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 2217381909 127 LSAAHSVLGAHPFSRLDVLIVPANFPSLGMASPHIMFLSQSILTGGNHLCGTrLCHEIAHAWFGLAIGARDWTEEWLSEG 206
Cdd:cd09599   234 LKAAEKLYGPYVWGRYDLLVLPPSFPYGGMENPCLTFATPTLIAGDRSLVDV-IAHEIAHSWSGNLVTNANWEHFWLNEG 312

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 207 FATHLEdvfwataqqlapyeaR---------EQQELRACLRWRRLQDEMQCSPEEM--QVLRPskdktghtsdsgasvIK 275
Cdd:cd09599   313 FTVYLE---------------RrilerlygeEYRQFEAILGWKDLQESIKEFGEDPpyTLLVP---------------DL 362

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 276 HGLNPEKIFMQVHYLKGYFLLRFLAKRLGDETYFSFLRKFVHTFHGQLILSQDFLQMLLENIPEEKRLELSVENIyQDWL 355
Cdd:cd09599   363 KGVDPDDAFSSVPYEKGFQFLYYLEQLGGREVFDPFLRAYFKKFAFQSIDTEDFKDFLLEYFAEDKPEILDKIDW-DAWL 441

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 2217381909 127 LSAAHSVLGAHPFSRLDVLIVPANFPSLGMASPHIMFLSQSILTGGNHLCGTrLCHEIAHAWFGLAIGARDWTEEWLSEG 206
Cdd:cd09599   234 LKAAEKLYGPYVWGRYDLLVLPPSFPYGGMENPCLTFATPTLIAGDRSLVDV-IAHEIAHSWSGNLVTNANWEHFWLNEG 312

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 207 FATHLEdvfwataqqlapyeaR---------EQQELRACLRWRRLQDEMQCSPEEM--QVLRPskdktghtsdsgasvIK 275
Cdd:cd09599   313 FTVYLE---------------RrilerlygeEYRQFEAILGWKDLQESIKEFGEDPpyTLLVP---------------DL 362

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 276 HGLNPEKIFMQVHYLKGYFLLRFLAKRLGDETYFSFLRKFVHTFHGQLILSQDFLQMLLENIPEEKRLELSVENIyQDWL 355
Cdd:cd09599   363 KGVDPDDAFSSVPYEKGFQFLYYLEQLGGREVFDPFLRAYFKKFAFQSIDTEDFKDFLLEYFAEDKPEILDKIDW-DAWL 441

leukotriene A-4 hydrolase/aminopeptidase; Members of this family represent a distinctive subset within the zinc metallopeptidase family M1 (pfam01433). The majority of the members of pfam01433 are aminopeptidases, but the sequences in this family for which the function is known are leukotriene A-4 hydrolase. A dual epoxide hydrolase and aminopeptidase activity at the same active site is indicated. The physiological substrate for aminopeptidase activity is not known.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 105 VFAPVCLTGACQETLLRLIPPCLSAAHSVLGAHPFSRLDVLIVPANFPSLGMASPHIMFLSQSILTGGNHLCGTrLCHEI 184
Cdd:TIGR02411 209 VYSEPEQLEKCQYEFENDTEKFIKTAEDLIFPYEWGQYDLLVLPPSFPYGGMENPNLTFATPTLIAGDRSNVDV-IAHEL 287

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 185 AHAWFGLAIGARDWTEEWLSEGFATHLEdvfwatAQQLAPYEAREQQELRACLRWRRLQDE---MQCSPEEMQVLRPSKD 261
Cdd:TIGR02411 288 AHSWSGNLVTNCSWEHFWLNEGWTVYLE------RRIIGRLYGEKTRHFSALIGWGDLQESvktLGETPEFTKLVVDLKD 361

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 262 KtghtsdsgasvikhglNPEKIFMQVHYLKGYFLLRFLAKRLGDETYFS-FLRKFVHTFHGQLILSQDFLQMLLENIPEE 340
Cdd:TIGR02411 362 N----------------DPDDAFSSVPYEKGFNFLFYLEQLLGGPAEFDpFLRHYFKKFAYKSLDTYQFKDALYEYFKDK 425

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 341 KRLELSVENIYQDWLESSGIP--KPlqrerraGAECGLARQVRAEVTKWIGVNRRPRKRKRREK-EEVFEKLLPDQLVLL 417
Cdd:TIGR02411 426 KKVDKLDAVDWETWLYSPGMPpvKP-------NFDTTLADECYALADRWVDAAKADDLSSFNAKdIKDFSSHQLVLFLET 498

                         330       340       350       360       370
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2217381909 418 LEHLLEQKTLSPRTLQSLQRTYHL-QDQDAEVRHRWCELIVKHKFTKAYKSVERFLQE 474
Cdd:TIGR02411 499 LTERGGDWALPEGHIKRLGDIYNFaASKNAEVRFRWFRLAIQAKLEDEYPLLADWLGT 556

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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2217381909 424 QKTLSPRTLQSLQRTYHLQD-QDAEVRHRWCELIVKHKFTKAYKSVERFLQE 474
Cdd:pfam09127  16 FSPLSPEQLKALDEVYKLSEsKNAEIRFRWLRLALKAKYEPAYPEVAEFLGE 67

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 2217381909 127 LSAAHSVLGAHPFSRLDVLIVPANFPSLGMASPHIMFLSQSILTGGNHLCGTrLCHEIAHAWFGLAIGARDWTEEWLSEG 206
Cdd:cd09599   234 LKAAEKLYGPYVWGRYDLLVLPPSFPYGGMENPCLTFATPTLIAGDRSLVDV-IAHEIAHSWSGNLVTNANWEHFWLNEG 312

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 207 FATHLEdvfwataqqlapyeaR---------EQQELRACLRWRRLQDEMQCSPEEM--QVLRPskdktghtsdsgasvIK 275
Cdd:cd09599   313 FTVYLE---------------RrilerlygeEYRQFEAILGWKDLQESIKEFGEDPpyTLLVP---------------DL 362

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 276 HGLNPEKIFMQVHYLKGYFLLRFLAKRLGDETYFSFLRKFVHTFHGQLILSQDFLQMLLENIPEEKRLELSVENIyQDWL 355
Cdd:cd09599   363 KGVDPDDAFSSVPYEKGFQFLYYLEQLGGREVFDPFLRAYFKKFAFQSIDTEDFKDFLLEYFAEDKPEILDKIDW-DAWL 441

leukotriene A-4 hydrolase/aminopeptidase; Members of this family represent a distinctive subset within the zinc metallopeptidase family M1 (pfam01433). The majority of the members of pfam01433 are aminopeptidases, but the sequences in this family for which the function is known are leukotriene A-4 hydrolase. A dual epoxide hydrolase and aminopeptidase activity at the same active site is indicated. The physiological substrate for aminopeptidase activity is not known.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 105 VFAPVCLTGACQETLLRLIPPCLSAAHSVLGAHPFSRLDVLIVPANFPSLGMASPHIMFLSQSILTGGNHLCGTrLCHEI 184
Cdd:TIGR02411 209 VYSEPEQLEKCQYEFENDTEKFIKTAEDLIFPYEWGQYDLLVLPPSFPYGGMENPNLTFATPTLIAGDRSNVDV-IAHEL 287

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 185 AHAWFGLAIGARDWTEEWLSEGFATHLEdvfwatAQQLAPYEAREQQELRACLRWRRLQDE---MQCSPEEMQVLRPSKD 261
Cdd:TIGR02411 288 AHSWSGNLVTNCSWEHFWLNEGWTVYLE------RRIIGRLYGEKTRHFSALIGWGDLQESvktLGETPEFTKLVVDLKD 361

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 262 KtghtsdsgasvikhglNPEKIFMQVHYLKGYFLLRFLAKRLGDETYFS-FLRKFVHTFHGQLILSQDFLQMLLENIPEE 340
Cdd:TIGR02411 362 N----------------DPDDAFSSVPYEKGFNFLFYLEQLLGGPAEFDpFLRHYFKKFAYKSLDTYQFKDALYEYFKDK 425

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 341 KRLELSVENIYQDWLESSGIP--KPlqrerraGAECGLARQVRAEVTKWIGVNRRPRKRKRREK-EEVFEKLLPDQLVLL 417
Cdd:TIGR02411 426 KKVDKLDAVDWETWLYSPGMPpvKP-------NFDTTLADECYALADRWVDAAKADDLSSFNAKdIKDFSSHQLVLFLET 498

                         330       340       350       360       370
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2217381909 418 LEHLLEQKTLSPRTLQSLQRTYHL-QDQDAEVRHRWCELIVKHKFTKAYKSVERFLQE 474
Cdd:TIGR02411 499 LTERGGDWALPEGHIKRLGDIYNFaASKNAEVRFRWFRLAIQAKLEDEYPLLADWLGT 556

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 2217381909 134 LGAHPFSRLDvlIVPANFPSLGMASPHIMFLSQSILTGGNHLCGTrLCHEIAHAWFGLAIG--ARDWTeeWLSEGFATHL 211
Cdd:cd09604   254 FGPYPYPELD--VVQGPFGGGGMEYPGLVFIGSRLYDPKRSLEGV-VVHEIAHQWFYGIVGndERREP--WLDEGLATYA 328

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 212 EDVFwataqqlapYEAREQQELRACLRWRRLQDEMQCSPEEmQVLRPSkDKTGHTSDSGASVikhglnpekifmqvhYLK 291
Cdd:cd09604   329 ESLY---------LEEKYGKEAADELLGRRYYRAYARGPGG-PINLPL-DTFPDGSYYSNAV---------------YSK 382

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2217381909 292 GYFLLRFLAKRLGDETYFSFLRKFVHTFHGQLILSQDFLQMLlenipeEKRLELSVENIYQDWL 355
Cdd:cd09604   383 GALFLEELREELGDEAFDKALREYYRRYKFKHPTPEDFFRTA------EEVSGKDLDWFFRGWL 440

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 2217381909 132 SVLGAHPFSRLDVLIVPANFpsLGMasPHimflsQSILT-GGNHLCGTR-----LCHEIAHAWFGLAIGARDWTEEWLSE 205
Cdd:cd09603   226 ELFGPYPFEKYGQVVVPDLG--GGM--EH-----QTATTyGNNFLNGDRgserlIAHELAHQWFGDSVTCADWADIWLNE 296

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 206 GFATHLEDVFWAtaqqlapyEAREQQELRAclrwrRLQDEMQcspeemQVLRPSKdktghtsdsgasVIKHGLNPEKIFM 285
Cdd:cd09603   297 GFATYAEWLWSE--------HKGGADAYRA-----YLAGQRQ------DYLNADP------------GPGRPPDPDDLFD 345

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*...
gi 2217381909 286 QVHYLKGYFLLRFLAKRLGDETYFSFLRKFVHTFHGQLILSQDFLQML 333
Cdd:cd09603   346 RDVYQKGALVLHMLRNLLGDEAFFAALRAYLARYAHGNVTTEDFIAAA 393

Peptidase M1 aminopeptidase N catalytic domain family which includes aminopeptidase N (APN), aminopeptidase Q (APQ), tricorn interacting factor F3, and endoplasmic reticulum aminopeptidase 1 (ERAP1); This M1 peptidase family includes eukaryotic and bacterial members: the catalytic domains of aminopeptidase N (APN), aminopeptidase Q (APQ, laeverin), endoplasmic reticulum aminopeptidase 1 (ERAP1) as well as tricorn interacting factor F3. Aminopeptidase N (APN; CD13; alanyl aminopeptidase; EC 3.4.11.2), a type II integral membrane protease, preferentially cleaves neutral amino acids from the N-terminus of oligopeptides and 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 considered a marker of differentiation since it is predominantly expressed on stem cells and on cells of the granulocytic and monocytic lineages at distinct stages of differentiation. Thus, APN inhibition may lead to the development of anti-cancer and anti-inflammatory drugs. ERAP1, also known as endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP), adipocyte derived leucine aminopeptidase (A-LAP), or aminopeptidase regulating tumor necrosis factor receptor I (THFRI) shedding (ARTS-1), associates with the closely related ER aminopeptidase ERAP2, for the final trimming of peptides within the ER for presentation by MHC class I molecules. ERAP1 is associated with ankylosing spondylitis (AS), an inflammatory arthritis that predominantly affects the spine. ERAP1 also aids in the shedding of membrane-bound cytokine receptors. The tricorn interacting factor F3, together with factors F1 and F2, degrades the tricorn protease products, producing free amino acids, thus completing the proteasomal degradation pathway. F3 is homologous to F2, but not F1, and shows a strong preference for glutamate in the P1' position. APQ, also known as laeverin, is specifically expressed in human embryo-derived extravillous trophoblasts (EVTs) that invade the uterus during early placentation. It cleaves the N-terminal amino acid of various peptides such as angiotensin III, endokinin C, and kisspeptin-10, all expressed in the placenta in large quantities. APN is 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 are also 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 2217381909  88 CRFQNASATTQEIIPHRVFAPVCLTGACQETLlRLIPPCLSAAHSVLG-AHPFSRLDVLIVPaNFPSLGMASP-HIMFLS 165
Cdd:cd09601   190 GDFEYIESTTKSGVPVRVYARPGKIEQGDFAL-EVAPKILDFYEDYFGiPYPLPKLDLVAIP-DFAAGAMENWgLITYRE 267

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 166 QSILTGGNHLCGTRL-------CHEIAHAWFG-LaIGARDWTEEWLSEGFATHLEdvfWATAQQLAP-YEAREQQelrac 236
Cdd:cd09601   268 TALLYDPKTSSASDKqrvaeviAHELAHQWFGnL-VTMKWWDDLWLNEGFATYME---YLAVDKLFPeWNMWDQF----- 338

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217381909 237 lrwrrLQDEMQcspeemQVLRpskdktghtSDSGASV------IKHGLNPEKIFMQVHYLKGYFLLRFLAKRLGDETYFS 310
Cdd:cd09601   339 -----VVDELQ------SALE---------LDSLASShpievpVESPSEISEIFDAISYSKGASVLRMLENFLGEEVFRK 398

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|....*.
gi 2217381909 311 FLRKFVHTFHGQLILSQDFLQMLLENIPEEKrlELSVENIYQDWLE 356
Cdd:cd09601   399 GLRKYLKKHAYGNATTDDLWEALQEASGESK--PLDVKEIMDSWTL 442