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Astacin became the founding member of a clan of metalloendopeptidases, for which Wolfram Bode coined the designation \u2018metzincins\u2019. This review recapitulates the discovery of the metzincin clan, which includes the astacins, MMPs (matrix metalloproteinases), serralysins and adamalysins\/ADAMs (A disintegrin and metalloproteinase enzymes). Currently, over a dozen subclans (families) have been assigned including the pappalysins, leishmanolysins, snapalysins, igalysins, helicolysins, and toxylysins.\n                  <\/jats:p>","DOI":"10.1515\/hsz-2026-0142","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T01:56:50Z","timestamp":1787104610000},"source":"Crossref","is-referenced-by-count":0,"title":["Structure of astacin and the discovery of metzincins"],"prefix":"10.1515","author":[{"given":"F. Xavier","family":"Gomis-R\u00fcth","sequence":"first","affiliation":[{"name":"Department of Structural and Molecular Biology, Molecular Biology Institute of Barcelona (IBMB) , Higher Scientific Research Council (CSIC), Barcelona Science Park , Helix Building, c\/ Baldiri Reixac, 15-21, E-08028 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1515-6994","authenticated-orcid":false,"given":"Walter","family":"St\u00f6cker","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology, Faculty of Biology , Johannes Gutenberg University Mainz , Dietrich-Gresemund-Weg 2, D-55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"2026081901564517200_j_hsz-2026-0142_ref_001","doi-asserted-by":"crossref","unstructured":"A celebration of structural biology. (2021). Nat. Methods (Editorial) 18: 427, https:\/\/doi.org\/10.1038\/s41592-021-01163-x.","DOI":"10.1038\/s41592-021-01163-x"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_002","doi-asserted-by":"crossref","unstructured":"Arolas, J.L., Broder, C., Jefferson, T., Guevara, T., Sterchi, E.E., Bode, W., St\u00f6cker, W., Becker-Pauly, C., and Gomis-R\u00fcth, F.X. (2012). Structural basis for the sheddase function of human meprin \u03b2 metalloproteinase at the plasma membrane. Proc. Natl. Acad. Sci. USA 109: 16131\u201316136, https:\/\/doi.org\/10.1073\/pnas.1211076109.","DOI":"10.1073\/pnas.1211076109"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_003","doi-asserted-by":"crossref","unstructured":"Arolas, J.L., Goulas, T., Cuppari, A., and Gomis-R\u00fcth, F.X. (2018). Multiple architectures and mechanisms of latency in metallopeptidase zymogens. Chem. Rev. 118: 5581\u20135597, https:\/\/doi.org\/10.1021\/acs.chemrev.8b00030.","DOI":"10.1021\/acs.chemrev.8b00030"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_004","doi-asserted-by":"crossref","unstructured":"Barrett, A.J. and Rawlings, N.D. (1991). Types and families of endopeptidases. Biochem. Soc. Trans. 19: 707\u2013715, https:\/\/doi.org\/10.1042\/bst0190707.","DOI":"10.1042\/bst0190707"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_005","doi-asserted-by":"crossref","unstructured":"Bartlett, P.A. and Marlowe, C.K. (1987). Evaluation of intrinsic binding-energy from a hydrogen-bonding group in an enzyme-inhibitor. Science 235: 569\u2013571, https:\/\/doi.org\/10.1126\/science.3810155.","DOI":"10.1126\/science.3810155"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_006","doi-asserted-by":"crossref","unstructured":"Baumann, U., Wu, S., Flaherty, K.M., and McKay, D.B. (1993). Three-dimensional structure of the alkaline protease of Pseudomonas aeruginosa: a two-domain protein with a calcium binding parallel beta roll motif. EMBO J. 12: 3357\u20133364, https:\/\/doi.org\/10.1002\/j.1460-2075.1993.tb06009.x.","DOI":"10.1002\/j.1460-2075.1993.tb06009.x"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_007","doi-asserted-by":"crossref","unstructured":"Bayly-Jones, C., Lupton, C.J., Fritz, C., Venugopal, H., Ramsbeck, D., Wermann, M., J\u00e4ger, C., de Marco, A., Schilling, S., Schlenzig, D., et al.. (2022). Helical ultrastructure of the metalloprotease meprin-\u03b1 in complex with a small molecule inhibitor. Nat. Commun. 13: 6178, https:\/\/doi.org\/10.1038\/s41467-022-33893-7.","DOI":"10.1038\/s41467-022-33893-7"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_008","doi-asserted-by":"crossref","unstructured":"Becker-Pauly, C. and Pietrzik, C.U. (2017). The metalloprotease meprin \u03b2 is an alternative \u03b2-secretase of APP. Front. Mol. 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Nature 385: 729\u2013733, https:\/\/doi.org\/10.1038\/385729a0.","DOI":"10.1038\/385729a0"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_011","doi-asserted-by":"crossref","unstructured":"Blake, C.C.F., Fenn, R.H., North, A.C.T., Phillips, D.C., and Poljak, R.J. (1962). Structure of lysozyme: a Fourier map of the electron density at 6 \u00c5 resolution obtained by X-ray diffraction. Nature 196: 1173\u20131176, https:\/\/doi.org\/10.1038\/1961173a0.","DOI":"10.1038\/1961173a0"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_012","doi-asserted-by":"crossref","unstructured":"Blake, C.C.F., Koenig, D.F., Mair, G.A., North, A.C.T., Phillips, D.C., and Sarma, V.R. (1965). Structure of hen egg-white lysozyme: a three-dimensional Fourier synthesis at 2 \u00c5 resolution. Nature 206: 757\u2013761, https:\/\/doi.org\/10.1038\/206757a0.","DOI":"10.1038\/206757a0"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_013","doi-asserted-by":"crossref","unstructured":"Blobel, C.P. (2005). 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FEBS Lett. 331: 134\u2013140, https:\/\/doi.org\/10.1016\/0014-5793(93)80312-i.","DOI":"10.1016\/0014-5793(93)80312-I"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_016","doi-asserted-by":"crossref","unstructured":"Bode, W., Reinemer, P., Huber, R., Kleine, T., Schnierer, S., and Tschesche, H. (1994). The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity. EMBO J. 13: 1263\u20131269, https:\/\/doi.org\/10.1002\/j.1460-2075.1994.tb06378.x.","DOI":"10.1002\/j.1460-2075.1994.tb06378.x"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_017","doi-asserted-by":"crossref","unstructured":"Bode, W. and Schwager, P. (1975). The refined crystal structure of bovine \u03b2-trypsin at 1.8 \u00c5 resolution. J.\u00a0Mol. Biol. 98: 693\u2013717, https:\/\/doi.org\/10.1016\/s0022-2836(75)80005-2.","DOI":"10.1016\/S0022-2836(75)80005-2"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_018","doi-asserted-by":"crossref","unstructured":"Brinckerhoff, C.E. and Matrisian, L.M. (2002). Matrix metalloproteinases: a tail of a frog that became a prince. Nat. Rev. Mol. Cell Biol. 3: 207\u2013214, https:\/\/doi.org\/10.1038\/nrm763.","DOI":"10.1038\/nrm763"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_019","doi-asserted-by":"crossref","unstructured":"Broder, C. and Becker-Pauly, C. (2013). The metalloproteases meprin \u03b1 and meprin \u03b2: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis. Biochem. J. 450: 253\u2013264, https:\/\/doi.org\/10.1042\/bj20121751.","DOI":"10.1042\/BJ20121751"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_020","doi-asserted-by":"crossref","unstructured":"Button, L.L. and McMaster, W.R. (1988). Molecular cloning of the major surface antigen of leishmania. J.\u00a0Exp. Med. 167: 724\u2013729, https:\/\/doi.org\/10.1084\/jem.167.2.724.","DOI":"10.1084\/jem.167.2.724"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_021","doi-asserted-by":"crossref","unstructured":"Cerd\u00e0-Costa, N. and Gomis-R\u00fcth, F.X. (2014). Architecture and function of metallopeptidase catalytic domains. Protein Sci. 23: 123\u2013144, https:\/\/doi.org\/10.1002\/pro.2400.","DOI":"10.1002\/pro.2400"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_022","doi-asserted-by":"crossref","unstructured":"Colige, A., Li, S.-W., Sieron, A.L., Nusgens, B.V., Prockop, D.J., and Lapi\u00e8re, C.M. (1997). cDNA cloning and expression of bovine procollagen I N-proteinase: a new member of the superfamily of zinc-metalloproteinases with binding sites for cells and other matrix components. Proc. Natl. Acad. Sci. 94: 2374\u20132379, https:\/\/doi.org\/10.1073\/pnas.94.6.2374.","DOI":"10.1073\/pnas.94.6.2374"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_023","doi-asserted-by":"crossref","unstructured":"Deisenhofer, J., Epp, O., Miki, K., Huber, R., and Michel, H. (1985). Structure of the protein subunits in the photosynthetic reaction centre of Rhodopseudomonas viridis at 3\u00c5 resolution. Nature 318: 618\u2013624, https:\/\/doi.org\/10.1038\/318618a0.","DOI":"10.1038\/318618a0"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_024","doi-asserted-by":"crossref","unstructured":"Delepelaire, P. and Wandersman, C. (1989). Protase secretion by Erwinia chrysantemi . Proteases B and C are synthesized and secreted as zymogens without a signal peptide. J.\u00a0Biol. Chem. 264: 9083\u20139099, https:\/\/doi.org\/10.1016\/s0021-9258(18)81905-6.","DOI":"10.1016\/S0021-9258(18)81905-6"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_025","doi-asserted-by":"crossref","unstructured":"Dumermuth, E., Sterchi, E.E., Jiang, W.P., Wolz, R.L., Bond, J.S., Flannery, A.V., and Beynon, R.J. (1991). The astacin family of metalloendopeptidases. J.\u00a0Biol. Chem. 266: 21381\u201321385, https:\/\/doi.org\/10.1016\/s0021-9258(18)54648-2.","DOI":"10.1016\/S0021-9258(18)54648-2"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_026","doi-asserted-by":"crossref","unstructured":"Eckhard, U., K\u00f6rschgen, H., von Wiegen, N., St\u00f6cker, W., and Gomis-R\u00fcth, F.X. (2021). The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin \u03b2 by endogenous fetuin-B. Proc. Natl. Acad. Sci. USA 118: e2023839118, https:\/\/doi.org\/10.1073\/pnas.2023839118.","DOI":"10.1073\/pnas.2023839118"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_027","doi-asserted-by":"crossref","unstructured":"Eldering, J.A., Gr\u00fcnberg, J., Hahn, D., Croes, H.J., Fransen, J.A., and Sterchi, E.E. (1997). Polarised expression of human intestinal N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase (human meprin) alpha and beta subunits in Madin-Darby canine kidney cells. Eur. J.\u00a0Biochem. 247: 920\u2013932, https:\/\/doi.org\/10.1111\/j.1432-1033.1997.00920.x.","DOI":"10.1111\/j.1432-1033.1997.00920.x"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_028","doi-asserted-by":"crossref","unstructured":"Fischer, E. (1894). Einfluss der Configuration auf die Wirkung der Enzyme. Ber. Dtsch. Chem. Ges. 27: 2985\u20132993, https:\/\/doi.org\/10.1002\/cber.18940270364.","DOI":"10.1002\/cber.18940270364"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_029","doi-asserted-by":"crossref","unstructured":"Gomis-R\u00fcth, F.X. (2003). Structural aspects of the metzincin clan of metalloendopeptidases. Mol. Biotech. 24: 157\u2013202.","DOI":"10.1385\/MB:24:2:157"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_030","doi-asserted-by":"crossref","unstructured":"Gomis-R\u00fcth, F.X. (2009). Catalytic domain architecture of metzincin metalloproteases. J.\u00a0Biol. Chem. 284: 15353\u201315357, https:\/\/doi.org\/10.1074\/jbc.r800069200.","DOI":"10.1074\/jbc.R800069200"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_031","doi-asserted-by":"crossref","unstructured":"Gomis-R\u00fcth, F.X., Botelho, T.O., and Bode, W. (2012). A standard orientation for metallopeptidases. Biochim. Biophys. 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EMBO J. 12: 4151\u20134157, https:\/\/doi.org\/10.1002\/j.1460-2075.1993.tb06099.x.","DOI":"10.1002\/j.1460-2075.1993.tb06099.x"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_034","doi-asserted-by":"crossref","unstructured":"Gomis-R\u00fcth, F.X. and St\u00f6cker, W. (2023). Structural and evolutionary insights into astacin metallopeptidases. Front. Mol. Biosci. 9: 1080836, https:\/\/doi.org\/10.3389\/fmolb.2022.1080836.","DOI":"10.3389\/fmolb.2022.1080836"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_035","doi-asserted-by":"crossref","unstructured":"Gomis-R\u00fcth, F.X., St\u00f6cker, W., Huber, R., Zwilling, R., and Bode, W. (1993b). Refined 1,8 \u00c5 X-ray crystal structure of astacin, a zinc-endopeptidase from the crayfish Astacus astacus L. structure determination, refinement, molecular structure and comparison with thermolysin. J.\u00a0Mol. Biol. 229: 945\u2013968, https:\/\/doi.org\/10.1006\/jmbi.1993.1098.","DOI":"10.1006\/jmbi.1993.1098"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_036","doi-asserted-by":"crossref","unstructured":"Hasty, K.A., Pourmotabbed, T.F., Goldberg, G.I., Thompson, J.P., Spinella, D.G., Stevens, R.M., and Mainardi, C.L. (1990). Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. J.\u00a0Biol. Chem. 265: 11421\u201311424, https:\/\/doi.org\/10.1016\/s0021-9258(19)38413-3.","DOI":"10.1016\/S0021-9258(19)38413-3"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_037","doi-asserted-by":"crossref","unstructured":"Hillier, L.W., Graves, T.A., Fulton, R.S., Fulton, L.A., Pepin, K.H., Minx, P., Wagner-McPherson, C., Layman, D., Wylie, K., Sekhon, M., et al.. (2005). Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature 434: 724\u2013731, https:\/\/doi.org\/10.1038\/nature03466.","DOI":"10.1038\/nature03466"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_038","doi-asserted-by":"crossref","unstructured":"Jongeneel, C.V., Bouvier, J., and Bairoch, A. (1989). A unique signature identifies a family of zinc-dependent metallopeptidases. FEBS Lett. 242: 211\u2013214, https:\/\/doi.org\/10.1016\/0014-5793(89)80471-5.","DOI":"10.1016\/0014-5793(89)80471-5"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_039","doi-asserted-by":"crossref","unstructured":"J\u00fcrgens, G., Wieschaus, E., N\u00fcsslein-Volhard, C., and Kluding, H. (1984). Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster. Wilhelm Roux\u2019s Arch. Dev. Biol. 193: 283\u2013295, https:\/\/doi.org\/10.1007\/bf00848157.","DOI":"10.1007\/BF00848157"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_040","doi-asserted-by":"crossref","unstructured":"Kessler, E., Takahara, K., Biniaminov, L., Brusel, M., and Greenspan, D.S. (1996). Bone morphogenetic protein-1: the type I procollagen C-Proteinase. Science 271: 360\u2013362, https:\/\/doi.org\/10.1126\/science.271.5247.360.","DOI":"10.1126\/science.271.5247.360"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_041","doi-asserted-by":"crossref","unstructured":"Kleemann, S.G., Keung, W.M., and Riordan, J.F. (1986). Metal binding to angiotensin converting enzyme: implications for the metal binding site. J.\u00a0Inorg. 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J.\u00a0Biochem. 121: 304\u2013308, https:\/\/doi.org\/10.1093\/oxfordjournals.jbchem.a021587.","DOI":"10.1093\/oxfordjournals.jbchem.a021587"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_044","doi-asserted-by":"crossref","unstructured":"Li, SW, Sieron, A.L., Fertala, A., Hojima, Y., Arnold, W.V., and Prockop, D.J. (1996). The C-proteinase that processes procollagens to fibrillar collagens is identical to the protein previously identified as bone morphogenic protein-1. Proc. Nat. Acad. Sci. USA 93: 5127\u20135130, https:\/\/doi.org\/10.1073\/pnas.93.10.5127.","DOI":"10.1073\/pnas.93.10.5127"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_045","doi-asserted-by":"crossref","unstructured":"Lipscomb, W.N., Coppola, J.C., Hartsuck, J.A., Ludwig, M.L., Muirhead, H., Searl, J., and Steitz, T.A. (1966). The structure of carboxypeptidase A: III. Molecular structure at 6 \u00c5 resolution. J.\u00a0Mol. Biol. 19: 423\u2013IN3, https:\/\/doi.org\/10.1016\/s0022-2836(66)80014-1.","DOI":"10.1016\/S0022-2836(66)80014-1"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_046","doi-asserted-by":"crossref","unstructured":"Maskos, K., Fernandez-Catalan, C., Huber, R., Bourenkov, G.P., Bartunik, H., Ellestad, G.A., Reddy, P., Wolfson, M.F., Rauch, C.T., Castner, B.J., et al.. (1998). Crystal structure of the catalytic domain of human tumor necrosis factor-\u03b1-converting enzyme. Proc. Natl. Acad. Sci. USA 95: 3408\u20133412, https:\/\/doi.org\/10.1073\/pnas.95.7.3408.","DOI":"10.1073\/pnas.95.7.3408"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_047","doi-asserted-by":"crossref","unstructured":"Matthews, B.W., Jansonius, J.N., Colman, P.M., Schoenborn, B.P., and Dupourque, D. (1972). Three-dimensional structure of thermolysin. Nat. 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J.\u00a0Mol. Biol. 77: 417\u2013436, https:\/\/doi.org\/10.1016\/0022-2836(73)90448-8.","DOI":"10.1016\/0022-2836(73)90448-8"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_062","doi-asserted-by":"crossref","unstructured":"Rydel, T.J., Ravichandran, K.G., Tulinsky, A., Bode, W., Huber, R., Roitsch, C., and Fenton, J.W. (1990). The structure of a complex of recombinant hirudin and human \u03b1-thrombin. Science 249: 277\u2013280, https:\/\/doi.org\/10.1126\/science.2374926.","DOI":"10.1126\/science.2374926"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_063","doi-asserted-by":"crossref","unstructured":"Sato, H., Takiso, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994). A matrix metalloproteinase expressed on the surface of invasive tumour cells. 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Science 242: 1528\u20131534, https:\/\/doi.org\/10.1126\/science.3201241.","DOI":"10.1126\/science.3201241"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_088","doi-asserted-by":"crossref","unstructured":"Zwilling, R. (1968). Zur Evolution der Endopeptidasen, IV. \u03b1- und \u03b2-Protease aus Tenebrio molitor. Hoppe-Seyler\u2018s Z. Physiol. Chem. 349: 326\u2013332, https:\/\/doi.org\/10.1515\/bchm2.1968.349.1.326.","DOI":"10.1515\/bchm2.1968.349.1.326"},{"key":"2026081901564517200_j_hsz-2026-0142_ref_089","doi-asserted-by":"crossref","unstructured":"Zwilling, R., and Pfleiderer, G. (1967). Zur Evolution der Endopeptidasen, II. Eigenschaften der \u03b1-Protease aus dem Gift von Crotalus atrox. Hoppe-Seyler\u2018s Z. Physiol. 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