The Immunosuppressant Brasilicardin: Determination of the Biosynthetic Gene Cluster in the Heterologous Host Amycolatopsis japonicum.

Autor: Schwarz PN; Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), Eberhard Karls University of Tübingen, Tübingen, Germany., Buchmann A; Department of Pharmaceutical Biology, Pharmaceutical Institute, Eberhard Karls University of Tübingen, Tübingen, Germany., Roller L; Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), Eberhard Karls University of Tübingen, Tübingen, Germany., Kulik A; Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), Eberhard Karls University of Tübingen, Tübingen, Germany., Gross H; Department of Pharmaceutical Biology, Pharmaceutical Institute, Eberhard Karls University of Tübingen, Tübingen, Germany.; German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany., Wohlleben W; Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), Eberhard Karls University of Tübingen, Tübingen, Germany.; German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany., Stegmann E; Microbiology/Biotechnology, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), Eberhard Karls University of Tübingen, Tübingen, Germany.; German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.
Jazyk: angličtina
Zdroj: Biotechnology journal [Biotechnol J] 2018 Feb; Vol. 13 (2). Date of Electronic Publication: 2017 Nov 13.
DOI: 10.1002/biot.201700527
Abstrakt: Nocardia terpenica IFM 0406 is the producer of the immunosuppressants brasilicardins A-D. Brasilicardin is a promising compound because of its unique mode of action and its higher potency and reduced toxicity compared to today's standard drugs. However, production of brasilicardin is so far hampered as Nocardia terpenica IFM 0406 synthesizes brasilicardin in only low amounts and represents a human pathogen (biosafety level 2 BSL2). In order to achieve a safe and high yield production of brasilicardin A (BraA), the authors heterologously express the brasilicardin gene cluster in the nocardioform actinomycete Amycolatopsis japonicum (A. japonicum::bcaAB01), which is fast growing, genetically accessible and closely related to N. terpenica IFM 0406. In A. japonicum::bcaAB01, four brasilicardin congeners, intermediates of the BraA biosynthesis, are produced. Investigation of the genes flanking the previously defined brasilicardin biosynthetic gene cluster revealed two novel genes (bra0, bra12), which are involved in brasilicardin biosynthesis: bra12 encodes a transcriptional activator of the brasilicardin gene cluster. bra0 codes for a dioxygenase involved in methoxylation of brasilicardin. Based on this finding the authors are able to revise the proposed brasilicardin biosynthesis.
(© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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