5 大腸菌によるアンサマイシン型ポリケタイド前駆体の生合成(口頭発表の部)

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概要

• 論文の詳細を見る

• Ansamycins such as rifamycin, ansamitocin and geldanamycin are an important class of polyketide natural products. Their biosynthetic pathways are especially complex since they involve the formation of 3-amino-5-hydroxybenzoic acid (AHBA) followed by backbone assembly by a hybrid nonribosomal peptide synthetase (NRPS) / polyketide synthase (PKS). We have reconstituted the ability to synthesize P8/1-OG. an intermediate in rifamycin biosynthesis, in an extensively manipulated strain of E. coli. The parent strain, BAP1, contains the sfp phosphopantetheinyl transferase gene from Bacillus subtilis, which post-translationally modifies NRPS and PKS modules. AHBA biosynthesis in this host required introduction of seven genes from Amycolatopsis mediterranei (which produces rifamycin) and Actinosynnema pretiosum (which produces ansamitocin). Since the 4-module RifA protein (530kDa) from the rifamycin synthetase could not be efficiently produced in an intact form in E. coli, it was genetically split into two bimodular proteins separated by matched linker pairs to facilitate efficient inter-polypeptide transfer of a biosynthetic intermediate. A derivative of BAP1 was engineered that harbors the AHBA biosynthetic operon, the bicistronic RifA construct and the pccB and accAl genes from Streptomyces coelicolor, which enable methylmalonyl-CoA biosynthesis. Fermentation of this strain of E. coli yielded P8/1-OG and an N-acetyl P8/1-OG analog. In addition to providing a fundamentally new route to shikimate and ansamycin-type compounds, this result enables further genetic manipulation of AHBA-derived polyketide natural products with unprecedented power.

• 天然有機化合物討論会の論文
• 2003-09-01

著者

• FLOSS Heinz

  Department of Chemistry, Box 351 700, University of Washington

• Floss Heinz

  Department Of Chemistry University Of Washington

• Floss Heinz

  Department Of Chemistry Box 351700 University Of Washington

• 渡辺 賢二

  Departments Of Chemical Engineering Chemistry And Biochemistry Stanford University

• Rude Mathew

  Departments of Chemical Engineering, Chemistry, and Biochemistry, Stanford University

• Khosla Chaitan

  Departments of Chemical Engineering, Chemistry, and Biochemistry, Stanford University

• Kahne Daniel

  Department of Chemistry, Princeton University

• Walsh Christopher

  Departments of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

• Rude Mathew

  Departments Of Chemical Engineering Chemistry And Biochemistry Stanford University

• Kahne Daniel

  Department Of Chemistry Princeton University

• Khosla Chaitan

  Departments Of Chemical Engineering Chemistry And Biochemistry Stanford University

• Khosla Chaitan

  Department Of Chemical Engineering Stanford University

• Walsh Christopher

  Departments Of Biological Chemistry And Molecular Pharmacology Harvard Medical School

関連論文

• Recent Developments in the Maytansinoid Antitumor Agents
• Thioesterases and the Premature Termination of Polyketide Chain Elongation in Rifamycin B Biosynthesis by Amycolatopsis mediterranei S699
• Biosynthesis of the Shikimata-derived Starter Unit of the Immunosuppressant Ascomycin: Stereochemistry of the 1,4-Conjugate Elimination
• Identification of Four Genes from the Granaticin Biosynthetic Gene Cluster of Streptomyces violaceoruber Tu22 Involved in the Biosynthesis of L-Phodinose
• New Type II Manumycins Produced by Streptomyces nodosus ssp. asukaensis and Their Biosynthesis
• 5 大腸菌によるアンサマイシン型ポリケタイド前駆体の生合成(口頭発表の部)
• Erythromycin Biosynthesis Highly Efficient Incorporation of Polyketide Chain Elongation Intermediates into 6-Deoxyerythronolide B in an Engineered Streptomyces Host
• Improved precursor-directed biosynthesis in E. coli via directed evolution
• Engineered biosynthesis of the antiparasitic agent frenolicin B and rationally designed analogs in a heterologous host
• The biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), the precursor of mC_7N units in ansamycin and mitomycin antibiotics : a review
• In vitro and in vivo activity of frenolicin B against Plasmodium falciparum and P berghei
• Professor Dr Hans Zahner : an appreciation

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