Gluzincin Peptidase family (thermolysin-like proteinases, TLPs) which includes peptidases M1, M2, M3, M4, M13, M32 and M36 (fungalysins); The Gluzincin family (thermolysin-like peptidases or TLPs) includes several zinc-dependent metallopeptidases such as M1, M2, M3, M4, M13, M32, M36 peptidases (MEROPS classification), which contain the HEXXH motif as part of their active site. Peptidases in this family bind a single catalytic zinc ion which is tetrahedrally co-ordinated by three amino acid ligands and a water molecule that forms the nucleophile on activation during catalysis. The M1 family includes aminopeptidase N (APN) and leukotriene A4 hydrolase (LTA4H). APN preferentially cleaves neutral amino acids from the N-terminus of oligopeptides and is present in a variety of human tissues and cell types. LTA4H is a bifunctional enzyme, possessing an aminopeptidase as well as an epoxide hydrolase activity such that the two activities occupy different, but overlapping sites. The M3_like peptidases include the M2_ACE, M3 or neurolysin-like family (subfamilies M3B_PepF and M3A) and M32_Taq peptidases. The M2 peptidase angiotensin converting enzyme (ACE, EC 3.4.15.1) catalyzes the conversion of decapeptide angiotensin I to the potent vasopressor octapeptide angiotensin II. ACE is a key component of the renin-angiotensin system that regulates blood pressure, thus ACE inhibitors are important for the treatment of hypertension. M3A includes thimet oligopeptidase (TOP; endopeptidase 3.4.24.15), neurolysin (3.4.24.16), and the mitochondrial intermediate peptidase; and M3B includes oligopeptidase F. The M32 family includes eukaryotic enzymes from protozoa Trypanosoma cruzi, a causative agent of Chagas' disease, and from Leishmania major, a parasite that causes leishmaniasis, making these enzymes attractive targets for drug development. The M4 family includes secreted protease thermolysin (EC 3.4.24.27), pseudolysin, aureolysin, and neutral protease as well as bacillolysin (EC 3.4.24.28) that degrade extracellular proteins and peptides for bacterial nutrition, especially prior to sporulation. Thermolysin is widely used as a nonspecific protease to obtain fragments for peptide sequencing as well as in production of the artificial sweetener aspartame. The M13 family includes neprilysin (EC 3.4.24.11) and endothelin-converting enzyme I (ECE-1, EC 3.4.24.71), which fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity and are prime therapeutic targets for selective inhibition. The peptidase M36 fungalysin family includes endopeptidases from pathogenic fungi. Fungalysin hydrolyzes extracellular matrix proteins such as elastin and keratin. Aspergillus fumigatus causes the pulmonary disease aspergillosis by invading the lungs of immuno-compromised animals and secreting fungalysin that possibly breaks down proteinaceous structural barriers.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 244 IRIWYKTKPEGRSVTW-----TSDQSgRPCVYTVGSPINNRALFPCQEPPVAMSTWQATVRAAASFVVLMSGENSAKPtq 318
Cdd:cd09599    98 VKIEYSTTPQATALQWltpeqTAGKK-HPYLFTQCQAIHARSLFPCQDTPSVKSTYSATVTVPKGLTALMSALRTGEK-- 174

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 319 lwEECSSWYYYVTM--PMPASTFTIAVGcwtemkmetwssnDLAtERPFSPseanfrHVGVCShmEypcrfqnasattqe 396
Cdd:cd09599   175 --EEAGTGTYTFEQpvPIPSYLIAIAVG-------------DLE-SREIGP------RSGVWA--E-------------- 216

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1886308758 397 iiPHRVfapvcltgACQETLLRLIPPCLSAAHSVLGAHPFSRLDVLIVPANFPSLGM 453
Cdd:cd09599   217 --PSVV--------DAAAEEFADTEKFLKAAEKLYGPYVWGRYDLLVLPPSFPYGGM 263

Peptidase M1 family including Leukotriene A4 hydrolase catalytic domain; This model represents the N-terminal catalytic domain of leukotriene A4 hydrolase (LTA4H; E.C. 3.3.2.6) and the close homolog cold-active aminopeptidase (Colwellia psychrerythraea-type peptidase; ColAP), both members of the aminopeptidase M1 family. LTA4H is a bifunctional enzyme, possessing an aminopeptidase as well as an epoxide hydrolase activity. The two activities occupy different, but overlapping sites. The activity and physiological relevance of the aminopeptidase is poorly understood while the epoxide hydrolase converts leukotriene A4 (LTA4) into leukotriene B4 (LTB4), a potent chemotaxin that is fundamental to the inflammatory response of mammals. It accepts a variety of substrates, including some opioid, di- and tripeptides, as well as chromogenic aminoacyl-p-nitroanilide derivatives. The aminopeptidase activity of LTA4H is possibly involved in the processing of peptides related to inflammation and host defense. Kinetic analysis shows that LTA4H hydrolyzes arginyl tripeptides with high efficiency and specificity, indicating its function as an arginyl aminopeptidase. Thermodynamic characterization using different biophysical methods shows that structurally distinct inhibitors of the LTA4H occupy different regions of the binding site; while some (RB202, ARM1 and SC57461A) bind to the hydrophobic hydrolase side, both bestatin and captopril are located at the hydrophilic peptidase side. LTB4H overexpression is associated with different pathological conditions and diseases such as cystic fibrosis, coronary heart disease, sepsis, shock, connective tissue disease, and chronic obstructive pulmonary disease. It is also overexpressed in certain human cancers, and has been identified as a functionally important target for mediating anticancer properties of resveratrol, a well-known red wine polyphenolic compound with cancer chemopreventive activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 244 IRIWYKTKPEGRSVTW-----TSDQSgRPCVYTVGSPINNRALFPCQEPPVAMSTWQATVRAAASFVVLMSGENSAKPtq 318
Cdd:cd09599    98 VKIEYSTTPQATALQWltpeqTAGKK-HPYLFTQCQAIHARSLFPCQDTPSVKSTYSATVTVPKGLTALMSALRTGEK-- 174

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 319 lwEECSSWYYYVTM--PMPASTFTIAVGcwtemkmetwssnDLAtERPFSPseanfrHVGVCShmEypcrfqnasattqe 396
Cdd:cd09599   175 --EEAGTGTYTFEQpvPIPSYLIAIAVG-------------DLE-SREIGP------RSGVWA--E-------------- 216

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1886308758 397 iiPHRVfapvcltgACQETLLRLIPPCLSAAHSVLGAHPFSRLDVLIVPANFPSLGM 453
Cdd:cd09599   217 --PSVV--------DAAAEEFADTEKFLKAAEKLYGPYVWGRYDLLVLPPSFPYGGM 263

Aminopeptidase N, contains DUF3458 domain [Amino acid transport and metabolism];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 217 ELLFDTDTWSLQIRKTGAQTATDfPHAIRIWYKTKPEGRSVTW---TSDQSGRPCVYTVGSPINNRALFPCQEPPVAMST 293
Cdd:COG0308    69 PLDFTRDGERLTITLPKPLAPGE-TFTLEIEYSGKPSNGGEGLyrsGDPPDGPPYLYTQCEPEGARRWFPCFDHPDDKAT 147

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 294 WQATVRAAASFVVLMSGeNSAKPTQLWEECSSWYYYVTMPMPASTFTIAVGcwtemkmetwssndlaterpfspseanfr 373
Cdd:COG0308   148 FTLTVTVPAGWVAVSNG-NLVSETELGDGRTTWHWADTQPIPTYLFALAAG----------------------------- 197

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 374 hvgvcshmeypcRFQNASATTQEIIPHRVFAPVCLTGACQETLLRLiPPCLSAAHSVLG-AHPFSRLDVLIVPaNFPSLG 452
Cdd:COG0308   198 ------------DYAVVEDTFASGVPLRVYVRPGLADKAKEAFEST-KRMLDFFEELFGvPYPFDKYDQVAVP-DFNFGA 263

                  .
gi 1886308758 453 M 453
Cdd:COG0308   264 M 264

Peptidase M1 family including Leukotriene A4 hydrolase catalytic domain; This model represents the N-terminal catalytic domain of leukotriene A4 hydrolase (LTA4H; E.C. 3.3.2.6) and the close homolog cold-active aminopeptidase (Colwellia psychrerythraea-type peptidase; ColAP), both members of the aminopeptidase M1 family. LTA4H is a bifunctional enzyme, possessing an aminopeptidase as well as an epoxide hydrolase activity. The two activities occupy different, but overlapping sites. The activity and physiological relevance of the aminopeptidase is poorly understood while the epoxide hydrolase converts leukotriene A4 (LTA4) into leukotriene B4 (LTB4), a potent chemotaxin that is fundamental to the inflammatory response of mammals. It accepts a variety of substrates, including some opioid, di- and tripeptides, as well as chromogenic aminoacyl-p-nitroanilide derivatives. The aminopeptidase activity of LTA4H is possibly involved in the processing of peptides related to inflammation and host defense. Kinetic analysis shows that LTA4H hydrolyzes arginyl tripeptides with high efficiency and specificity, indicating its function as an arginyl aminopeptidase. Thermodynamic characterization using different biophysical methods shows that structurally distinct inhibitors of the LTA4H occupy different regions of the binding site; while some (RB202, ARM1 and SC57461A) bind to the hydrophobic hydrolase side, both bestatin and captopril are located at the hydrophilic peptidase side. LTB4H overexpression is associated with different pathological conditions and diseases such as cystic fibrosis, coronary heart disease, sepsis, shock, connective tissue disease, and chronic obstructive pulmonary disease. It is also overexpressed in certain human cancers, and has been identified as a functionally important target for mediating anticancer properties of resveratrol, a well-known red wine polyphenolic compound with cancer chemopreventive activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 244 IRIWYKTKPEGRSVTW-----TSDQSgRPCVYTVGSPINNRALFPCQEPPVAMSTWQATVRAAASFVVLMSGENSAKPtq 318
Cdd:cd09599    98 VKIEYSTTPQATALQWltpeqTAGKK-HPYLFTQCQAIHARSLFPCQDTPSVKSTYSATVTVPKGLTALMSALRTGEK-- 174

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 319 lwEECSSWYYYVTM--PMPASTFTIAVGcwtemkmetwssnDLAtERPFSPseanfrHVGVCShmEypcrfqnasattqe 396
Cdd:cd09599   175 --EEAGTGTYTFEQpvPIPSYLIAIAVG-------------DLE-SREIGP------RSGVWA--E-------------- 216

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1886308758 397 iiPHRVfapvcltgACQETLLRLIPPCLSAAHSVLGAHPFSRLDVLIVPANFPSLGM 453
Cdd:cd09599   217 --PSVV--------DAAAEEFADTEKFLKAAEKLYGPYVWGRYDLLVLPPSFPYGGM 263

Aminopeptidase N, contains DUF3458 domain [Amino acid transport and metabolism];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 217 ELLFDTDTWSLQIRKTGAQTATDfPHAIRIWYKTKPEGRSVTW---TSDQSGRPCVYTVGSPINNRALFPCQEPPVAMST 293
Cdd:COG0308    69 PLDFTRDGERLTITLPKPLAPGE-TFTLEIEYSGKPSNGGEGLyrsGDPPDGPPYLYTQCEPEGARRWFPCFDHPDDKAT 147

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 294 WQATVRAAASFVVLMSGeNSAKPTQLWEECSSWYYYVTMPMPASTFTIAVGcwtemkmetwssndlaterpfspseanfr 373
Cdd:COG0308   148 FTLTVTVPAGWVAVSNG-NLVSETELGDGRTTWHWADTQPIPTYLFALAAG----------------------------- 197

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886308758 374 hvgvcshmeypcRFQNASATTQEIIPHRVFAPVCLTGACQETLLRLiPPCLSAAHSVLG-AHPFSRLDVLIVPaNFPSLG 452
Cdd:COG0308   198 ------------DYAVVEDTFASGVPLRVYVRPGLADKAKEAFEST-KRMLDFFEELFGvPYPFDKYDQVAVP-DFNFGA 263

                  .
gi 1886308758 453 M 453
Cdd:COG0308   264 M 264