Peptidase M14 Aspartoacylase (ASPA) subfamily; Aspartoacylase (ASPA) belongs to the Succinylglutamate desuccinylase/aspartoacylase subfamily of the M14 family of metallocarboxypeptidases. ASPA (also known as aminoacylase 2; EC:3.5.1.15) cleaves N-acetyl L-aspartic acid (NAA) into aspartate and acetate. NAA is abundant in the brain, and hydrolysis of NAA by ASPA may help maintain white matter. ASPA is an NAA scavenger in other tissues. Mutations in the gene encoding ASPA cause Canavan disease (CD), a fatal progressive neurodegenerative disorder involving dysmyelination and spongiform degeneration of white matter in children. This enzyme binds zinc which is necessary for activity. Measurement of elevated NAA levels in urine is used in the diagnosis of CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  11 KKIAIFGGTHGNELTGVFLVTHWLRNGTEVHRAGLDVKPFITNPRAVEKCTRYIDCDLNRVFDLENLSKEmSEDLPYEVR 90
Cdd:cd06909    1 KRVAIVGGTHGNELTGVYLVKHWLKNPELIERKSFEVHPLLANPRAVEQCRRYIDTDLNRCFSLENLSSA-PSSLPYEVR 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  91 RAQEINHLFGPKNsDDAYDLVFDLHNTTSNMGCTLILEDSRnDFLIQMFHYIKTCMapLPCSVYLIEHPSLKYATTRSIA 170
Cdd:cd06909   80 RAREINQILGPKG-NPACDFIIDLHNTTSNMGITLILSSSD-DFTLKLAAYLQQRL--PPVRVLLHESPSKESPFLRSVA 155

                        170       180
                 ....*....|....*....|....*..
gi 755537112 171 KYPVGKEFPPCS-----IDVYKIMEKV 192
Cdd:cd06909  156 KHGFTIEVGPVPqgvlrADIFEQTRKL 182

Succinylglutamate desuccinylase [Amino acid transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  10 IKKIAIFGGTHGNELTGVFLVTHWLRNGTEVHRA-GLDVKPFITNPRAVEKCTRYIDCDLNRVFDLENLSKEMSedlpYE 88
Cdd:COG2988   24 IKAVVISGGIHGNETAPIELLDKLLQDLLLGERPlSFRLLLILGNPAAMRAGRRYLDEDLNRLFGGRHLQNPES----YE 99

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  89 VRRAQEINHLFGPK-NSDDAYDLVFDLHNTTSNMGCTLI--LEDSRNDFLIQMFHYIKTCM--APL----PCSV---YLI 156
Cdd:COG2988  100 AARAKELEQAVGPFfAAGGRVRLHIDLHTAIRNSGHERFavYPFRGRPFDLALLAYLAAAGpeAVVlhhaPGGTfshFSA 179

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112 157 EH--------------------PSLKYATTRSIAKYPVGKEFPPCS---IDVYKIMEKVDyprnESGDmAAVIHPNLQDQ 213
Cdd:COG2988  180 ELcgaqaftlelgkvrpfgqndLSRFAATEEALRALLSGAELPEHPaqdLDLYRVVQQII----KHGD-DFMLHPDLDTL 254

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|.
gi 755537112 214 DWKPLHPGDPVFvSLDGKVIPLGGDcTVYPVFVNEAAYYEK 254
Cdd:COG2988  255 NFTPLPPGTLLA-EDGGKEYRVEGD-EERIVFPNEAVYYGQ 293

Peptidase M14 Aspartoacylase (ASPA) subfamily; Aspartoacylase (ASPA) belongs to the Succinylglutamate desuccinylase/aspartoacylase subfamily of the M14 family of metallocarboxypeptidases. ASPA (also known as aminoacylase 2; EC:3.5.1.15) cleaves N-acetyl L-aspartic acid (NAA) into aspartate and acetate. NAA is abundant in the brain, and hydrolysis of NAA by ASPA may help maintain white matter. ASPA is an NAA scavenger in other tissues. Mutations in the gene encoding ASPA cause Canavan disease (CD), a fatal progressive neurodegenerative disorder involving dysmyelination and spongiform degeneration of white matter in children. This enzyme binds zinc which is necessary for activity. Measurement of elevated NAA levels in urine is used in the diagnosis of CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  11 KKIAIFGGTHGNELTGVFLVTHWLRNGTEVHRAGLDVKPFITNPRAVEKCTRYIDCDLNRVFDLENLSKEmSEDLPYEVR 90
Cdd:cd06909    1 KRVAIVGGTHGNELTGVYLVKHWLKNPELIERKSFEVHPLLANPRAVEQCRRYIDTDLNRCFSLENLSSA-PSSLPYEVR 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  91 RAQEINHLFGPKNsDDAYDLVFDLHNTTSNMGCTLILEDSRnDFLIQMFHYIKTCMapLPCSVYLIEHPSLKYATTRSIA 170
Cdd:cd06909   80 RAREINQILGPKG-NPACDFIIDLHNTTSNMGITLILSSSD-DFTLKLAAYLQQRL--PPVRVLLHESPSKESPFLRSVA 155

                        170       180
                 ....*....|....*....|....*..
gi 755537112 171 KYPVGKEFPPCS-----IDVYKIMEKV 192
Cdd:cd06909  156 KHGFTIEVGPVPqgvlrADIFEQTRKL 182

Succinylglutamate desuccinylase [Amino acid transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  10 IKKIAIFGGTHGNELTGVFLVTHWLRNGTEVHRA-GLDVKPFITNPRAVEKCTRYIDCDLNRVFDLENLSKEMSedlpYE 88
Cdd:COG2988   24 IKAVVISGGIHGNETAPIELLDKLLQDLLLGERPlSFRLLLILGNPAAMRAGRRYLDEDLNRLFGGRHLQNPES----YE 99

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  89 VRRAQEINHLFGPK-NSDDAYDLVFDLHNTTSNMGCTLI--LEDSRNDFLIQMFHYIKTCM--APL----PCSV---YLI 156
Cdd:COG2988  100 AARAKELEQAVGPFfAAGGRVRLHIDLHTAIRNSGHERFavYPFRGRPFDLALLAYLAAAGpeAVVlhhaPGGTfshFSA 179

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112 157 EH--------------------PSLKYATTRSIAKYPVGKEFPPCS---IDVYKIMEKVDyprnESGDmAAVIHPNLQDQ 213
Cdd:COG2988  180 ELcgaqaftlelgkvrpfgqndLSRFAATEEALRALLSGAELPEHPaqdLDLYRVVQQII----KHGD-DFMLHPDLDTL 254

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|.
gi 755537112 214 DWKPLHPGDPVFvSLDGKVIPLGGDcTVYPVFVNEAAYYEK 254
Cdd:COG2988  255 NFTPLPPGTLLA-EDGGKEYRVEGD-EERIVFPNEAVYYGQ 293

Succinylglutamate desuccinylase/aspartoacylase; uncharacterized; A functionally uncharacterized subgroup of the Succinylglutamate desuccinylase (ASTE)/aspartoacylase (ASPA) subfamily which is part of the M14 family of metallocarboxypeptidases. ASTE catalyzes the fifth and last step in arginine catabolism by the arginine succinyltransferase pathway, and aspartoacylase (ASPA, also known as aminoacylase 2, and ACY-2; EC:3.5.1.15) cleaves N-acetyl L-aspartic acid (NAA) into aspartate and acetate. NAA is abundant in the brain, and hydrolysis of NAA by ASPA may help maintain white matter. ASPA is an NAA scavenger in other tissues. Mutations in the gene encoding ASPA cause Canavan disease (CD), a fatal progressive neurodegenerative disorder involving dysmyelination and spongiform degeneration of white matter in children. This enzyme binds zinc which is necessary for activity. Measurement of elevated NAA levels in urine is used in the diagnosis of CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  13 IAIFGGTHGNELTGVF--------LVTHWLRNGTevhragldVKPFITNPRAVEKCTRYIDCDLNRVFDLENLSKEmsed 84
Cdd:cd18430    1 LAVLGAVHGNETCGTRaverllaeLPSGALQKGP--------VTLVPANERAYAEGVRFCEEDLNRVFPGDPDPDT---- 68

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 755537112  85 lpYEVRRAQEINHLFgpknsdDAYDLVFDLHNTTSNmGCTLILEDSRND 133
Cdd:cd18430   69 --YERRLANRLCPEL------EGHDVVLDLHSTHSG-GQPFAILDYGDK 108

Peptidase M14-like domain similar to rapid encystment phenotype 34 (REP34); This family includes Francisella tularensis protein rapid encystment phenotype 34 (REP34) which is a zinc-containing monomeric protein demonstrating carboxypeptidase B-like activity. REP34 possesses a novel topology with its substrate binding pocket deviating from the canonical M14 peptidases with a possible catalytic role for a conserved tyrosine and distinct S1' recognition site. Thus, REP34, identified as an active carboxypeptidase and a potential key F. tularensis effector protein, may help elucidate a mechanistic understanding of F. tularensis infection of phagocytic cells. A functionally uncharacterized subgroup of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding carboxypeptidases (CPs) which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Two major subfamilies of the M14 family, defined based on sequence and structural homology, are the A/B and N/E subfamilies. Enzymes belonging to the A/B subfamily are normally synthesized as inactive precursors containing preceding signal peptide, followed by an N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The A/B enzymes can be further divided based on their substrate specificity; Carboxypeptidase A-like (CPA-like) enzymes favor hydrophobic residues while carboxypeptidase B-like (CPB-like) enzymes only cleave the basic residues lysine or arginine. The A forms have slightly different specificities, with Carboxypeptidase A1 (CPA1) preferring aliphatic and small aromatic residues, and CPA2 preferring the bulky aromatic side chains. Enzymes belonging to the N/E subfamily enzymes are not produced as inactive precursors and instead rely on their substrate specificity and subcellular compartmentalization to prevent inappropriate cleavages. They contain an extra C-terminal transthyretin-like domain, thought to be involved in folding or formation of oligomers. MCPs can also be classified based on their involvement in specific physiological processes; the pancreatic MCPs participate only in alimentary digestion and include carboxypeptidase A and B (A/B subfamily), while others, namely regulatory MCPs or the N/E subfamily, are involved in more selective reactions, mainly in non-digestive tissues and fluids, acting on blood coagulation/fibrinolysis, inflammation and local anaphylaxis, pro-hormone and neuropeptide processing, cellular response and others. Another MCP subfamily, is that of succinylglutamate desuccinylase /aspartoacylase, which hydrolyzes N-acetyl-L-aspartate (NAA), and deficiency in which is the established cause of Canavan disease. Another subfamily (referred to as subfamily C) includes an exceptional type of activity in the MCP family, that of dipeptidyl-peptidase activity of gamma-glutamyl-(L)-meso-diaminopimelate peptidase I which is involved in bacterial cell wall metabolism.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  11 KKIAIFGGTHGNELTGVFLVTHWLRNGTE--VHRAGLDVKPFItNPRAVEKCTRYIDC--DLNRVFDLENLSKEmsedlp 86
Cdd:cd06231   43 PRVLISAGIHGDEPAGVEALLRFLESLAEkyLRRVNLLVLPCV-NPWGFERNTRENADgiDLNRSFLKDSPSPE------ 115

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  87 yevRRAQeINHLFgpknSDDAYDLVFDLHnttsnmgctlilEDSRNDfliqmfhyiktcmaplpcSVYLiehpslkYATT 166
Cdd:cd06231  116 ---VRAL-MEFLA----SLGRFDLHLDLH------------EDWDSD------------------GFYL-------YELG 150

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 755537112 167 RSIAKYPVGKEFPPCSIDVYKIMEKVDYPRNESGdmaaVIHPnlqdQDWKPLHPGDP 223
Cdd:cd06231  151 PALKAGRDGLQAVDAVIPPDPISLTIDGSPAPDG----VILR----PDDPAERPGWP 199

Peptidase M14 carboxypeptidase Csd4 and similar proteins; This family includes peptidase M14 carboxypeptidase Csd4 from H. pylori which has been shown to be DL-carboxypeptidase with a modified zinc binding site containing a glutamine residue in place of a conserved histidine. It is an archetype of a new carboxypeptidase subfamily with a domain arrangement that differs from this family of peptide-cleaving enzymes. Csd4 plays a role in trimming uncrosslinked peptidoglycan peptide chains by cleaving the amide bond between meso-diaminopimelate and iso-D-glutamic acid in truncated peptidoglycan side chains. It acts as a cell shape determinant, similar to Campylobacter jejuni Pgp1. The M14 family of metallocarboxypeptidases (MCPs), also known as funnelins, are zinc-binding carboxypeptidases (CPs) which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Two major subfamilies of the M14 family, defined based on sequence and structural homology, are the A/B and N/E subfamilies. Enzymes belonging to the A/B subfamily are normally synthesized as inactive precursors containing preceding signal peptide, followed by an N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The A/B enzymes can be further divided based on their substrate specificity; Carboxypeptidase A-like (CPA-like) enzymes favor hydrophobic residues while carboxypeptidase B-like (CPB-like) enzymes only cleave the basic residues lysine or arginine. The A forms have slightly different specificities, with Carboxypeptidase A1 (CPA1) preferring aliphatic and small aromatic residues, and CPA2 preferring the bulky aromatic side chains. Enzymes belonging to the N/E subfamily enzymes are not produced as inactive precursors and instead rely on their substrate specificity and subcellular compartmentalization to prevent inappropriate cleavage. They contain an extra C-terminal transthyretin-like domain, thought to be involved in folding or formation of oligomers. MCPs can also be classified based on their involvement in specific physiological processes; the pancreatic MCPs participate only in alimentary digestion and include carboxypeptidase A and B (A/B subfamily), while others, namely regulatory MCPs or the N/E subfamily, are involved in more selective reactions, mainly in non-digestive tissues and fluids, acting on blood coagulation/fibrinolysis, inflammation and local anaphylaxis, pro-hormone and neuropeptide processing, cellular response and others. Another MCP subfamily, is that of succinylglutamate desuccinylase /aspartoacylase, which hydrolyzes N-acetyl-L-aspartate (NAA), and deficiency in which is the established cause of Canavan disease. Another subfamily (referred to as subfamily C) includes an exceptional type of activity in the MCP family, that of dipeptidyl-peptidase activity of gamma-glutamyl-(L)-meso-diaminopimelate peptidase I which is involved in bacterial cell wall metabolism.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112   7 KEPIKKIAIFGGTHGNE----LTGVFLVTHWLRNGTevhragLDVKPFItNPRAVEKCTRYIDCDLNRVFDLENLSKems 82
Cdd:cd06243   13 REPGPTLLIIGGIQGDEpggfLAADLLADLYLVKGN------VIVVPRL-NFPSILRNHRGLNGDMNRKFAALDKKD--- 82

                         90       100       110
                 ....*....|....*....|....*....|...
gi 755537112  83 edlpYEVRRAQEINHLFGPKNSddayDLVFDLH 115
Cdd:cd06243   83 ----PEYKTIQEIKSLIADFRP----DVVLHLH 107

Peptidase M14 Succinylglutamate desuccinylase (ASTE) subfamily; Peptidase M14 Succinylglutamate desuccinylase (ASTE, also known as N-succinyl-L-glutamate amidohydrolase, N2-succinylglutamate desuccinylase, and SGDS; EC 3.5.1.96) belongs to the Succinylglutamate desuccinylase (ASTE)/aspartoacylase (ASPA) subfamily of the M14 family of metallocarboxypeptidases. This group includes succinylglutamate desuccinylase that catalyzes the fifth and last step in arginine catabolism by the arginine succinyltransferase pathway. It hydrolyzes N-succinyl-L-glutamate to succinate and L-glutamate.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  18 GTHGNELTGVFLVTHWLRNgteVHRAGLDVKP---FI-TNPRAVEKCTRYIDCDLNRVFDLENLSKEMSedlpYEVRRAQ 93
Cdd:cd03855   51 GIHGNETAPIEILDQLIND---LIRGELALAHrllFIfGNPPAIRQGKRFIEENLNRLFSGRHSKLPPS----YETARAA 123

                         90       100
                 ....*....|....*....|....*....
gi 755537112  94 EI----NHLFgpknsDDAYDLV---FDLH 115
Cdd:cd03855  124 ELeqavADFF-----AKASGEVrwhLDLH 147

Peptidase M14 Succinylglutamate desuccinylase (ASTE)/aspartoacylase (ASPA)-like; uncharacterized subgroup; A functionally uncharacterized subgroup of the Succinylglutamate desuccinylase (ASTE)/aspartoacylase (ASPA) subfamily which is part of the M14 family of metallocarboxypeptidases. ASTE catalyzes the fifth and last step in arginine catabolism by the arginine succinyltransferase pathway, and aspartoacylase (ASPA, also known as aminoacylase 2, and ACY-2; EC:3.5.1.15) cleaves N-acetyl L-aspartic acid (NAA) into aspartate and acetate. NAA is abundant in the brain, and hydrolysis of NAA by ASPA may help maintain white matter. ASPA is an NAA scavenger in other tissues. Mutations in the gene encoding ASPA cause Canavan disease (CD), a fatal progressive neurodegenerative disorder involving dysmyelination and spongiform degeneration of white matter in children. This enzyme binds zinc which is necessary for activity. Measurement of elevated NAA levels in urine is used in the diagnosis of CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  20 HGNELTGVFLVTHWLRNGTEvhRAGLDVKPFITNPRAVEKCTRYID--CDLNRVFDlenlskemSEDLPYEVRRAQEINH 97
Cdd:cd06256   44 HGNEPTGLRAVQRLLKTGQA--PLPRTLLLFIGNVDAAKAGVRRLPgqPDYNRCWP--------GPFETPEGRLAAAVLE 113

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 755537112  98 LF---GPknsddayDLVFDLHNTTSN---MGCtLILEDSRNDFLIQMF 139
Cdd:cd06256  114 RLdtlRP-------FASIDIHNNTGKnphYAC-VNRLDAAHLRLASLF 153

succinylglutamate desuccinylase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755537112  18 GTHGNELTGVFLVTHWLR---NGTEVHRAGLDVkpFITNPRAVEKCTRYIDCDLNRVFDlenlSKEMSEDLPYEVRRAQE 94
Cdd:PRK05324  55 GIHGNETAPIELLDQLVRdllAGELPLRARLLV--ILGNPPAMRAGKRYLDEDLNRLFG----GRHQQFPGSDEARRAAE 128

                         90       100
                 ....*....|....*....|....*
gi 755537112  95 INHL----FgpKNSDDAYDLVFDLH 115
Cdd:PRK05324 129 LEQAvedfF--AAGAERVRWHYDLH 151