A One-Pot Chemoenzymatic Synthesis for the Universal Precursor of Antidiabetes and Antiviral Bis-Indolylquinones Patrick Schneider, Monika Weber, Karen.

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Presentation transcript:

A One-Pot Chemoenzymatic Synthesis for the Universal Precursor of Antidiabetes and Antiviral Bis-Indolylquinones Patrick Schneider, Monika Weber, Karen Rosenberger, Dirk Hoffmeister Chemistry & Biology Volume 14, Issue 6, Pages 635-644 (June 2007) DOI: 10.1016/j.chembiol.2007.05.005 Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 1 Chemical Structures of Bioactive Fungal Bis-Indolylquinones Biosynthetic steps catalyzed by TdiA and TdiD are also shown. Chemistry & Biology 2007 14, 635-644DOI: (10.1016/j.chembiol.2007.05.005) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 2 Organization of the Terrequinone A Biosynthetic Locus in Aspergillus nidulans Black arrows indicate the transcriptional direction and symbolize the genetic cluster. Open arrows represent genes outside the cluster. The modular architecture of the tdiA gene product is highlighted by abbreviations: A (adenylation domain), PCP (peptidyl carrier protein), TE (thioesterase/cyclase). Chemistry & Biology 2007 14, 635-644DOI: (10.1016/j.chembiol.2007.05.005) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 3 HPLC Chromatograms (A) Natural product analyses of A. nidulans strains TN02A7 (WT), TMW3.7 (ΔtdiD), TMW8.3 (tdiD complementation), rNI773 (WT), and TMW1.2 (ΔtdiA), recorded at 280 nm. Sterigmatocystin elutes after 8.8 min, terrequinone A after 11.1 min, when applying the solvent gradient described in the Experimental Procedures. (B) Authentic references: L-tryptophan (L-trp, retention time 5.9 min), indole-3-pyruvate (I3P, retention time 2.1 min), and di-demethylasterriquinone D (DDAQ D, retention time 6.6 min). (C) Enzyme assays: coupled two-enzyme one-pot reaction (TdiA + TdiD), and single enzyme assays for TdiA and TdiD, respectively. APCI-MS traces (negative mode) are given for DDAQ D (M-H+ = 369), L-tryptophan (L-Trp, M-H+ = 203), and indole-3-pyruvate (I3P, M-H+ = 202). Lines indicate the corresponding chromatographic peaks. Chemistry & Biology 2007 14, 635-644DOI: (10.1016/j.chembiol.2007.05.005) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 4 Electrophoretic Analysis of Heterologously Expressed Proteins Hexahistidine-tagged enzymes TdiA (left lane, calculated mass: 107.6 kDa) and TdiD (right lane, calculated mass: 47.7 kDa) after SDS-polyacrylamide gel electrophoresis (12% Laemmli gel). Molecular weight markers on the center lane are (top to bottom) 97, 66, and 45 kDa, respectively. Chemistry & Biology 2007 14, 635-644DOI: (10.1016/j.chembiol.2007.05.005) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 5 Reaction Schemes The metabolic steps catalyzed by (A) the transaminase TdiD and (B) by the bis-indolylquinone synthetase TdiA constitute the initial events during bisindolylquinone biosynthesis. Chemistry & Biology 2007 14, 635-644DOI: (10.1016/j.chembiol.2007.05.005) Copyright © 2007 Elsevier Ltd Terms and Conditions