Peptidase M4 family including thermolysin, protealysin, aureolysin, and neutral protease; This peptidase M4 family includes several endopeptidases such as thermolysin (EC 3.4.24.27), aureolysin (the extracellular metalloproteinase from Staphylococcus aureus), neutral protease from Bacillus cereus, protealysin, and bacillolysin (EC 3.4.24.28). Typically, the M4 peptidases consist of a presequence (signal sequence), a propeptide sequence, and a peptidase unit. The presequence is cleaved off during export while the propeptide has inhibitory and chaperone functions and facilitates folding. The propeptide remains attached until the peptidase is secreted and can be safely activated. All 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 active site is found between two sub-domains; the N-terminal domain contains the HEXXH zinc-binding motif while the helical C-terminal domain, which is unique for the family, carries the third zinc ligand. These peptidases are secreted eubacterial endopeptidases from Gram-positive or Gram-negative sources that degrade extracellular proteins and peptides for bacterial nutrition. They are selectively inhibited by Steptomyces metalloproteinase inhibitor (SMPI) as well as by phosphoramidon from Streptomyces tanashiensis. A large number of these enzymes are implicated as key factors in the pathogenesis of various diseases, including gastritis, peptic ulcer, gastric carcinoma, cholera and several types of bacterial infections, and are therefore important drug targets. Some enzymes of the family can function at extremes of temperatures, while some function in organic solvents, thus rendering them novel targets for biotechnological applications. Thermolysin is widely used as a nonspecific protease to obtain fragments for peptide sequencing. It has also been used in production of the artificial sweetener aspartame.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406  59 RDIYDAKQTQELPGTQ---VRYEGQPSNGDVAVDEAYDYLGITHDFFWKEYQRDSLDNKGLILTGTVHYGREYQNAFWNG 135
Cdd:cd09597    1 RRTYDANNGTTLPGSLvvpVRGEGTAASGDSAAVDAHYNAGKVYDFYKNVFGRNSIDGKGMPLVSSVHYGDNYDNAFWNG 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406 136 QQMVFGDGDGEIFNrFTIAIDVVAHELSHGVTETEAGLIYFEQSGALNESLSDVFGSLVKQYHlKQTADKADWLIGEGLL 215
Cdd:cd09597   81 SQMVFGDGDGGTFP-FLTSLDVVAHELTHGVTEYTAGLIYSGQSGALNESFSDIFGALVEQYA-NGTADKADWLIGEDIF 158

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406 216 AKGinGKGLRSMSEPGTAyddpllgkDPQPAHMKDFIKTREDNGGVHLNSGIPNRAFYLAATAIG------GYAWEKAGY 289
Cdd:cd09597  159 TKG--GGALRSMSNPSTD--------GGQPDHMSDYYTTYNDNGGVHINSGIPNKAFYLLATGGGgngtvtGIGIEKAGK 228

                        250       260       270       280       290
                 ....*....|....*....|....*....|....*....|....*....|.
gi 647320406 290 AWYDTVCDRnLAQDADFEAFAKLTIAHGEKR--SGSDVGAAIKQAWEQVGV 338
Cdd:cd09597  229 IWYRALTNY-LTPTSTFADARRATLQAAKDLygANSAEVAAVKKAWDAVGV 278

Peptidase M4 family including thermolysin, protealysin, aureolysin, and neutral protease; This peptidase M4 family includes several endopeptidases such as thermolysin (EC 3.4.24.27), aureolysin (the extracellular metalloproteinase from Staphylococcus aureus), neutral protease from Bacillus cereus, protealysin, and bacillolysin (EC 3.4.24.28). Typically, the M4 peptidases consist of a presequence (signal sequence), a propeptide sequence, and a peptidase unit. The presequence is cleaved off during export while the propeptide has inhibitory and chaperone functions and facilitates folding. The propeptide remains attached until the peptidase is secreted and can be safely activated. All 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 active site is found between two sub-domains; the N-terminal domain contains the HEXXH zinc-binding motif while the helical C-terminal domain, which is unique for the family, carries the third zinc ligand. These peptidases are secreted eubacterial endopeptidases from Gram-positive or Gram-negative sources that degrade extracellular proteins and peptides for bacterial nutrition. They are selectively inhibited by Steptomyces metalloproteinase inhibitor (SMPI) as well as by phosphoramidon from Streptomyces tanashiensis. A large number of these enzymes are implicated as key factors in the pathogenesis of various diseases, including gastritis, peptic ulcer, gastric carcinoma, cholera and several types of bacterial infections, and are therefore important drug targets. Some enzymes of the family can function at extremes of temperatures, while some function in organic solvents, thus rendering them novel targets for biotechnological applications. Thermolysin is widely used as a nonspecific protease to obtain fragments for peptide sequencing. It has also been used in production of the artificial sweetener aspartame.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406  59 RDIYDAKQTQELPGTQ---VRYEGQPSNGDVAVDEAYDYLGITHDFFWKEYQRDSLDNKGLILTGTVHYGREYQNAFWNG 135
Cdd:cd09597    1 RRTYDANNGTTLPGSLvvpVRGEGTAASGDSAAVDAHYNAGKVYDFYKNVFGRNSIDGKGMPLVSSVHYGDNYDNAFWNG 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406 136 QQMVFGDGDGEIFNrFTIAIDVVAHELSHGVTETEAGLIYFEQSGALNESLSDVFGSLVKQYHlKQTADKADWLIGEGLL 215
Cdd:cd09597   81 SQMVFGDGDGGTFP-FLTSLDVVAHELTHGVTEYTAGLIYSGQSGALNESFSDIFGALVEQYA-NGTADKADWLIGEDIF 158

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406 216 AKGinGKGLRSMSEPGTAyddpllgkDPQPAHMKDFIKTREDNGGVHLNSGIPNRAFYLAATAIG------GYAWEKAGY 289
Cdd:cd09597  159 TKG--GGALRSMSNPSTD--------GGQPDHMSDYYTTYNDNGGVHINSGIPNKAFYLLATGGGgngtvtGIGIEKAGK 228

                        250       260       270       280       290
                 ....*....|....*....|....*....|....*....|....*....|.
gi 647320406 290 AWYDTVCDRnLAQDADFEAFAKLTIAHGEKR--SGSDVGAAIKQAWEQVGV 338
Cdd:cd09597  229 IWYRALTNY-LTPTSTFADARRATLQAAKDLygANSAEVAAVKKAWDAVGV 278

Thermolysin metallopeptidase, alpha-helical domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406  171 AGLIYFEQSGALNESLSDVFGSLVKQYHLKQTaDKADWLIGEGLLAKGINGKGLRSMSEPGTAyddpllgkDPQPAHMKD 250
Cdd:pfam02868   1 AGLVYSGESGALNESFSDIFGTAVEQYANGQT-DKADWLIGEEIYTPGIGGDALRSMSNPSSD--------GPQPDHYDD 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406  251 FIKTREDNGGVHLNSGIPNRAFYLAATA-------IGGYAWEKAGYAWYDTVCDRnLAQDADFEAFAKLTIAHGEKR--S 321
Cdd:pfam02868  72 YVTGTGDNGGVHINSGIPNKAFYLLAEGgthngvtVTGIGREKAGKIWYRALTDY-LTPTTNFAEARTATIQAAKDLygA 150

                         170
                  ....*....|....*..
gi 647320406  322 GSDVGAAIKQAWEQVGV 338
Cdd:pfam02868 151 GSAEVQAVKNAWDAVGV 167

Peptidase M4 family including thermolysin, protealysin, aureolysin, and neutral protease; This peptidase M4 family includes several endopeptidases such as thermolysin (EC 3.4.24.27), aureolysin (the extracellular metalloproteinase from Staphylococcus aureus), neutral protease from Bacillus cereus, protealysin, and bacillolysin (EC 3.4.24.28). Typically, the M4 peptidases consist of a presequence (signal sequence), a propeptide sequence, and a peptidase unit. The presequence is cleaved off during export while the propeptide has inhibitory and chaperone functions and facilitates folding. The propeptide remains attached until the peptidase is secreted and can be safely activated. All 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 active site is found between two sub-domains; the N-terminal domain contains the HEXXH zinc-binding motif while the helical C-terminal domain, which is unique for the family, carries the third zinc ligand. These peptidases are secreted eubacterial endopeptidases from Gram-positive or Gram-negative sources that degrade extracellular proteins and peptides for bacterial nutrition. They are selectively inhibited by Steptomyces metalloproteinase inhibitor (SMPI) as well as by phosphoramidon from Streptomyces tanashiensis. A large number of these enzymes are implicated as key factors in the pathogenesis of various diseases, including gastritis, peptic ulcer, gastric carcinoma, cholera and several types of bacterial infections, and are therefore important drug targets. Some enzymes of the family can function at extremes of temperatures, while some function in organic solvents, thus rendering them novel targets for biotechnological applications. Thermolysin is widely used as a nonspecific protease to obtain fragments for peptide sequencing. It has also been used in production of the artificial sweetener aspartame.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406  59 RDIYDAKQTQELPGTQ---VRYEGQPSNGDVAVDEAYDYLGITHDFFWKEYQRDSLDNKGLILTGTVHYGREYQNAFWNG 135
Cdd:cd09597    1 RRTYDANNGTTLPGSLvvpVRGEGTAASGDSAAVDAHYNAGKVYDFYKNVFGRNSIDGKGMPLVSSVHYGDNYDNAFWNG 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406 136 QQMVFGDGDGEIFNrFTIAIDVVAHELSHGVTETEAGLIYFEQSGALNESLSDVFGSLVKQYHlKQTADKADWLIGEGLL 215
Cdd:cd09597   81 SQMVFGDGDGGTFP-FLTSLDVVAHELTHGVTEYTAGLIYSGQSGALNESFSDIFGALVEQYA-NGTADKADWLIGEDIF 158

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406 216 AKGinGKGLRSMSEPGTAyddpllgkDPQPAHMKDFIKTREDNGGVHLNSGIPNRAFYLAATAIG------GYAWEKAGY 289
Cdd:cd09597  159 TKG--GGALRSMSNPSTD--------GGQPDHMSDYYTTYNDNGGVHINSGIPNKAFYLLATGGGgngtvtGIGIEKAGK 228

                        250       260       270       280       290
                 ....*....|....*....|....*....|....*....|....*....|.
gi 647320406 290 AWYDTVCDRnLAQDADFEAFAKLTIAHGEKR--SGSDVGAAIKQAWEQVGV 338
Cdd:cd09597  229 IWYRALTNY-LTPTSTFADARRATLQAAKDLygANSAEVAAVKKAWDAVGV 278

Thermolysin metallopeptidase, alpha-helical domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406  171 AGLIYFEQSGALNESLSDVFGSLVKQYHLKQTaDKADWLIGEGLLAKGINGKGLRSMSEPGTAyddpllgkDPQPAHMKD 250
Cdd:pfam02868   1 AGLVYSGESGALNESFSDIFGTAVEQYANGQT-DKADWLIGEEIYTPGIGGDALRSMSNPSSD--------GPQPDHYDD 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406  251 FIKTREDNGGVHLNSGIPNRAFYLAATA-------IGGYAWEKAGYAWYDTVCDRnLAQDADFEAFAKLTIAHGEKR--S 321
Cdd:pfam02868  72 YVTGTGDNGGVHINSGIPNKAFYLLAEGgthngvtVTGIGREKAGKIWYRALTDY-LTPTTNFAEARTATIQAAKDLygA 150

                         170
                  ....*....|....*..
gi 647320406  322 GSDVGAAIKQAWEQVGV 338
Cdd:pfam02868 151 GSAEVQAVKNAWDAVGV 167

Thermolysin metallopeptidase, catalytic domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 647320406   81 PSNGDVAVDeAYDYLGITHDFFWKEYQRDSLDNKGLILTGTVHYGREYQNAFWNGQQMVFGDGDGEIFNRFTIAIDVVAH 160
Cdd:pfam01447  61 DGNQSNAVD-AHYGAAKTYDYYKNWFGRNSIDNDGMGIYSRVHYGNNYNNAFWDGSQMTYGDGDGNTFFPPLVSLDVVGH 139

                  ....*...
gi 647320406  161 ELSHGVTE 168
Cdd:pfam01447 140 EMTHGVTE 147

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 647320406  94 YLGITHDFFWKEYQRDSLDNKGLILTGTVHYGREYQ----NAFWNGQ-QMVFGDGDGEifnRFTIAIDVVAHELSHGVTE 168
Cdd:cd09594    3 YAHETYKYYEELLGRTSFRYPVSPIYSLLVYPAYVEvnayNAMWIPStNIFYGAGILD---TLSGTIDVLAHELTHAFTG 79

                         90       100
                 ....*....|....*....|....*.
gi 647320406 169 TEAGLIYFEQSGALNESLSDVFGSLV 194
Cdd:cd09594   80 QFSNLMYSWSSGWLNEGISDYFGGLV 105