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 983616486   1 MPPSFPFGGMENPCLTFVTPCLLAGDRSLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQRRISTILFGAAYTCL 80
Cdd:cd09599  254 LPPSFPYGGMENPCLTFATPTLIAGDRSLVDVIAHEIAHSWSGNLVTNANWEHFWLNEGFTVYLERRILERLYGEEYRQF 333

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486  81 EAATGRALLRQHMDITGEENPLNKLrVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGdQDQFDSFLKAYVHEFKFRSI 160
Cdd:cd09599  334 EAILGWKDLQESIKEFGEDPPYTLL-VPDLKGVDPDDAFSSVPYEKGFQFLYYLEQLGG-REVFDPFLRAYFKKFAFQSI 411

                        170       180       190
                 ....*....|....*....|....*....|....
gi 983616486 161 LADDFLDFYLEYFPELKKkrvDIIPGFEFDRWLN 194
Cdd:cd09599  412 DTEDFKDFLLEYFAEDKP---EILDKIDWDAWLY 442

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 983616486   1 MPPSFPFGGMENPCLTFVTPCLLAGDRSLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQRRISTILFGAAYTCL 80
Cdd:cd09599  254 LPPSFPYGGMENPCLTFATPTLIAGDRSLVDVIAHEIAHSWSGNLVTNANWEHFWLNEGFTVYLERRILERLYGEEYRQF 333

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486  81 EAATGRALLRQHMDITGEENPLNKLrVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGdQDQFDSFLKAYVHEFKFRSI 160
Cdd:cd09599  334 EAILGWKDLQESIKEFGEDPPYTLL-VPDLKGVDPDDAFSSVPYEKGFQFLYYLEQLGG-REVFDPFLRAYFKKFAFQSI 411

                        170       180       190
                 ....*....|....*....|....*....|....
gi 983616486 161 LADDFLDFYLEYFPELKKkrvDIIPGFEFDRWLN 194
Cdd:cd09599  412 DTEDFKDFLLEYFAEDKP---EILDKIDWDAWLY 442

Peptidase family M1 domain; Members of this family are aminopeptidases. The members differ widely in specificity, hydrolysing acidic, basic or neutral N-terminal residues. This family includes leukotriene-A4 hydrolase, this enzyme also has an aminopeptidase activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486    3 PSFPFGGMENPCLTFVTPCLLAGD---------RSLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQRRISTILF 73
Cdd:pfam01433  32 PDFSAGAMENWGLITYRETLLLYDpgnsstsdkQRVASVIAHELAHQWFGNLVTMKWWDDLWLNEGFATYMEYLGTDALF 111

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486   74 GAAYTCLEAATGRALLRQHMDITGEENPLNklrVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGDqDQFDSFLKAYVH 153
Cdd:pfam01433 112 PEWNIWEQFLLDEVQNAMARDALDSSHPIT---QNVNDPSEIDDIFDAIPYEKGASVLRMLETLLGE-EVFQKGLRSYLK 187

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 983616486  154 EFKFRSILADDFLDFYLEYfpeLKKKRVDIIpgfeFDRW 192
Cdd:pfam01433 188 KFQYGNATTEDLWDALSEA---SGPLDVDSF----MDTW 219

Leukotriene A4 hydrolase, C-terminal; Members of this family adopt a structure consisting of two layers of parallel alpha-helices, five in the inner layer and four in the outer, arranged in an antiparallel manner, with perpendicular loops containing short helical segments on top. They are required for the formation of a deep cleft harbouring the catalytic Zn2+ site in Leukotriene A4 hydrolase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486  240 WKTYQLVYFLDKILQKSPLPPGNVKKLGDTYpSISNARNAELRLRWGQIVLKNDHQEDFWKVKEFLHNQGKQKYTLPLYH 319
Cdd:pfam09127   1 WSSNQKVVFLERLLEFSPLSPEQLKALDEVY-KLSESKNAEIRFRWLRLALKAKYEPAYPEVAEFLGEVGRMKFVRPLYR 79

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 983616486  320 AMMggsEVAQTLAKETFASTASQLHSNVVNYVQQI 354
Cdd:pfam09127  80 ALN---KVDRDLAVETFEKNKDFYHPICRAMVEKD 111

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 983616486   1 MPPSFPFGGMENPCLTFVTPCLLAGDRSLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQRRISTILFGAAYTCL 80
Cdd:cd09599  254 LPPSFPYGGMENPCLTFATPTLIAGDRSLVDVIAHEIAHSWSGNLVTNANWEHFWLNEGFTVYLERRILERLYGEEYRQF 333

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486  81 EAATGRALLRQHMDITGEENPLNKLrVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGdQDQFDSFLKAYVHEFKFRSI 160
Cdd:cd09599  334 EAILGWKDLQESIKEFGEDPPYTLL-VPDLKGVDPDDAFSSVPYEKGFQFLYYLEQLGG-REVFDPFLRAYFKKFAFQSI 411

                        170       180       190
                 ....*....|....*....|....*....|....
gi 983616486 161 LADDFLDFYLEYFPELKKkrvDIIPGFEFDRWLN 194
Cdd:cd09599  412 DTEDFKDFLLEYFAEDKP---EILDKIDWDAWLY 442

Peptidase family M1 domain; Members of this family are aminopeptidases. The members differ widely in specificity, hydrolysing acidic, basic or neutral N-terminal residues. This family includes leukotriene-A4 hydrolase, this enzyme also has an aminopeptidase activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486    3 PSFPFGGMENPCLTFVTPCLLAGD---------RSLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQRRISTILF 73
Cdd:pfam01433  32 PDFSAGAMENWGLITYRETLLLYDpgnsstsdkQRVASVIAHELAHQWFGNLVTMKWWDDLWLNEGFATYMEYLGTDALF 111

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486   74 GAAYTCLEAATGRALLRQHMDITGEENPLNklrVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGDqDQFDSFLKAYVH 153
Cdd:pfam01433 112 PEWNIWEQFLLDEVQNAMARDALDSSHPIT---QNVNDPSEIDDIFDAIPYEKGASVLRMLETLLGE-EVFQKGLRSYLK 187

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 983616486  154 EFKFRSILADDFLDFYLEYfpeLKKKRVDIIpgfeFDRW 192
Cdd:pfam01433 188 KFQYGNATTEDLWDALSEA---SGPLDVDSF----MDTW 219

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486   3 PSFPFGGMENPCLTFVTPCLLAGDR-------SLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQRRISTILFGA 75
Cdd:COG0308  257 PDFNFGAMENQGLVTFGEKVLADETatdadyeRRESVIAHELAHQWFGNLVTCADWDDLWLNEGFATYMEQLFSEDLYGK 336

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486  76 AytclEAATGRALLRQHMDITGEENPlNKLRVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGDqDQFDSFLKAYVHEF 155
Cdd:COG0308  337 D----AADRIFVGALRSYAFAEDAGP-NAHPIRPDDYPEIENFFDGIVYEKGALVLHMLRTLLGD-EAFRAGLRLYFARH 410

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 983616486 156 KFRSILADDFLDfYLEyfpelKKKRVDIipGFEFDRWLNTPGWPPYLPDLS 206
Cdd:COG0308  411 AGGNATTEDFLA-ALE-----EASGRDL--SAFFDQWLYQAGLPTLEVEYE 453

Peptidase M1 family similar to aminopeptidase N catalytic domain; This family contains mostly bacterial and some archaeal M1 peptidases with smilarity to the catalytic domain of aminopeptidase N (APN; CD13; alanyl aminopeptidase; EC 3.4.11.2), a type II integral membrane protease belonging to the M1 gluzincin family. APN preferentially cleaves neutral amino acids from the N-terminus of oligopeptides and, in higher eukaryotes, is present in a variety of human tissues and cell types (leukocyte, fibroblast, endothelial and epithelial cells). APN expression is dysregulated in inflammatory diseases such as chronic pain, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyosytis and pulmonary sarcoidosis, and is enhanced in tumor cells such as melanoma, renal, prostate, pancreas, colon, gastric and thyroid cancers. It is predominantly expressed on stem cells and on cells of the granulocytic and monocytic lineages at distinct stages of differentiation, thus considered a marker of differentiation. Thus, APN inhibition may lead to the development of anti-cancer and anti-inflammatory drugs. APNs are also present in many pathogenic bacteria and represent potential drug targets. Some APNs have been used commercially, such as one from Lactococcus lactis used in the food industry. APN also serves as a receptor for coronaviruses, although the virus receptor interaction site seems to be distinct from the enzymatic site and aminopeptidase activity is not necessary for viral infection. APNs have also been extensively studied as putative Cry toxin receptors. Cry1 proteins are pore-forming toxins that bind to the midgut epithelial cell membrane of susceptible insect larvae, causing extensive damage. Several different toxins, including Cry1Aa, Cry1Ab, Cry1Ac, Cry1Ba, Cry1Ca and Cry1Fa, have been shown to bind to APNs; however, a direct role of APN in cytotoxicity has been yet to be firmly established.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486   7 FGGMENPCLTFVTPCLLAGDRSLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQrristilfgAAYTclEAATGR 86
Cdd:cd09603  245 GGGMEHQTATTYGNNFLNGDRGSERLIAHELAHQWFGDSVTCADWADIWLNEGFATYAE---------WLWS--EHKGGA 313

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486  87 ALLRQHMDitGEENPLNKLRVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGDqDQFDSFLKAYVHEFKFRSILADDFL 166
Cdd:cd09603  314 DAYRAYLA--GQRQDYLNADPGPGRPPDPDDLFDRDVYQKGALVLHMLRNLLGD-EAFFAALRAYLARYAHGNVTTEDFI 390

                 ..
gi 983616486 167 DF 168
Cdd:cd09603  391 AA 392

Peptidase M1 family similar to aminopeptidase N catalytic domain; This family contains bacterial M1 peptidases with smilarity to the catalytic domain of aminopeptidase N (APN; CD13; alanyl aminopeptidase; EC 3.4.11.2), a type II integral membrane protease belonging to the M1 gluzincin family. APN preferentially cleaves neutral amino acids from the N-terminus of oligopeptides and, in higher eukaryotes, is present in a variety of human tissues and cell types (leukocyte, fibroblast, endothelial and epithelial cells). APN expression is dysregulated in inflammatory diseases such as chronic pain, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyosytis and pulmonary sarcoidosis, and is enhanced in tumor cells such as melanoma, renal, prostate, pancreas, colon, gastric and thyroid cancers. It is predominantly expressed on stem cells and on cells of the granulocytic and monocytic lineages at distinct stages of differentiation, thus considered a marker of differentiation. Thus, APN inhibition may lead to the development of anti-cancer and anti-inflammatory drugs. APNs are also present in many pathogenic bacteria and represent potential drug targets. Some APNs have been used commercially, such as one from Lactococcus lactis used in the food industry. APN also serves as a receptor for coronaviruses, although the virus receptor interaction site seems to be distinct from the enzymatic site and aminopeptidase activity is not necessary for viral infection. APNs have also been extensively studied as putative Cry toxin receptors. Cry1 proteins are pore-forming toxins that bind to the midgut epithelial cell membrane of susceptible insect larvae, causing extensive damage. Several different toxins, including Cry1Aa, Cry1Ab, Cry1Ac, Cry1Ba, Cry1Ca and Cry1Fa, have been shown to bind to APNs; however, a direct role of APN in cytotoxicity has been yet to be firmly established.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486   5 FPFGGMENPCLTFVTPCLLAGDRSLADVIIHEISHSWFGNLVTN--ANWGefWLNEGFTMYAQRRISTILFGAAYTCLEA 82
Cdd:cd09604  269 FGGGGMEYPGLVFIGSRLYDPKRSLEGVVVHEIAHQWFYGIVGNdeRREP--WLDEGLATYAESLYLEEKYGKEAADELL 346

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486  83 ATGRALLRQHMDITGEENPLNKLrvkiepgvDPDDTYNETPYEKGFCFVSYLAHLVGDqDQFDSFLKAYVHEFKFRSILA 162
Cdd:cd09604  347 GRRYYRAYARGPGGPINLPLDTF--------PDGSYYSNAVYSKGALFLEELREELGD-EAFDKALREYYRRYKFKHPTP 417

                 ....*.
gi 983616486 163 DDFLDF 168
Cdd:cd09604  418 EDFFRT 423

aminopeptidase N, Streptomyces lividans type; This family is a subset of the members of the zinc metallopeptidase family M1 (pfam01433), with a single member characterized in Streptomyces lividans 66 and designated aminopeptidase N. The spectrum of activity may differ somewhat from the aminopeptidase N clade of E. coli and most other Proteobacteria, well separated phylogenetically within the M1 family. The M1 family also includes leukotriene A-4 hydrolase/aminopeptidase (with a bifunctional active site).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486    3 PSFPFGGMENP-CLTF---------VTPCLLAGdrsLADVIIHEISHSWFGNLVTNANWGEFWLNEGFTMYAQRRISTil 72
Cdd:TIGR02412 254 PEFNAGAMENAgCVTFaenflhraeATRAEKEN---RAGVILHEMAHMWFGDLVTMRWWNDLWLNESFAEYMGTLASA-- 328

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486   73 fgAAYTCLEAATGRALLRQHMDITGEENPL-NKLRVKIEPGVDPDDTYNETPYEKGFCFVSYLAHLVGDQDqFDSFLKAY 151
Cdd:TIGR02412 329 --EATEYTDAWTTFAAQGKQWAYEADQLPTtHPIVADVADLADALSNFDGITYAKGASVLKQLVAWVGEEA-FFAGVNAY 405

                         170
                  ....*....|....*.
gi 983616486  152 VHEFKFRSILADDFLD 167
Cdd:TIGR02412 406 FKRHAFGNATLDDLID 421

Peptidase M1 family, including aminopeptidase N catalytic domain; This model represents the catalytic domain of aminopeptidase N (APN; CD13; alanyl aminopeptidase; EC 3.4.11.2), a type II integral membrane protease belonging to the M1 gluzincin family. It includes bacterial-type alanyl aminopeptidases as well as PfA-M1 aminopeptidase (Plasmodium falciparum-type). APN preferentially cleaves neutral amino acids from the N-terminus of oligopeptides and, in higher eukaryotes, is present in a variety of human tissues and cell types (leukocyte, fibroblast, endothelial and epithelial cells). APN expression is dysregulated in inflammatory diseases such as chronic pain, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyosytis and pulmonary sarcoidosis, and is enhanced in tumor cells such as melanoma, renal, prostate, pancreas, colon, gastric and thyroid cancers. It is predominantly expressed on stem cells and on cells of the granulocytic and monocytic lineages at distinct stages of differentiation, thus considered a marker of differentiation. Thus, APN inhibition may lead to the development of anti-cancer and anti-inflammatory drugs. APNs are also present in many pathogenic bacteria and represent potential drug targets. Some APNs have been used commercially, such as one from Lactococcus lactis used in the food industry. APN also serves as a receptor for coronaviruses, although the virus receptor interaction site seems to be distinct from the enzymatic site and aminopeptidase activity is not necessary for viral infection. APNs have also been extensively studied as putative Cry toxin receptors. Cry1 proteins are pore-forming toxins that bind to the midgut epithelial cell membrane of susceptible insect larvae, causing extensive damage. Several different toxins, including Cry1Aa, Cry1Ab, Cry1Ac, Cry1Ba, Cry1Ca and Cry1Fa, have been shown to bind to APNs; however, a direct role of APN in cytotoxicity has been yet to be firmly established.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 983616486   3 PSFPFGGMENPCLT-FVTPCLLAGDRSLAD--------VIIHEISHSWFGNLVTNANWGEFWLNEGFTMY 63
Cdd:cd09600  249 DDFNMGAMENKGLNiFNSKYVLADPETATDadyeriesVIAHEYFHNWTGNRVTCRDWFQLSLKEGLTVF 318