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Production of Tyrian purple indigoid dye from tryptophan in Escherichia coli

Abstract

Tyrian purple, mainly composed of 6,6'-dibromoindigo (6BrIG), is an ancient dye extracted from sea snails and was recently demonstrated as a biocompatible semiconductor material. However, its synthesis remains limited due to uncharacterized biosynthetic pathways and the difficulty of regiospecific bromination. Here, we introduce an effective 6BrIG production strategy in Escherichia coli using tryptophan 6-halogenase SttH, tryptophanase TnaA and flavin-containing monooxygenase MaFMO. Since tryptophan halogenases are expressed in highly insoluble forms in E. coli, a flavin reductase (Fre) that regenerates FADH2 for the halogenase reaction was used as an N-terminal soluble tag of SttH. A consecutive two-cell reaction system was designed to overproduce regiospecifically brominated precursors of 6BrIG by spatiotemporal separation of bromination and bromotryptophan degradation. These approaches led to 315.0 mg l−1 6BrIG production from tryptophan and successful synthesis of regiospecifically dihalogenated indigos. Furthermore, it was demonstrated that 6BrIG overproducing cells can be directly used as a bacterial dye.

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Fig. 1: Biosynthesis of 6,6'-dibromoindigo (6BrIG) using three enzymes in E. coli.
Fig. 2: Construction of SttH and Fre fusion enzyme to enhance the solubility and activity of SttH.
Fig. 3: 6-Br-indole production using Fre-L3–SttH and TnaA from the coexpression reaction system or the consecutive two-cell reaction system.
Fig. 4: Tyrian purple production from Trp through the consecutive two-cell reaction system.
Fig. 5: E. coli cell pellets comprising Tyrian purple dye can be used directly as a cellular dye.
Fig. 6: Applying the fusion strategy and the consecutive two-cell reaction system to synthesize dihalogenated indigos from Trp.

Data availability

The datasets generated during and/or analyzed during the current study are contained in the published article (and its Supplementary Information), or are available from the corresponding author on reasonable request.

Code availability

The codes used during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank H.-N.B. of the National Center for Inter-University Research Facilities at Seoul National University for assistance with the NMR experiments. This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (grant no. NRF-2017R1E1A1A01073523 to B.-G.K.), by Industrial Strategic technology development program funded By the Ministry of Trade, Industry & Energy (Korea) (grant no. 20002734 to B.-G.K.), by the NRF funded by the Korean government (grant no. MSIT-2018R1C1B5044988 to H.-J.J.) and by the Basic Science Research Program through the NRF funded by the Ministry of Education (grant no. NRF-2020R1A6A1A03044977 to J.K. and Y.-G.K.).

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Contributions

J.L. and J.K. designed the research. J.L. and J.K. carried out the experiment and interpreted the results under the guidance and direction of B.-G.K. J.L. and J.K. wrote the manuscript with support from B.-G.K. Y.-G.K., H.-J.J., H.R.K., and K.-Y.C. revised the manuscript and provided critical feedback. J.E.S. performed dyeing experiments. W.-S.S. performed MALDI–TOF MS analysis. E.-J.K. contributed to gene construction and culture system.

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Correspondence to Byung-Gee Kim.

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Extended data

Extended Data Fig. 1 TnaA activities toward Trp and 6-Br-Trp in the whole-cell reaction.

a, Trp and 6-Br-Trp consumption was monitored in the whole-cell reaction of the strain ΔtnaA TnaA for 6 h. Data are presented as mean values ± s.d. from three biologically independent samples. b, HPLC chromatograms of the reactions with Trp (B, C and D) or 6-Br-Trp (E, F and G), respectively, at different time points. A: Authentic standards: Trp; phenol as an internal standard; and 6-Br-Trp. B, C and D: The reaction using Trp at 0 h, 1 h and 6 h. E, F and G: The reaction using 6-Br-Trp at 0 h, 1 h and 6 h.

Extended Data Fig. 2 Docking simulation of SttH and RebH with indole.

a, SttH (PDB ID: 5HY5) with indole. b, RebH (PDB ID: 2OAL) with indole. The distances between the catalytic residues (Lys and Glu) and the specific carbons (C2, C3, or C6) of the indole ring are indicated, respectively. The catalytic residues (that is lysine and glutamate) of SttH were closer to C6 than the other carbons of indole, and those of RebH were closer to C2 and C3. These results could explain the regioselectivities of the brominated indoles generated by SttH and RebH.

Extended Data Fig. 3 Production of 6-Br-Trp through the whole-cell reactions.

a, Production of 6-Br-Trp in the whole-cell reactions for 30 h. b, Concentrations of 6-Br-Trp and Trp after 24 h of whole-cell reactions using ΔtnaA Fre-L3-SttH with different concentrations of tryptophan, [Trp]0. Data are presented as mean values ± s.d. from three biologically independent samples.

Extended Data Fig. 4 Evaluation of MBP (Maltose-binding protein) as a soluble tag of SttH.

a, SDS-PAGE analysis of Fre-L3-SttH and MBP-L3-SttH. Boxes indicate the expression of Fre-L3-SttH and MBP-L3-SttH. M: marker, T: total fraction of the cell lysates, S: soluble fraction of the cell lysates. Representative gel of two independent experiments. b, 6-Br-Trp productions with the whole-cell reactions using ΔtnaA SttH, ΔtnaA MBP-L3-SttH, ΔtnaA SttH+Fre, ΔtnaA MBP-L3-SttH+Fre and three ΔtnaA Fre-L(1, 2, and 3)-SttH. Data are presented as mean values ± s.d. from three biologically independent samples.

Extended Data Fig. 5 Comparison of Fre-L3-SttH and TnaA activities toward Trp in the whole-cell reactions of ΔtnaA, ΔtnaA Fre-L3-SttH, and ΔtnaA TnaA for 12 h.

Data are presented as mean values ± s.d. from three biologically independent samples.

Extended Data Fig. 6 Tyrian purple production using the strain ΔtnaA TnaA+ CYP102G4.

Concentrations of 6-Br-Trp, 6-Br-indole, and 6BrIG during the whole-cell reactions of ΔtnaA TnaA+CYP102G4 for 12 h. The cells of ΔtnaA TnaA+CYP102G4 were added into the supernatant of the reaction mixture from ΔtnaA Fre-L3-SttH. Data are presented as mean values ± s.d. from four biologically independent samples.

Extended Data Fig. 7 Dyeing wool fabrics with chemical 6BrIG, 6BrIG cell dye, chemical indigo, and indigo cell dye.

a, Cell dye production in a 500 mL reaction volume in a 3 L baffled glass flask. 6BrIG cell dye (left) and indigo cell dye (right) obtained by the consecutive two-cell reaction systems with and without Fre-L3-SttH expression. b, Color indicators of the wool fabrics dyed with chemical 6BrIG, 6BrIG cell dye, chemical indigo, and indigo cell dye. L*: brightness; a*: the more positive value it is, the closer it is to red, and the more negative value it is, the closer it is to green; b*: the more positive value it is, the closer it is to yellow, and the more negative value it is, the closer it is to blue. Color differences between the chemical dyes and the cell dyes were expressed as \(\Delta {\mathrm{E}}_{ab}^ \ast\), CIELAB color difference index. c, Wool fabrics (2×2 cm2) dyed with chemical indigo or the indigo cell dye, respectively. The color depth of dyed fabrics was measured in K/S values. Data are presented as mean values ± s.d. from three biologically independent samples.

Extended Data Fig. 8 Synthesis scheme of dihalogenated indigos through the fusion strategy and the consecutive two-cell reaction system.

Fre-L3-PyrH, Fre-L3-SttH, and Fre-L3-RebH were used to produce halogenated tryptophans. TnaA and MaFMO were used to produce dihalogenated indigos from the halogenated tryptophans.

Extended Data Fig. 9 HPLC chromatograms for the whole-cell reactions of the halogenase fusion enzymes (Fre-L3-SttH, Fre-L3-PyrH, and Fre-L3-RebH) after 24 h.

Since the residual Trp was not present after the halogenation reaction in the consecutive two-cell reaction system, it was presumed that regular indigo byproduct would not be generated in the whole-cell reaction of the strain ΔtnaA TnaA+MaFMO. a and b: Authentic standards: Trp; phenol as an internal standard; 7-Cl-Trp (7-Cl); 5-Cl-Trp (5-Cl); and 6-Cl-Trp (6-Cl). Chlorination reaction of Fre-L3-PyrH (c), Fre-L3-SttH (d) and Fre-L3-RebH (e) using NaCl and Trp. F and G: Authentic standards: Trp; phenol as an internal standard; 7-Br-Trp (7-Br); 5-Br-Trp (5-Br); and 6-Br-Trp (6-Br). Bromination reaction of Fre-L3-PyrH (h), Fre-L3-SttH (i) and Fre-L3-RebH (j) using NaBr and Trp.

Extended Data Fig. 10 The absorption spectra of the dihalogenated indigos in DMSO:H2O = 50:50 % (v/v) solution.

The absorption maxima are as follows: 5,5’-Dichloroindigo (55CL), 645 nm; 5,5’-dibromoindigo (55BR), 623 nm; 6,6’-dichloroindigo (66CL), 527 nm; 6,6’-dibromoindigo (66BR), 520 nm; 7,7’-dichloroindigo (77CL), 600 nm; and 7,7’-dibromoindigo (77BR), 570 nm.

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Supplementary Tables 1–5, Figs. 1–10, Note 1 and references.

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Lee, J., Kim, J., Song, J.E. et al. Production of Tyrian purple indigoid dye from tryptophan in Escherichia coli. Nat Chem Biol 17, 104–112 (2021). https://doi.org/10.1038/s41589-020-00684-4

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