{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:09:43Z","timestamp":1791925783111,"version":"4.3.4"},"reference-count":92,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2013,3,27]],"date-time":"2013-03-27T00:00:00Z","timestamp":1364342400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Antibiot"],"published-print":{"date-parts":[[2013,7]]},"DOI":"10.1038\/ja.2013.24","type":"journal-article","created":{"date-parts":[[2013,3,27]],"date-time":"2013-03-27T07:18:30Z","timestamp":1364368710000},"page":"401-410","source":"Crossref","is-referenced-by-count":84,"title":["Origins of the \u03b2-lactam rings in natural products"],"prefix":"10.1038","volume":"66","author":[{"given":"Kapil","family":"Tahlan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,3,27]]},"reference":[{"key":"BFja201324_CR1","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s00253-003-1274-y","volume":"61","author":"RP Elander","year":"2003","unstructured":"Elander, R. P. Industrial production of beta-lactam antibiotics. Appl. Microbiol. Biotechnol. 61, 385\u2013392 (2003).","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"BFja201324_CR2","first-page":"10","volume":"9","author":"P Liras","year":"2006","unstructured":"Liras, P. & Martin, J. F. Gene clusters for \u03b2-lactam antibiotics and control of their expression: why have clusters evolved, and from where did they originate? Int. Microbiol. 9, 10\u201319 (2006).","journal-title":"Int. Microbiol."},{"key":"BFja201324_CR3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1039\/C2NP20065A","volume":"30","author":"RB Hamed","year":"2013","unstructured":"Hamed, R. B. et al. The enzymes of beta-lactam biosynthesis. Nat. Prod. Rep. 30, 21\u2013107 (2013).","journal-title":"Nat. Prod. Rep."},{"key":"BFja201324_CR4","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/S0076-6879(09)04816-2","volume":"458","author":"P Liras","year":"2009","unstructured":"Liras, P. & Demain, A. L. Chapter 16. Enzymology of beta-lactam compounds with cephem structure produced by actinomycete. Methods Enzymol. 458, 401\u2013429 (2009).","journal-title":"Methods Enzymol."},{"key":"BFja201324_CR5","doi-asserted-by":"publisher","first-page":"4251","DOI":"10.1039\/b505964j","volume":"2005","author":"NJ Kershaw","year":"2005","unstructured":"Kershaw, N. J., Caines, M. E., Sleeman, M. C. & Schofield, C. J. The enzymology of clavam and carbapenem biosynthesis. Chem. Commun. 2005, 4251\u20134263 (2005).","journal-title":"Chem. Commun."},{"key":"BFja201324_CR6","first-page":"167","volume-title":"Streptomyces: Molecular Biology and Biotechnology","author":"P Liras","year":"2011","unstructured":"Liras, P., Santamarta, I. & Perez-Redondo, R. Clavulanic acid and clavams biosynthesis and regulation in Streptomyces: Molecular Biology and Biotechnology ed. Dyson P., 167\u2013178 Caister Academic Press: Wymondham, UK, (2011)."},{"key":"BFja201324_CR7","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1007\/s10295-012-1191-0","volume":"39","author":"SE Jensen","year":"2012","unstructured":"Jensen, S. E. Biosynthesis of clavam metabolites. J. Ind. Microbiol. Biotechnol. 39, 1407\u20131419 (2012).","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"BFja201324_CR8","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1351\/pac198759030475","volume":"59","author":"AG Brown","year":"1987","unstructured":"Brown, A. G. Discovery and development of new \u03b2-lactam antibiotics. Pure Appl. Chem. 59, 475\u2013484 (1987).","journal-title":"Pure Appl. Chem."},{"key":"BFja201324_CR9","first-page":"226","volume":"10","author":"A Fleming","year":"1929","unstructured":"Fleming, A. On the antibacterial action of a Penicillium, with special reference to their use in the isolation of B. influenzae. Brit. J. Exp. Pathol. 10, 226\u2013236 (1929).","journal-title":"Brit. J. Exp. Pathol."},{"key":"BFja201324_CR10","first-page":"97","volume-title":"Antibiotics Containing the Beta-Lactam Structure","author":"RP Elander","year":"1983","unstructured":"Elander, R. P. Strain improvement and preservation of \u03b2-lactam-producing microorganisms in Antibiotics Containing the Beta-Lactam Structure eds Demain A. L., Solomon N. A., 97\u2013146 Springer-Verlag: Berlin, (1983)."},{"key":"BFja201324_CR11","first-page":"1761","volume":"38","author":"K Kitano","year":"1974","unstructured":"Kitano, K. et al. Production of cephalosporin antibiotics by strains belonging to the genera Arachnomyces, Anixiopsis and Spiroidium. Agr. Biol. Chem. 38, 1761\u20131762 (1974).","journal-title":"Agr. Biol. Chem."},{"key":"BFja201324_CR12","doi-asserted-by":"publisher","first-page":"298","DOI":"10.7164\/antibiotics.27.298","volume":"27","author":"CE Higgens","year":"1974","unstructured":"Higgens, C. E., Hamill, R. L., Sands, T. H., Hoehn, M. M. & Davis, N. E. Letter: The occurrence of deacetoxycephalosporin C in fungi and streptomycetes. J. Antibiot. 27, 298\u2013300 (1974).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR13","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1146\/annurev.mi.34.100180.001111","volume":"34","author":"H Aoki","year":"1980","unstructured":"Aoki, H. & Okuhara, M. Natural beta-lactam antibiotics. Annu. Rev. Microbiol. 34, 159\u2013181 (1980).","journal-title":"Annu. Rev. Microbiol."},{"key":"BFja201324_CR14","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1023\/A:1001738823146","volume":"75","author":"AL Demain","year":"1999","unstructured":"Demain, A. L. & Elander, R. P. The beta-lactam antibiotics: past, present, and future. Antonie Van Leeuwenhoek 75, 5\u201319 (1999).","journal-title":"Antonie Van Leeuwenhoek"},{"key":"BFja201324_CR15","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.7164\/antibiotics.37.1528","volume":"37","author":"H Ono","year":"1984","unstructured":"Ono, H., Nozaki, Y., Katayama, N. & Okazaki, H. Cephabacins, new cephem antibiotics of bacterial origin. I. Discovery and taxonomy of the producing organisms and fermentation. J. Antibiot. 37, 1528\u20131535 (1984).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR16","doi-asserted-by":"publisher","first-page":"773","DOI":"10.7164\/antibiotics.37.773","volume":"37","author":"PD Singh","year":"1984","unstructured":"Singh, P. D., Young, M. G., Johnson, J. H., Cimarusti, C. M. & Sykes, R. B. Bacterial production of 7-formamidocephalosporins. Isolation and structure determination. J. Antibiot. 37, 773\u2013780 (1984).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR17","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1098\/rspb.1990.0081","volume":"241","author":"MA Penalva","year":"1990","unstructured":"Penalva, M. A., Moya, A., Dopazo, J. & Ramon, D. Sequences of isopenicillin N synthetase genes suggest horizontal gene transfer from prokaryotes to eukaryotes. Proc. Biol. Sci. 241, 164\u2013169 (1990).","journal-title":"Proc. Biol. Sci."},{"key":"BFja201324_CR18","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1007\/s10295-009-0683-z","volume":"37","author":"PR Jensen","year":"2010","unstructured":"Jensen, P. R. Linking species concepts to natural product discovery in the post-genomic era. J. Ind. Microbiol. Biotechnol. 37, 219\u2013224 (2010).","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"BFja201324_CR19","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/0167-7799(90)90148-Q","volume":"8","author":"G Cohen","year":"1990","unstructured":"Cohen, G., Shiffman, D., Mevarech, M. & Aharonowitz, Y. Microbial isopenicillin N synthase genes: structure, function, diversity and evolution. Trends Biotechnol. 8, 105\u2013111 (1990).","journal-title":"Trends Biotechnol."},{"key":"BFja201324_CR20","doi-asserted-by":"publisher","first-page":"3817","DOI":"10.1128\/jb.170.9.3817-3826.1988","volume":"170","author":"BJ Weigel","year":"1988","unstructured":"Weigel, B. J. et al. Cloning and expression in Escherichia coli of isopenicillin N synthetase genes from Streptomyces lipmanii and Aspergillus nidulans. J. Bacteriol. 170, 3817\u20133826 (1988).","journal-title":"J. Bacteriol."},{"key":"BFja201324_CR21","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1021\/jm00088a028","volume":"35","author":"GW Huffman","year":"1992","unstructured":"Huffman, G. W. et al. Substrate specificity of isopenicillin N synthase. J. Med. Chem. 35, 1897\u20131914 (1992).","journal-title":"J. Med. Chem."},{"key":"BFja201324_CR22","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/42990","volume":"387","author":"PL Roach","year":"1997","unstructured":"Roach, P. L. et al. Structure of isopenicillin N synthase complexed with substrate and the mechanism of penicillin formation. Nature 387, 827\u2013830 (1997).","journal-title":"Nature"},{"key":"BFja201324_CR23","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1111\/j.1432-1033.1996.0736r.x","volume":"242","author":"PL Roach","year":"1996","unstructured":"Roach, P. L. et al. Anaerobic crystallisation of an isopenicillin N synthase.Fe(II).substrate complex demonstrated by X-ray studies. Eur. J. Biochem. 242, 736\u2013740 (1996).","journal-title":"Eur. J. Biochem."},{"key":"BFja201324_CR24","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/375700a0","volume":"375","author":"PL Roach","year":"1995","unstructured":"Roach, P. L. et al. Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes. Nature 375, 700\u2013704 (1995).","journal-title":"Nature"},{"key":"BFja201324_CR25","doi-asserted-by":"publisher","first-page":"483","DOI":"10.7164\/antibiotics.35.483","volume":"35","author":"SE Jensen","year":"1982","unstructured":"Jensen, S. E., Westlake, D. W. & Wolfe, S. Cyclization of \u03b4-(L-\u03b1-aminoadipyl)-L-cysteinyl-D-valine to penicillins by cell-free extracts of Streptomyces clavuligerus. J. Antibiot. 35, 483\u2013490 (1982).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR26","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/0378-1119(88)90557-4","volume":"62","author":"BK Leskiw","year":"1988","unstructured":"Leskiw, B. K. et al. Cloning and nucleotide sequence determination of the isopenicillin N synthetase gene from Streptomyces clavuligerus. Gene 62, 187\u2013196 (1988).","journal-title":"Gene"},{"key":"BFja201324_CR27","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/318191a0","volume":"318","author":"SM Samson","year":"1985","unstructured":"Samson, S. M. et al. Isolation, sequence determination and expression in Escherichia coli of the isopenicillin N synthetase gene from Cephalosporium acremonium. Nature 318, 191\u2013194 (1985).","journal-title":"Nature"},{"key":"BFja201324_CR28","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1126\/science.6546810","volume":"224","author":"IJ Hollander","year":"1984","unstructured":"Hollander, I. J., Shen, Y. Q., Heim, J., Demain, A. L. & Wolfe, S. A pure enzyme catalyzing penicillin biosynthesis. Science 224, 610\u2013612 (1984).","journal-title":"Science"},{"key":"BFja201324_CR29","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1042\/bj1940645","volume":"194","author":"GS Jayatilake","year":"1981","unstructured":"Jayatilake, G. S., Huddleston, J. A. & Abraham, E. P. Conversion of isopenicillin N into penicillin N in cell-free extracts of Cephalosporium acremonium. Biochem. J. 194, 645\u2013647 (1981).","journal-title":"Biochem. J."},{"key":"BFja201324_CR30","first-page":"275","volume":"8","author":"DT Jones","year":"1992","unstructured":"Jones, D. T., Taylor, W. R. & Thornton, J. M. The rapid generation of mutation data matrices from protein sequences. Comput. Appl. Biosci. 8, 275\u2013282 (1992).","journal-title":"Comput. Appl. Biosci."},{"key":"BFja201324_CR31","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1111\/j.1558-5646.1985.tb00420.x","volume":"39","author":"J Felsenstein","year":"1985","unstructured":"Felsenstein, J. Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39, 783\u2013791 (1985).","journal-title":"Evolution"},{"key":"BFja201324_CR32","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.1093\/molbev\/msr121","volume":"28","author":"K Tamura","year":"2011","unstructured":"Tamura, K. et al. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol. Biol. Evol. 28, 2731\u20132739 (2011).","journal-title":"Mol. Biol. Evol."},{"key":"BFja201324_CR33","doi-asserted-by":"publisher","first-page":"6619","DOI":"10.1021\/bi047478q","volume":"44","author":"AJ Long","year":"2005","unstructured":"Long, A. J. et al. Structural studies on the reaction of isopenicillin N synthase with the truncated substrate analogues delta-(L-alpha-aminoadipoyl)-L-cysteinyl-glycine and delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-alanine. Biochemistry 44, 6619\u20136628 (2005).","journal-title":"Biochemistry"},{"key":"BFja201324_CR34","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1146\/annurev.mi.46.100192.002333","volume":"46","author":"Y Aharonowitz","year":"1992","unstructured":"Aharonowitz, Y., Cohen, G. & Martin, J. F. Penicillin and cephalosporin biosynthetic genes: structure, organization, regulation, and evolution. Annu. Rev. Microbiol. 46, 461\u2013495 (1992).","journal-title":"Annu. Rev. Microbiol."},{"key":"BFja201324_CR35","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1099\/00207713-21-4-326","volume":"21","author":"CE Higgens","year":"1971","unstructured":"Higgens, C. E. & Kastner, R. E. Streptomyces clavuligerus sp. nov., a \u03b2-lactam antibiotic producer. Int. J. Syst. Bacteriol. 21, 326\u2013331 (1971).","journal-title":"Int. J. Syst. Bacteriol."},{"key":"BFja201324_CR36","doi-asserted-by":"publisher","first-page":"266b","DOI":"10.1039\/C3976000266B","volume":"1976","author":"TT Howarth","year":"1976","unstructured":"Howarth, T. T., Brown, A. G. & King, T. J. Clavulanic acid, a novel \u03b2-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis. Chem. Commun. 1976, 266b\u2013267b (1976).","journal-title":"Chem. Commun."},{"key":"BFja201324_CR37","first-page":"1","volume":"29","author":"M Jamin","year":"1995","unstructured":"Jamin, M., Wilkin, J. M. & Frere, J. M. Bacterial DD-transpeptidases and penicillin. Essays Biochem 29, 1\u201324 (1995).","journal-title":"Essays Biochem"},{"key":"BFja201324_CR38","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1007\/978-94-011-2928-2_5","volume-title":"The Chemistry of \u03b2-Lactams","author":"JM Frere","year":"1992","unstructured":"Frere, J. M., Nguyen-Disteche, M., Coyette, J. & Joris, B. Mode of action: interaction with the penicillin binding proteins in The Chemistry of \u03b2-Lactams ed. Page M. I., 148\u2013197 Blackie Academic & Professional: Glasgow, (1992)."},{"key":"BFja201324_CR39","first-page":"199","volume-title":"The Chemistry of \u03b2-Lactams","author":"SG Waley","year":"1992","unstructured":"Waley, S. G. \u03b2-lactamase: mechanism of action in The Chemistry of \u03b2-Lactams ed. Page M. I., 199\u2013228 Blackie Academic & Professional: Glasgow, (1992)."},{"key":"BFja201324_CR40","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/359700a0","volume":"359","author":"NC Strynadka","year":"1992","unstructured":"Strynadka, N. C. et al. Molecular structure of the acyl-enzyme intermediate in \u03b2-lactam hydrolysis at 1.7 A resolution. Nature 359, 700\u2013705 (1992).","journal-title":"Nature"},{"key":"BFja201324_CR41","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/978-94-011-2928-2_7","volume-title":"The Chemistry of \u03b2-Lactams","author":"RF Pratt","year":"1992","unstructured":"Pratt, R. F. \u03b2-lactamase: inhibition in The Chemistry of \u03b2-Lactams ed. Page M. I., 229\u2013271 Blackie Academic & Professional: Glasgow, (1992)."},{"key":"BFja201324_CR42","doi-asserted-by":"publisher","first-page":"12421","DOI":"10.1021\/bi961044g","volume":"35","author":"RP Brown","year":"1996","unstructured":"Brown, R. P., Aplin, R. T. & Schofield, C. J. Inhibition of TEM-2 \u03b2-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometry. Biochemistry 35, 12421\u201312432 (1996).","journal-title":"Biochemistry"},{"key":"BFja201324_CR43","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1023\/A:1001755724055","volume":"75","author":"SE Jensen","year":"1999","unstructured":"Jensen, S. E. & Paradkar, A. S. Biosynthesis and molecular genetics of clavulanic acid. Antonie Van Leeuwenhoek 75, 125\u2013133 (1999).","journal-title":"Antonie Van Leeuwenhoek"},{"key":"BFja201324_CR44","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1039\/C39790000282","volume":"1979","author":"D Brown","year":"1979","unstructured":"Brown, D., Evans, J. R. & Fletton, R. A. Structures of three novel \u03b2-lactams isolated from Streptomyces clavuligerus. Chem. Commun. 1979, 282\u2013283 (1979).","journal-title":"Chem. Commun."},{"key":"BFja201324_CR45","doi-asserted-by":"publisher","first-page":"208","DOI":"10.7164\/antibiotics.36.208","volume":"36","author":"DL Pruess","year":"1983","unstructured":"Pruess, D. L. & Kellett, M. Ro-22-5417, a new clavam antibiotic from Streptomyces clavuligerus I. Discovery and biological activity. J. Antibiot. 36, 208\u2013212 (1983).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR46","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/BF00406126","volume":"147","author":"F Rohl","year":"1987","unstructured":"Rohl, F., Rabenhorst, J. & Zahner, H. Biological properties and mode of action of clavams. Arch. Microbiol. 147, 315\u2013320 (1987).","journal-title":"Arch. Microbiol."},{"key":"BFja201324_CR47","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1016\/S0960-894X(01)80946-X","volume":"3","author":"JW Janc","year":"1993","unstructured":"Janc, J. W., Egan, L. A. & Townsend, C. A. Emerging evidence for a shared biosynthetic pathway among clavulanic acid and the structurally diverse clavam metabolites. Bioorg. Med. Chem. Lett. 3, 2313\u20132316 (1993).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"BFja201324_CR48","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1021\/ja963107o","volume":"119","author":"LA Egan","year":"1997","unstructured":"Egan, L. A., Busby, R. W., IwataReuyl, D. & Townsend, C. A. Probable role of clavaminic acid as the terminal intermediate in the common pathway to clavulanic acid and the antipodal clavam metabolites. J. Am. Chem. Soc. 119, 2348\u20132355 (1997).","journal-title":"J. Am. Chem. Soc."},{"key":"BFja201324_CR49","doi-asserted-by":"publisher","first-page":"9082","DOI":"10.1073\/pnas.95.16.9082","volume":"95","author":"BO Bachmann","year":"1998","unstructured":"Bachmann, B. O., Li, R. & Townsend, C. A. \u03b2-Lactam synthetase: a new biosynthetic enzyme. Proc. Natl Acad. Sci. USA 95, 9082\u20139086 (1998).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFja201324_CR50","doi-asserted-by":"publisher","first-page":"11187","DOI":"10.1021\/bi000709i","volume":"39","author":"BO Bachmann","year":"2000","unstructured":"Bachmann, B. O. & Townsend, C. A. Kinetic mechanism of the \u03b2-lactam synthetase of Streptomyces clavuligerus. Biochemistry 39, 11187\u201311193 (2000).","journal-title":"Biochemistry"},{"key":"BFja201324_CR51","doi-asserted-by":"publisher","first-page":"2325","DOI":"10.1039\/a806713i","volume":"1998","author":"HJ McNaughton","year":"1998","unstructured":"McNaughton, H. J. et al. \u03b2-lactam synthetase: implications for \u03b2-lactamase evolution. Chem. Commun. 1998, 2325\u20132326 (1998).","journal-title":"Chem. Commun."},{"key":"BFja201324_CR52","doi-asserted-by":"publisher","first-page":"4959","DOI":"10.1021\/bi900432n","volume":"48","author":"ML Raber","year":"2009","unstructured":"Raber, M. L., Arnett, S. O. & Townsend, C. A. A conserved tyrosyl-glutamyl catalytic dyad in evolutionarily linked enzymes: carbapenam synthetase and beta-lactam synthetase. Biochemistry 48, 4959\u20134971 (2009).","journal-title":"Biochemistry"},{"key":"BFja201324_CR53","doi-asserted-by":"publisher","first-page":"2904","DOI":"10.1002\/cbic.200900389","volume":"10","author":"ML Raber","year":"2009","unstructured":"Raber, M. L., Castillo, A., Greer, A. & Townsend, C. A. A conserved lysine in beta-lactam synthetase assists ring cyclization: implications for clavam and carbapenem biosynthesis. Chembiochem 10, 2904\u20132912 (2009).","journal-title":"Chembiochem"},{"key":"BFja201324_CR54","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1074\/jbc.M805390200","volume":"284","author":"ML Raber","year":"2009","unstructured":"Raber, M. L., Freeman, M. F. & Townsend, C. A. Dissection of the stepwise mechanism to beta-lactam formation and elucidation of a rate-determining conformational change in beta-lactam synthetase. J. Biol. Chem. 284, 207\u2013217 (2009).","journal-title":"J. Biol. Chem."},{"key":"BFja201324_CR55","doi-asserted-by":"publisher","first-page":"14752","DOI":"10.1073\/pnas.232361199","volume":"99","author":"MT Miller","year":"2002","unstructured":"Miller, M. T., Bachmann, B. O., Townsend, C. A. & Rosenzweig, A. C. The catalytic cycle of \u03b2-lactam synthetase observed by x-ray crystallographic snapshots. Proc. Natl Acad. Sci. USA 99, 14752\u201314757 (2002).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFja201324_CR56","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1038\/90394","volume":"8","author":"MT Miller","year":"2001","unstructured":"Miller, M. T., Bachmann, B. O., Townsend, C. A. & Rosenzweig, A. C. Structure of \u03b2-lactam synthetase reveals how to synthesize antibiotics instead of asparagine. Nat. Struct. Biol. 8, 684\u2013689 (2001).","journal-title":"Nat. Struct. Biol."},{"key":"BFja201324_CR57","doi-asserted-by":"publisher","first-page":"R161","DOI":"10.1186\/gb-2008-9-11-r161","volume":"9","author":"JH Saw","year":"2008","unstructured":"Saw, J. H. et al. Encapsulated in silica: genome, proteome and physiology of the thermophilic bacterium Anoxybacillus flavithermus WK1. Genome Biol 9, R161 (2008).","journal-title":"Genome Biol"},{"key":"BFja201324_CR58","doi-asserted-by":"publisher","first-page":"287","DOI":"10.7164\/antibiotics.32.287","volume":"32","author":"D Butterworth","year":"1979","unstructured":"Butterworth, D., Cole, M., Hanscomb, G. & Rolinson, G. N. Olivanic acids, a family of beta-lactam antibiotics with beta-lactamase inhibitory properties produced by Streptomyces species. I. Detection, properties and fermentation studies. J. Antibiot. 32, 287\u2013294 (1979).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7164\/antibiotics.32.1","volume":"32","author":"JS Kahan","year":"1979","unstructured":"Kahan, J. S. et al. Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties. J. Antibiot. 32, 1\u201312 (1979).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR60","doi-asserted-by":"publisher","first-page":"628","DOI":"10.7164\/antibiotics.34.628","volume":"34","author":"EO Stapley","year":"1981","unstructured":"Stapley, E. O. et al. Epithienamycins-novel beta-lactams related to thienamycin. I. Production and antibacterial activity. J. Antibiot. 34, 628\u2013636 (1981).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR61","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/S1074-5521(03)00069-3","volume":"10","author":"LE Nunez","year":"2003","unstructured":"Nunez, L. E., Mendez, C., Brana, A. F., Blanco, G. & Salas, J. A. The biosynthetic gene cluster for the beta-lactam carbapenem thienamycin in Streptomyces cattleya. Chem. Biol. 10, 301\u2013311 (2003).","journal-title":"Chem. Biol."},{"key":"BFja201324_CR62","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1046\/j.1365-2958.1996.00125.x","volume":"22","author":"SJ McGowan","year":"1996","unstructured":"McGowan, S. J. et al. Analysis of bacterial carbapenem antibiotic production genes reveals a novel beta-lactam biosynthesis pathway. Mol. Microbiol. 22, 415\u2013426 (1996).","journal-title":"Mol. Microbiol."},{"key":"BFja201324_CR63","doi-asserted-by":"publisher","first-page":"6730","DOI":"10.1074\/jbc.M311824200","volume":"279","author":"MC Sleeman","year":"2004","unstructured":"Sleeman, M. C. & Schofield, C. J. Carboxymethylproline synthase (CarB), an unusual carbon-carbon bond-forming enzyme of the crotonase superfamily involved in carbapenem biosynthesis. J. Biol. Chem. 279, 6730\u20136736 (2004).","journal-title":"J. Biol. Chem."},{"key":"BFja201324_CR64","doi-asserted-by":"publisher","first-page":"7836","DOI":"10.1021\/bi034361d","volume":"42","author":"B Gerratana","year":"2003","unstructured":"Gerratana, B., Stapon, A. & Townsend, C. A. Inhibition and alternate substrate studies on the mechanism of carbapenam synthetase from Erwinia carotovora. Biochemistry 42, 7836\u20137847 (2003).","journal-title":"Biochemistry"},{"key":"BFja201324_CR65","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.1002\/cbic.201100366","volume":"12","author":"MJ Bodner","year":"2011","unstructured":"Bodner, M. J. et al. Definition of the common and divergent steps in carbapenem beta-lactam antibiotic biosynthesis. Chembiochem 12, 2159\u20132165 (2011).","journal-title":"Chembiochem"},{"key":"BFja201324_CR66","doi-asserted-by":"publisher","first-page":"40996","DOI":"10.1074\/jbc.M307901200","volume":"278","author":"MT Miller","year":"2003","unstructured":"Miller, M. T., Gerratana, B., Stapon, A., Townsend, C. A. & Rosenzweig, A. C. Crystal structure of carbapenam synthetase (CarA). J. Biol. Chem. 278, 40996\u201341002 (2003).","journal-title":"J. Biol. Chem."},{"key":"BFja201324_CR67","doi-asserted-by":"publisher","first-page":"492","DOI":"10.7164\/antibiotics.29.492","volume":"29","author":"H Aoki","year":"1976","unstructured":"Aoki, H., Sakai, H., Kohsaka, M., Konomi, T. & Hosoda, J. Nocardicin A, a new monocyclic beta-lactam antibiotic. I. Discovery, isolation and characterization. J. Antibiot. 29, 492\u2013500 (1976).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR68","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/289590a0","volume":"289","author":"A Imada","year":"1981","unstructured":"Imada, A., Kitano, K., Kintaka, K., Muroi, M. & Asai, M. Sulfazecin and isosulfazecin, novel beta-lactam antibiotics of bacterial origin. Nature 289, 590\u2013591 (1981).","journal-title":"Nature"},{"key":"BFja201324_CR69","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.3390\/toxins3081038","volume":"3","author":"SO Duke","year":"2011","unstructured":"Duke, S. O. & Dayan, F. E. Modes of action of microbially-produced phytotoxins. Toxins 3, 1038\u20131064 (2011).","journal-title":"Toxins"},{"key":"BFja201324_CR70","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1248\/bpb.23.262","volume":"23","author":"S Funayama","year":"2000","unstructured":"Funayama, S. et al. Cytotoxic alkaloids of Pachysandra terminalis. Biol. Pharm. Bull. 23, 262\u2013264 (2000).","journal-title":"Biol. Pharm. Bull."},{"key":"BFja201324_CR71","doi-asserted-by":"publisher","first-page":"5290","DOI":"10.1021\/ol102351z","volume":"12","author":"E Aviles","year":"2010","unstructured":"Aviles, E. & Rodriguez, A. D. Monamphilectine A, a potent antimalarial beta-lactam from marine sponge Hymeniacidon sp: isolation, structure, semisynthesis, and bioactivity. Org. Lett. 12, 5290\u20135293 (2010).","journal-title":"Org. Lett."},{"key":"BFja201324_CR72","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/ja.2012.52","volume":"65","author":"M Takagi","year":"2012","unstructured":"Takagi, M. & Shin-Ya, K. Construction of a natural product library containing secondary metabolites produced by actinomycetes. J. Antibiot. 65, 443\u2013447 (2012).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR73","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1007\/s10295-010-0721-x","volume":"37","author":"E Cundliffe","year":"2010","unstructured":"Cundliffe, E. & Demain, A. L. Avoidance of suicide in antibiotic-producing microbes. J. Ind. Microbiol. Biotechnol. 37, 643\u2013672 (2010).","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"BFja201324_CR74","doi-asserted-by":"publisher","first-page":"7712","DOI":"10.1021\/bi3011384","volume":"51","author":"TA Wencewicz","year":"2012","unstructured":"Wencewicz, T. A. & Walsh, C. T. Pseudomonas syringae Self-Protection from Tabtoxinine-beta-Lactam by Ligase TblF and Acetylase Ttr. Biochemistry 51, 7712\u20137725 (2012).","journal-title":"Biochemistry"},{"key":"BFja201324_CR75","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7164\/antibiotics.28.1","volume":"28","author":"JP Scannell","year":"1975","unstructured":"Scannell, J. P. et al. Antimetabolites produced by microorganisms. XII (S)-alanyl-3-[alpha-(S)-chloro-3-(S)-hydroxy 2-oxo-3-azetidinylmethyl]-(S)-alanine, a new beta-lactam containing natural product. J. Antibiot. 28, 1\u20136 (1975).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR76","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1002\/hlca.19900730228","volume":"73","author":"P Roth","year":"1990","unstructured":"Roth, P., Hadener, A. & Tamm, C. Further studies on the biosynthesis of tabtoxin (wildfire toxin): incorporation of [2,3-13C2] pyruvate into the \u03b2-lactam moiety. Helv. Chim. Acta 73, 476\u2013482 (1990).","journal-title":"Helv. Chim. Acta"},{"key":"BFja201324_CR77","doi-asserted-by":"crossref","first-page":"4994","DOI":"10.1016\/S0021-9258(18)61144-5","volume":"262","author":"CJ Unkefer","year":"1987","unstructured":"Unkefer, C. J., London, R. E., Durbin, R. D., Uchytil, T. F. & Langston-Unkefer, P. J. The biosynthesis of tabtoxinine-beta-lactam. Use of specifically 13C-labeled glucose and 13C NMR spectroscopy to identify its biosynthetic precursors. J. Biol. Chem. 262, 4994\u20134999 (1987).","journal-title":"J. Biol. Chem."},{"key":"BFja201324_CR78","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/hlca.19870700220","volume":"70","author":"B Muller","year":"1987","unstructured":"Muller, B., Hadener, A. & Tamm, C. Studies on the biosynthesis of tabtoxin (wildfire toxin). Origin of the carbonyl C-atom of the \u03b2-lactam moiety from the C1-pool. Helv. Chim. Acta 70, 412\u2013422 (1987).","journal-title":"Helv. Chim. Acta"},{"key":"BFja201324_CR79","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/ja.2005.109","volume":"58","author":"TG Kinscherf","year":"2005","unstructured":"Kinscherf, T. G. & Willis, D. K. The biosynthetic gene cluster for the beta-lactam antibiotic tabtoxin in Pseudomonas syringae. J. Antibiot. 58, 817\u2013821 (2005).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR80","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.chembiol.2004.04.012","volume":"11","author":"M Gunsior","year":"2004","unstructured":"Gunsior, M. et al. The biosynthetic gene cluster for a monocyclic beta-lactam antibiotic, nocardicin A. Chem. Biol. 11, 927\u2013938 (2004).","journal-title":"Chem. Biol."},{"key":"BFja201324_CR81","doi-asserted-by":"publisher","first-page":"46","DOI":"10.4056\/sigs.21137","volume":"1","author":"M Land","year":"2009","unstructured":"Land, M. et al. Complete genome sequence of Actinosynnema mirum type strain (101). Stand. Genomic Sci. 1, 46\u201353 (2009).","journal-title":"Stand. Genomic Sci."},{"key":"BFja201324_CR82","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.chembiol.2011.10.020","volume":"19","author":"JM Davidsen","year":"2012","unstructured":"Davidsen, J. M. & Townsend, C. A. In vivo characterization of nonribosomal peptide synthetases NocA and NocB in the biosynthesis of nocardicin A. Chem. Biol. 19, 297\u2013306 (2012).","journal-title":"Chem. Biol."},{"key":"BFja201324_CR83","doi-asserted-by":"crossref","first-page":"4068","DOI":"10.1128\/JB.180.16.4068-4079.1998","volume":"180","author":"DC Alexander","year":"1998","unstructured":"Alexander, D. C. & Jensen, S. E. Investigation of the Streptomyces clavuligerus cephamycin C gene cluster and its regulation by the CcaR protein. J. Bacteriol. 180, 4068\u20134079 (1998).","journal-title":"J. Bacteriol."},{"key":"BFja201324_CR84","first-page":"2813","volume":"103","author":"CA Townsend","year":"1981","unstructured":"Townsend, C. A. & Brown, A. M. Biosynthetic studies of nocardicin A. J. Am. Chem. Soc. 103, 2813\u20132814 (1981).","journal-title":"J. Am. Chem. Soc."},{"key":"BFja201324_CR85","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.7164\/antibiotics.37.1536","volume":"37","author":"S Harada","year":"1984","unstructured":"Harada, S., Tsubotani, S., Ono, H. & Okazaki, H. Cephabacins, new cephem antibiotics of bacterial origin. II. Isolation and characterization. J. Antibiot. 37, 1536\u20131545 (1984).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR86","doi-asserted-by":"publisher","first-page":"510","DOI":"10.7164\/antibiotics.39.510","volume":"39","author":"HD King","year":"1986","unstructured":"King, H. D., Langharig, J. & Sanglier, J. J. Clavamycins, new clavam antibiotics from two variants of Streptomyces hygroscopicus. I. Taxonomy of the producing organisms, fermentation, and biological activities. J. Antibiot. 39, 510\u2013515 (1986).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR87","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1039\/C39870001736","volume":"1987","author":"SW Elson","year":"1987","unstructured":"Elson, S. W. et al. Isolation of two novel intracellular \u03b2-lactams and a novel dioxygenase cyclising enzyme from Streptomyces clavuligerus. Chem. Commun. 1987, 1736\u20131738 (1987).","journal-title":"Chem. Commun."},{"key":"BFja201324_CR88","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.7164\/antibiotics.41.1231","volume":"41","author":"BW Bycroft","year":"1988","unstructured":"Bycroft, B. W., Maslen, C., Box, S. J., Brown, A. & Tyler, J. W. The biosynthetic implications of acetate and glutamate incorporation into (3R,5R)-carbapenam-3-carboxylic acid and (5R)-carbapen-2-em-3-carboxylic acid by Serratia sp. J. Antibiot. 41, 1231\u20131242 (1988).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR89","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/291489a0","volume":"291","author":"RB Sykes","year":"1981","unstructured":"Sykes, R. B. et al. Monocyclic beta-lactam antibiotics produced by bacteria. Nature 291, 489\u2013491 (1981).","journal-title":"Nature"},{"key":"BFja201324_CR90","doi-asserted-by":"publisher","first-page":"295","DOI":"10.7164\/antibiotics.35.295","volume":"35","author":"JS Wells","year":"1982","unstructured":"Wells, J. S. et al. EM5400, a family of monobactam antibiotics produced by Agrobacterium radiobacter. I. Taxonomy, fermentation and biological properties. J. Antibiot. 35, 295\u2013299 (1982).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR91","doi-asserted-by":"publisher","first-page":"184","DOI":"10.7164\/antibiotics.35.184","volume":"35","author":"JS Wells","year":"1982","unstructured":"Wells, J. S. et al. SQ 26,180, a novel monobactam. I Taxonomy, fermentation and biological properties. J. Antibiot. 35, 184\u2013188 (1982).","journal-title":"J. Antibiot."},{"key":"BFja201324_CR92","doi-asserted-by":"publisher","first-page":"3473","DOI":"10.1016\/S0040-4039(01)89330-8","volume":"6","author":"T Kikuchi","year":"1965","unstructured":"Kikuchi, T. & Uyeo, S. Studies on the alkaloids of Pachysandra terminalis Sieb. et Zucc. (6). Structure of pachystermine-A and -B, novel type alkaloids having beta-lactam ring system. Tetrahedron Lett. 6, 3473\u20133485 (1965).","journal-title":"Tetrahedron Lett."}],"container-title":["The Journal of Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/ja201324.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/ja201324","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/ja201324.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T17:19:31Z","timestamp":1684430371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ja201324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3,27]]},"references-count":92,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2013,7]]}},"alternative-id":["BFja201324"],"URL":"https:\/\/doi.org\/10.1038\/ja.2013.24","relation":{},"ISSN":["0021-8820","1881-1469"],"issn-type":[{"value":"0021-8820","type":"print"},{"value":"1881-1469","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,3,27]]}}}