEYLT 366
Cdd:cd05660   131 LAVTAEEKGLLGSRYYAANPIfplDKIVANL----NIDMIGRIGPtkdvLLIGSGSSElenilkeaAKAVGRVVDYDPNP 206

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2101147568 367 EHGypaeyaPFgSSSDYIGFLELGIPSSGIFTGAGPPQDV----------CYHTACDDIK-NINKEA 422
Cdd:cd05660   207 ENG------SF-YRSDHYNFAKKGVPVLFFFGGYDLGDGGkklakaylhtDYHKPADDVTeKWDYEG 266

PA: Protease-associated (PA) domain. The PA domain is an insert domain in a diverse fraction of proteases. The significance of the PA domain to many of the proteins in which it is inserted is undetermined. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate. Proteins into which the PA domain is inserted include the following: i) various signal peptide peptidases including, hSPPL2a and 2b which catalyze the intramembrane proteolysis of tumor necrosis factor alpha, ii) various proteins containing a C3H2C3 RING finger including, Arabidopsis ReMembR-H2 protein and various E3 ubiquitin ligases such as human GRAIL (gene related to anergy in lymphocytes), iii) EDEM3 (ER-degradation-enhancing mannosidase-like 3 protein), iv) various plant vacuolar sorting receptors such as Pisum sativum BP-80, v) glutamate carboxypeptidase II (GCPII), vi) yeast aminopeptidase Y, vii) Vibrio metschnikovii VapT, a sodium dodecyl sulfate (SDS) resistant extracellular alkaline serine protease, viii) lactocepin (a cell envelope-associated protease from Lactobacillus paracasei subsp. paracasei NCDO 151), ix) various subtilisin-like proteases such as melon Cucumisin, and x) human TfR (transferrin receptor) 1 and 2.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 109 VSLQYNHATPSPGGVTAPLVLIPIDDERGSGC--FEDQWKGIDMKGKIALIKRGKCHFINKLKLAKDNGASAAVVFNDNP 186
Cdd:cd00538     2 VILATTGYAGSALLFNPPSSPVGVVAGPLVGCgyGTTDDSGADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVIIYNNGD 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 2101147568 187 AQTAGSGSLGAENIGKLAPVGVITYDRGNAWADRLKSGETLEINL 231
Cdd:cd00538    82 DPGPQMGSVGLESTDPSIPTVGISYADGEALLSLLEAGKTVTVDL 126

M28 Zn-peptidase; uncharacterized subfamily; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 245 IIADTK-EGDPNNIVMLGAHLDSVQEGPGINDNGSGVAALLSIAESIKQKSFKNKLRFAFWGAEE-----SGMIGSNYYV 318
Cdd:cd05640    55 LIADLPgSYSQDKLILIGAHYDTVPGSPGADDNASGVAALLELARLLATLDPNHTLRFVAFDLEEypffaRGLMGSHAYA 134

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 2101147568 319 SNLSKEEASnIRFYYNYDMIAslqpYYIVYSNSEAHKTGAQyLYEYLT 366
Cdd:cd05640   135 EDLLRPLTP-IVGMLSLEMIG----YYDPFPHSQAYPAGFE-LHFYPH 176

PA_C5a_like: Protease-associated domain containing proteins like Streptococcus pyogenes C5a peptidase. This group contains various PA domain-containing proteins similar to S. pyogenes C5a, including, i) Vpr, a minor extracellular serine protease from Bacillus subtilis, ii) a large molecular mass collagenolytic protease from Geobacillus collagenovorans MO-1, and iii) PrtS, a cell envelope protease from Streptococcus thermophilus CNRZ 385. Proteins in this group belong to the peptidase S8 family. C5a peptidase is a cell surface serine protease which specifically inactivates C5a [a chemotactic peptide, which attracts polymorphonuclear leukocytes (PMNs)], by cleaving it to release a 7-residue carboxy-terminal fragment which contains the PMN binding site. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568  99 TGPEGEKVDAVSLQYNHATPSPGGVTAPLVlipiddERGSGCFEDqWKGIDMKGKIALIKRGKCHFINKLKLAKDNGASA 178
Cdd:cd02133     2 TLTSGNETLKLMPAFSGNPTDLLGKTYELV------DAGLGTPED-FEGKDVKGKIALIQRGEITFVEKIANAKAAGAVG 74

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2101147568 179 AVVFNDNPAQTAGSGSLGAEnigklAPVGVITYDRGNAWADRLKSGETLEINLIIDVITEK 239
Cdd:cd02133    75 VIIYNNVDGLIPGTLGEAVF-----IPVVFISKEDGEALKAALESSKKLTFNTKKEKATNP 130

PA domain; The PA (Protease associated) domain is found as an insert domain in diverse proteases. The PA domain is also found in a plant vacuolar sorting receptor Swiss:O22925 and members of the RZF family Swiss:O43567. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 124 TAPLVLIPiddergsGCFEDQW--KGIDMKGKIALIKRGKCHFINKLKLAKDNGASAAVVFNDNPAQTAGSGSLGAENIG 201
Cdd:pfam02225   1 TGPLVLAP-------GCYAGDGipADFDVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPPGAGGNELYP 73

                          90
                  ....*....|....*...
gi 2101147568 202 KL--APVGVITYDRGNAW 217
Cdd:pfam02225  74 DGiyIPAVGVSRADGEAL 91

PA_subtilisin_1: Protease-associated domain containing subtilisin-like proteases, subgroup 1. A subgroup of PA domain-containing subtilisin-like proteases. The significance of the PA domain to many of the proteins in which it is inserted is undetermined. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate. Proteins into which the PA domain is inserted include the following subtilisin-like proteases: i) melon cucumisin, ii) Arabidopsis thaliana Ara12, iii) Alnus glutinosa ag12, iv) members of the tomato P69 family, and v) tomato LeSBT2. However, these proteins belong to other subtilisin-like subgroups. Relatively little is known about proteins in this subgroup.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 117 TPSPGGVTAPLVL-IPIDDERGSGCfEDQWKGIDMKGKIALIKRGKCHFINKLKLAKDNGASAAVVFN--DNPAQTAGSG 193
Cdd:cd04818     6 GPALTNVTADVVLaGAAPASNTDGC-TAFTNAAAFAGKIALIDRGTCNFTVKVLNAQNAGAIAVIVANnvAGGAPITMGG 84

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2101147568 194 SLGAENIgklaPVGVITYDRGNAWADRLKSGETLEINL 231
Cdd:cd04818    85 DDPDITI----PAVMISQADGDALKAALAAGGTVTVTL 118

Zinc peptidases M18, M20, M28, and M42; Zinc peptidases play vital roles in metabolic and signaling pathways throughout all kingdoms of life. This hierarchy contains zinc peptidases that correspond to the MH clan in the MEROPS database, which contains 4 families (M18, M20, M28, M42). The peptidase M20 family includes carboxypeptidases such as the glutamate carboxypeptidase from Pseudomonas, the thermostable carboxypeptidase Ss1 of broad specificity from archaea and yeast Gly-X carboxypeptidase. The dipeptidases include bacterial dipeptidase, peptidase V (PepV), a non-specific eukaryotic dipeptidase, and two Xaa-His dipeptidases (carnosinases). There is also the bacterial aminopeptidase, peptidase T (PepT) that acts only on tripeptide substrates and has therefore been termed a tripeptidase. Peptidase family M28 contains aminopeptidases and carboxypeptidases, and has co-catalytic zinc ions. However, several enzymes in this family utilize other first row transition metal ions such as cobalt and manganese. Each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Glutamate carboxypeptidase II and plasma glutamate carboxypeptidase hydrolyze dipeptides. Peptidase families M18 and M42 contain metallo-aminopeptidases. M18 is widely distributed in bacteria and eukaryotes. However, only yeast aminopeptidase I and mammalian aspartyl aminopeptidase have been characterized in detail. Some M42 (also known as glutamyl aminopeptidase) enzymes exhibit aminopeptidase specificity while others also have acylaminoacyl-peptidase activity (i.e. hydrolysis of acylated N-terminal residues).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 245 IIADTKEGDPNNIVMLGAHLDSVQEGPGIN---------------------DNGSGVAALLSIAESIKQKSFKNK--LRF 301
Cdd:cd03873     2 LIARLGGGEGGKSVALGAHLDVVPAGEGDNrdppfaedteeegrlygrgalDDKGGVAAALEALKRLKENGFKPKgtIVV 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 302 AFWGAEESGMIGSNYYVSNLSKEEASNIRFYYNYDMIASLQPYYIVYSNSEahktgaqyLYEYLTE-----HGYPAEYAP 376
Cdd:cd03873    82 AFTADEEVGSGGGKGLLSKFLLAEDLKVDAAFVIDATAGPILQKGVVIRNP--------LVDALRKaarevGGKPQRASV 153

                         170       180       190
                  ....*....|....*....|....*....|....
gi 2101147568 377 FGSSSDYIGFLELGIPSSGIftgaGPPQDVCYHT 410
Cdd:cd03873   154 IGGGTDGRLFAELGIPGVTL----GPPGDKGAHS 183

M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific membrane antigen (PSMA, also called glutamate carboxypeptidase II or GCP-II)-like subfamily. PSMA is a homodimeric type II transmembrane protein containing three distinct domains: protease-like, apical or protease-associated (PA) and helical domains. The protease-like domain is a large extracellular portion (ectodomain). PSMA is over-expressed predominantly in prostate cancer (PCa) as well as in the neovasculature of most solid tumors, but not in the vasculature of the normal tissues. PSMA is considered a biomarker for PCa and possibly for use as an imaging and therapeutic target. The extracellular domain of PSMA possesses two unique enzymatic functions: N-acetylated, alpha-linked acidic dipeptidase (NAALADase) which cleaves terminal glutamate from the neurodipeptide N-acetyl-aspartyl-glutamate (NAAG), and folate hydrolase (FOLH) which cleaves the terminal glutamates from gamma-linked polyglutamates (carboxypeptidase). A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. Inhibition of GCP-II has been shown to be effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 253 DPNNIVMLGAHLDSvqEGPGINDNGSGVAALLSIAESIKQKSfKNKLR------FAFWGAEESGMIGSNYYVsnlsKEEA 326
Cdd:cd08022    72 EPDEYIILGNHRDA--WVFGAGDPNSGTAVLLEVARALGTLL-KKGWRprrtiiFASWDAEEYGLIGSTEWV----EENA 144

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 327 SNIR----FYYNYDMI---------ASLQPYYIVYSNS---EAHKTGAQYLYEYLTEHGYPAEYAPFGSSSDYIGFLE-L 389
Cdd:cd08022   145 DWLQeravAYLNVDVAvsgstlraaGSPLLQNLLREAAkevQDPDEGATLKYLPSWWDDTGGEIGNLGSGSDYTPFLDhL 224

                         170       180
                  ....*....|....*....|....*.
gi 2101147568 390 GIPSSGIFTGAGPPQDV-CYHTACDD 414
Cdd:cd08022   225 GIASIDFGFSGGPTDPYpHYHSNYDS 250

M28 Zn-peptidase Aeromonas (Vibrio) proteolytica aminopeptidase; Peptidase family M28; Aeromonas (Vibrio) proteolytica aminopeptidase (AAP; leucine aminopeptidase from Vibrio proteolyticus; Bacterial leucyl aminopeptidase; E.C. 3.4.11.10) subfamily. AAP is a small (32kDa), heat stable leucine aminopeptidase and is active as a monomer. Similar forms of the enzyme have been isolated from Escherichia coli and Staphylococcus thermophilus. Leucine aminopeptidases, in general, play important roles in many biological processes such as protein catabolism, hormone degradation, regulation of migration and cell proliferation, as well as HIV infection and proliferation. AAP is a broad-specificity enzyme, utilizing two zinc(II) ions in its active site to remove N-terminal amino acids, with preference for large hydrophobic amino acids in the P1 position of the substrate, Leu being the most efficiently cleaved. It can accommodate all residues, except Pro, Asp and Glu in the P1' position.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 254 PNNIVMLGAHLDSVQEG-------PGINDNGSGVAALL----SIAESIKQKSfkNKLRFAFWGAEESGMIGSNYYVSNLS 322
Cdd:cd03879    87 SDEIVVIGAHQDSINGSnpsngraPGADDDGSGTVTILealrVLLESGFQPK--NTIEFHWYAAEEGGLLGSQAIATQYK 164

                          90
                  ....*....|....*..
gi 2101147568 323 KEEAsNIRFYYNYDMIA 339
Cdd:cd03879   165 SEGK-NVKAMLQLDMTG 180

PA _GRAIL_like: Protease-associated (PA) domain GRAIL-like. This group includes PA domain containing E3 (ubiquitin ligases) similar to human GRAIL (gene related to anergy in lymphocytes) protein. Proteins in this group contain a C3H2C3 RING finger. E3 ubiquitin ligase is part of an enzymic cascade, the end result of which is the ubiquitination of proteins. In this cascade, E1 activates the ubiquitin, the activated ubiquitin is carried by E2, and E3 recognizes the acceptor protein as well as catalyzes the transfer of the activated ubiquitin from E2 to this acceptor. GRAIL, a transmembrane protein localized in the endosomes, controls the development of T cell clonal anergy, and may ubiquitinate membrane-associated targets for T cell activation. GRAIL1 is associated with, and regulated by, two isoforms of otubain 1 (the ubiquitin-specific protease). Additional E3s belonging to this group include human (h)Goliath and Xenopus GREUL1 (Goliath Related E3 Ubiquitin Ligase 1). hGoliath and GRAIL both have the property of self-ubiquitination. hGoliath is expressed in leukocytes; its expression and localization is not modified in leukemia. GREUL1 may play a role in the generation of anterior ectoderm. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2101147568 154 IALIKRGKCHFINKLKLAKDNGASAAVVFNDNPA--QTAGSGSLGAENIgklapVGV-ITYDRGNAWADRLKSG 224
Cdd:cd02122    63 IALIQRGNCTFEEKIKLAAERNASAVVIYNNPGTgnETVKMSHPGTGDI-----VAImITNPKGMEILELLERG 131

Peptidase family M20/M25/M40; This family includes a range of zinc metallopeptidases belonging to several families in the peptidase classification. Family M20 are Glutamate carboxypeptidases. Peptidase family M25 contains X-His dipeptidases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 259 MLGAHLDSVQE-----------------GPGINDNGSGVAALLSIAESIKQKSFKNK-LRFAFWGAEESGMIGSNYYVSN 320
Cdd:pfam01546   1 LLRGHMDVVPDeetwgwpfkstedgklyGRGHDDMKGGLLAALEALRALKEEGLKKGtVKLLFQPDEEGGMGGARALIED 80

                          90
                  ....*....|...
gi 2101147568 321 LsKEEASNIRFYY 333
Cdd:pfam01546  81 G-LLEREKVDAVF 92

alkaline phosphatase isozyme conversion aminopeptidase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2101147568 239 KRETWQ------IIAdTKEGD-PNNIVMLgAHLDS-----------------VQegpGINDNGSGVAALLSIAESIKQKS 294
Cdd:PRK10199   88 NRKNWHnvtgstVIA-AHEGKaPQQIIIM-AHLDTyapqsdadvdanlggltLQ---GMDDNAAGLGVMLELAERLKNVP 162

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2101147568 295 FKNKLRFAFWGAEESGMIGSNYYVSNLSKEEASNIRFYYNYD 336
Cdd:PRK10199  163 TEYGIRFVATSGEEEGKLGAENLLKRMSDTEKKNTLLVINLD 204

PA_GO-like: Protease-associated domain containing proteins like Arabidopsis thaliana growth-on protein GRO10. This group contains various PA domain-containing proteins similar to the functionally uncharacterized Arabidopsis GRO10. The PA domain may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.