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Biosynthesis and Heterologous Production of Vioprolides: Rational Biosynthetic Engineering and Unprecedented 4-Methylazetidinecarboxylic Acid Formation.
Yan, Fu; Auerbach, David; Chai, Yi; Keller, Lena; Tu, Qiang; Hüttel, Stephan; Glemser, Amelie; Grab, Hanusch A; Bach, Thorsten; Zhang, Youming; Müller, Rolf.
Afiliação
  • Yan F; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research, and Department of Pharmacy, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
  • Auerbach D; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research, and Department of Pharmacy, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
  • Chai Y; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research, and Department of Pharmacy, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
  • Keller L; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research, and Department of Pharmacy, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
  • Tu Q; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research, and Department of Pharmacy, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
  • Hüttel S; Helmholtz Centre for Infection Research, Department of Microbial Drugs, Braunschweig, Germany.
  • Glemser A; Helmholtz Centre for Infection Research, Department of Microbial Drugs, Braunschweig, Germany.
  • Grab HA; Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
  • Bach T; Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
  • Zhang Y; Shandong University-Helmholtz Joint Institute of Biotechnology, State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, Qingdao, P. R. China.
  • Müller R; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research, and Department of Pharmacy, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
Angew Chem Int Ed Engl ; 57(28): 8754-8759, 2018 07 09.
Article em En | MEDLINE | ID: mdl-29694699
Vioprolides are a promising class of anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35. Previously nothing had been reported about their biosynthesis, including the origin of the unusual 4-methylazetidinecarboxylic acid (MAZ) moiety. We describe the vioprolide biosynthetic gene cluster and solve the production obstacle by expression in three heterologous hosts. Starting from unstable production in the wild type at the single-digit mg L-1 scale, we developed a stable host that eventually allowed for yields of up to half a gram per liter in fermenters. Gene inactivations coupled with isotope feeding studies identified an S-adenosylmethionine (SAM)-dependent enzyme and a methyltransferase as being responsible for the generation of the MAZ building block by a proposed mechanism unprecedented in bacteria. Furthermore, nonnatural vioprolide derivatives were generated via rational genetic engineering.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Alemanha