Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Luo, Dan; Callari, Roberta; Hamberger, Britta; Wubshet, Sileshi Gizachew; Nielsen, Morten T.; Andersen-Ranberg, Johan; Hallström, Björn M.; Cozzi, Federico; Heider, Harald; Lindberg Møller, Birger; Staerk, Dan; Hamberger, Björn

doi:10.1073/pnas.1607504113

Title: Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Journal Article · 09 August 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1607504113 · OSTI ID:1288983

Luo, Dan ^[1]; Callari, Roberta ^[2]; Hamberger, Britta ^[1]; Wubshet, Sileshi Gizachew ^[3]; Nielsen, Morten T. ^[1]; Andersen-Ranberg, Johan ^[4]; Hallström, Björn M. ^[5]; Cozzi, Federico ^[1];

^[2]; Lindberg Møller, Birger ^[4];

^[3]; Hamberger, Björn ^[4]

Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark,
Evolva AS, CH-4153 Reinach, Switzerland,
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark,
Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark,, Center for Synthetic Biology “bioSYNergy,” DK-1871 Frederiksberg C, Denmark,
Science for Life Laboratory, School of Biotechnology, Kungliga Tekniska Högskolan Royal Institute of Technology, SE-171 21 Stockholm, Sweden

Significance Ingenol mebutate is a diterpene ester with a highly complex macrocyclic structure that has been approved for the treatment of actinic keratosis, a precondition of skin cancer. The current production of ingenol mebutate through plant extraction or chemical synthesis is inefficient and costly. Here, we describe the discovery of a biosynthetic route in Euphorbia lathyris L. (caper spurge) in which regio-specific oxidation of casbene is followed by an unconventional cyclization to yield jolkinol C, a probable key intermediate in the biosynthesis of macrocyclic diterpenes, including ingenol mebutate. These results can facilitate the biotechnological production of this high-value pharmaceutical and discovery of new biosynthetic intermediates with important bioactivities.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: FC02-07ER64494

OSTI ID:: 1288983

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 34 Vol. 113; ISSN 0027-8424

Publisher:: Proceedings of the National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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