{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:57:37Z","timestamp":1793199457984,"version":"4.5.0"},"reference-count":59,"publisher":"National Academy of Sciences","issue":"17","license":[{"start":{"date-parts":[[2019,4,5]],"date-time":"2019-04-05T00:00:00Z","timestamp":1554422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"MEXT, Japan","award":["JP16H06443"],"award-info":[{"award-number":["JP16H06443"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,4,23]]},"abstract":"<jats:p>\n                    Ascofuranone (AF) and ascochlorin (AC) are meroterpenoids produced by various filamentous fungi, including\n                    <jats:italic>Acremonium egyptiacum<\/jats:italic>\n                    (synonym:\n                    <jats:italic>Acremonium sclerotigenum<\/jats:italic>\n                    ), and exhibit diverse physiological activities. In particular, AF is a promising drug candidate against African trypanosomiasis and a potential anticancer lead compound. These compounds are supposedly biosynthesized through farnesylation of orsellinic acid, but the details have not been established. In this study, we present all of the reactions and responsible genes for AF and AC biosyntheses in\n                    <jats:italic>A. egyptiacum<\/jats:italic>\n                    , identified by heterologous expression, in vitro reconstruction, and gene deletion experiments with the aid of a genome-wide differential expression analysis. Both pathways share the common precursor, ilicicolin A epoxide, which is processed by the membrane-bound terpene cyclase (TPC) AscF in AC biosynthesis. AF biosynthesis branches from the precursor by hydroxylation at C-16 by the P450 monooxygenase AscH, followed by cyclization by a membrane-bound TPC AscI. All genes required for AC biosynthesis (\n                    <jats:italic>ascABCDEFG<\/jats:italic>\n                    ) and a transcriptional factor (\n                    <jats:italic>ascR<\/jats:italic>\n                    ) form a functional gene cluster, whereas those involved in the late steps of AF biosynthesis (\n                    <jats:italic>ascHIJ<\/jats:italic>\n                    ) are present in another distantly located cluster. AF is therefore a rare example of fungal secondary metabolites requiring multilocus biosynthetic clusters, which are likely to be controlled by the single regulator, AscR. Finally, we achieved the selective production of AF in\n                    <jats:italic>A. egyptiacum<\/jats:italic>\n                    by genetically blocking the AC biosynthetic pathway; further manipulation of the strain will lead to the cost-effective mass production required for the clinical use of AF.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1819254116","type":"journal-article","created":{"date-parts":[[2019,4,5]],"date-time":"2019-04-05T19:45:36Z","timestamp":1554493536000},"page":"8269-8274","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":117,"title":["Complete biosynthetic pathways of ascofuranone and ascochlorin in\n                    <i>Acremonium egyptiacum<\/i>"],"prefix":"10.1073","volume":"116","author":[{"given":"Yasuko","family":"Araki","sequence":"first","affiliation":[{"name":"Research and Development Division, Kikkoman Corporation, Noda City, Chiba 278-0037, 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Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;"},{"name":"School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki City, Nagasaki 852-8523, Japan;"},{"name":"Department of Host-Defense Biochemistry, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kisaburo","family":"Nagamune","sequence":"additional","affiliation":[{"name":"Department of Parasitology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;"},{"name":"Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Ito","sequence":"additional","affiliation":[{"name":"Research and Development Division, Kikkoman Corporation, Noda City, Chiba 278-0037, 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