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U.S.A."],"published-print":{"date-parts":[[2015,7,7]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    The natural product leinamycin (LNM), upon reductive activation by cellular thiols, exerts its antitumor activity by an episulfonium ion-mediated DNA alkylation. Manipulation of the LNM biosynthesis in\n                    <jats:italic>Streptomyces atroolivaceus<\/jats:italic>\n                    S-140 yielded a recombinant strain that produced an LNM biosynthetic intermediate, leinamycin E1 (LNM E1). Complementary to the reductive activation of LNM by cellular thiols, LNM E1 can be oxidatively activated by cellular reactive oxygen species (ROS) to generate a similar episulfonium ion intermediate, thereby alkylating DNA and leading to eventual cell death. The feasibility of exploiting LNM E1 as an anticancer prodrug activated by ROS was demonstrated in two prostate cancer cell lines, LNCaP and DU-145. The structure of LNM E1 also reveals critical new insights into LNM biosynthesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1506761112","type":"journal-article","created":{"date-parts":[[2015,6,10]],"date-time":"2015-06-10T13:23:59Z","timestamp":1433942639000},"page":"8278-8283","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":48,"title":["Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species"],"prefix":"10.1073","volume":"112","author":[{"given":"Sheng-Xiong","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong-Sik","family":"Yun","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirak S.","family":"Basu","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn R.","family":"Church","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun","family":"Ingenhorst","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy R.","family":"Lohman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong-Li","family":"Tang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Ju","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Wilding","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin\u2013Madison, Madison, WI 53705;"},{"name":"Department of Medicine, University of Wisconsin\u2013Madison, Madison, WI 53705;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;"},{"name":"Division of Pharmaceutical Sciences, University of Wisconsin\u2013Madison, Madison, WI 53705;"},{"name":"Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;"},{"name":"Natural Products Library Initiative, The Scripps Research Institute, Jupiter, FL 33458"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2015,6,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.7164\/antibiotics.42.1768","article-title":"Leinamycin, a new antitumor antibiotic from Streptomyces: Producing organism, fermentation and isolation","volume":"42","author":"Hara M","year":"1989","unstructured":"M Hara, , Leinamycin, a new antitumor antibiotic from Streptomyces: Producing organism, fermentation and isolation. 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