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(12) United States Patent (10) Patent No.: US 9,359,622 B2 Hilmer Et Al

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(12) United States Patent (10) Patent No.: US 9,359,622 B2 Hilmer Et Al US009359.622B2 (12) United States Patent (10) Patent No.: US 9,359,622 B2 Hilmer et al. (45) Date of Patent: Jun. 7, 2016 (54) METHOD FOR BOTECHNOLOGICAL (56) References Cited PRODUCTION OF DIHYDROCHALCONES U.S. PATENT DOCUMENTS (71) Applicant: Symrise AG, Holzminden (DE) 2005/02O8643 A1 9, 2005 Schmidt-Dannert et al. (72) Inventors: Jens Michael Hilmer, Holzminden OTHER PUBLICATIONS (DE); Egon Gross, Holzminden (DE); Chaparro-Riggers et al., Comparison of Three Enoate Reductases Gerhard Krammer, Holzminden (DE); and their Potential Use for Biotransformations, Adv. Synth. Catal. Jakob Peter Ley, Holzminden (DE); 2007, 349, 1521-31.* Mechthild Gall, Greifswald (DE); Uwe Ngaki et al., Evolution of the chalcone-isomerase fold from fatty-acid Bornscheuer, Griefswald (DE); Maren binding to stereospecific catalysis, Nature, May 2012, 485, 530-33 Thomsen, Greifswald (DE); Christin and Supplemental Information.* Peters, Greifswald (DE); Patrick Baldocket al., A Mechanism of Drug Action Revealed by Structural Jonczyk, Hannover (DE); Sascha Studies of Enoyl Reductase, Science, 1996, 274, 2107-10.* Uniprot, Accession No. V9P0A9, 2014. www.uniprot.org.* Beutel, Hannover (DE); Thomas Uniprot, Accession No. V9P074, 2014. www.uniprot.org.* Scheper, Hannover (DE) European Search Report dated Sep. 30, 2013. Schmidt, et al., “Biocatalytic Formation of a Bioactive (73) Assignee: SYMRISE AG, Holzminden (DE) Dihydrochalcone by Eubacterium Ramulus,” Journal of Biotechnol ogy, Elsevier Science Publishers, Amsterdam, NL, B.D. 150, Nov. 1, (*) Notice: Subject to any disclaimer, the term of this 2010, p. 150, XPO27489759. patent is extended or adjusted under 35 Schneider, et al., “Anaerobic Degradation of Flavonoids by U.S.C. 154(b) by 48 days. Eubacterium Ramulus.” Archives of Microbiology, Springer, DE, Bd. 173, Nr. 1, Jan. 1, 2000, pp. 71-75, XP008115183. (21) Appl. No.: 13/954,957 Herles, et al., “First Bacterial Chalcone Isomerase isolated from Eubacterium Ramulus.” Archives of Microbiology, Bd. 181, Nr. 6. (22) Filed: Jul. 30, 2013 Jun. 2004, pp. 428-434, XP002713878. Hwang, et al., “Production of Plant-Specific Flavonones by Prior Publication Data Escherichia coli Containing an Artificial Gene Cluster.” Applied and (65) Environmental Microbiology, American Society for Microbiology, US 2014/OO45233 A1 Feb. 13, 2014 US, Bd. 69, Nr. 5, May 1, 2003, pp. 2699-2706, XP008117399. Databse UniProt, Feb. 1, 1995, “RecName: Full=Chalcone (30) Foreign Application Priority Data flavonone isomerase 1: Short=Chalcone isomerase 1; EC=5.5.1.6; AltName: Full=Protein Transparent Testa 5.” XP002713879. Jul. 31, 2012 (DE) ......................... 10 2012 213 492 * cited by examiner (51) Int. C. CI2P 7/26 (2006.01) Primary Examiner — Robert Mondesi CI2N L/21 (2006.01) Assistant Examiner — Todd M Epstein CI2N 9/02 (2006.01) (74) Attorney, Agent, or Firm — Polsinelli PC CI2N 9/90 (2006.01) CI2N 15/53 (2006.01) (57) ABSTRACT CI2N I5/6 (2006.01) A method for production of a dihydrochalcone, especially of CI2N 15/63 (2006.01) phloretin, using a transgenic microorganism, containing a CI2R I/OI (2006.01) nucleic acid section (a), comprising or consisting of a gene CI2R L/19 (2006.01) coding for a bacterial chalcone isomerase, and/or a nucleic CI2R L/645 (2006.01) acid section (a'), comprising or consisting of a gene coding for CI2R L/865 (2006.01) a plant chalcone isomerase, and a nucleic acid section (b). CI2R L/84 (2006.01) comprising or consisting of a gene coding for a bacterial (52) U.S. C. enoate reductase, corresponding transgenic microorganisms, CPC. CI2P 7/26 (2013.01): CI2N 9/001 (2013.01); containing a nucleic acid section (a), comprising or consisting CI2N 9/90 (2013.01); CI2R I/01 (2013.01); of a gene coding for a bacterial chalcone isomerase, and/or a CI2R 1/19 (2013.01): CI2R I/645 (2013.01); nucleic acid section (a'), comprising or consisting of a gene CI2R 1/84 (2013.01): CI2R 1/865 (2013.01); coding for a plant chalcone isomerase, and/or a nucleic acid CI2Y 103/0.1031 (2013.01); C12Y505/01006 section (b), comprising or consisting of a gene coding for a (2013.01); Y02P 20/52 (2015.11) bacterial enoate reductase, and host cells, containing one or (58) Field of Classification Search more identical or different such vectors. None See application file for complete search history. 39 Claims, 6 Drawing Sheets U.S. Patent Jun. 7, 2016 Sheet 1 of 6 US 9,359,622 B2 Figure U.S. Patent Jun. 7, 2016 Sheet 2 of 6 US 9,359,622 B2 ::::::: 38:8; 3. of 3:38. Figure 2 U.S. Patent Jun. 7, 2016 Sheet 3 of 6 US 9,359,622 B2 3arri (98) sERED pE-238(+) 340 Figure 3 U.S. Patent Jun. 7, 2016 Sheet 4 of 6 US 9,359,622 B2 388x3 Figure 4 U.S. Patent Jun. 7, 2016 Sheet 5 of 6 US 9,359,622 B2 R. EAE - C - Resource ( R EAE - C - Resote: { extak G F Pic SOS-Page der Affeinigung SOS-Page der Aufreinigung {gefärbi mit Coomassie Bluie igefartt imit Siber) Figure 5 U.S. Patent Jun. 7, 2016 Sheet 6 of 6 US 9,359,622 B2 -8- Naringenin -- HPP-8- Phloretin-8- OD :400 16 40 350 i - 4-a-a-? - -8-Y. 4 35 300 2 30 s E. a > 250 10 25 s st w s : 5 200 0.8 2O s & S. 8x S 50 06 S2 15 a. S s wr 2. 2 OO O4 C O s s h SO 0.2 5 () O,t) ) Zeith Figure 6 US 9,359,622 B2 1. 2 METHOD FOR BOTECHNOLOGICAL Further aspects of the present invention and preferred con PRODUCTION OF DIHYDROCHALCONES figurations thereof can be seen from the following descrip tion, the exemplary embodiments and the claims. CROSS-REFERENCE TO RELATED APPLICATIONS BRIEF DESCRIPTION OF THE DRAWINGS This application claims the benefit of DE Patent Applica FIG. 1: Plasmid pET52b EREDstrep for heterologous tion Serial No. 10 2012 213 492.1, filed on 31 Jul. 2012, the expression and characterization of the ERED from E. ramu benefit of the earlier filing date of which is hereby claimed lus DSM 16296; under 35 USC S119(a)-(d) and (f). The application is hereby FIG. 2: Plasmid plT28b CHI for heterologous expression incorporated in its entirety as if fully set forth herein. 10 and characterization of the CHI from E. ramulus DSM 16296; FIG. 3: Plasmid pET22b ERED for heterologous expres SUBMISSION OF SEQUENCE LISTING sion and characterization of the ERED from E. ramulus DSM 16296; The Sequence Listing associated with this application is FIG. 4 is a graph showing lines representing without cell filed in electronic format via EFS-Web and hereby incorpo 15 extract, with cell extract E. coli Rosetta (without plasmid), rated by reference into the specification in its entirety. The and with cell extract E. coli Rosetta (with pBT28 HI); name of the text file containing the Sequence Listing is Sub FIG. 5 provides examples of the results of the individual stitute Sequence Listing 34430 7. The size of the text file is purification steps following expression of the vector 22 KB, and the text file was created on Dec. 3, 2015. pET28b CHI in E. coli; and FIG. 6 is a graph of Naringenin/HPP/Concentration uM BACKGROUND OF THE INVENTION against Phloretin concentration uM over time h. 1. Field of the Invention DETAILED DESCRIPTION OF THE PREFERRED The present invention primarily concerns a method for EMBODIMENTS production of a dihydrochalcone, especially of phloretin, or a 25 To facilitate an understanding of the principles and features method for reduction of flavanones using a transgenic micro of the various embodiments of the invention, various illustra organism, containing a nucleic acid section (a), comprising or tive embodiments are explained below. Although exemplary consisting of a gene coding for a bacterial chalcone embodiments of the invention are explained in detail, it is to isomerase, and/or a nucleic acid section (a'), comprising or be understood that other embodiments are contemplated. consisting of a gene coding for a plant chalcone isomerase, 30 Accordingly, it is not intended that the invention is limited in and a nucleic acid section (b), comprising or consisting of a its scope to the details of construction and arrangement of gene coding for a bacterial enoate reductase. components set forth in the following description or illus 2. Description of Related Art trated in the drawings. The invention is capable of other Dihydrochalcones, especially phloretin, are normally pro embodiments and of being practiced or carried out in various duced either by chemical reduction of chalcones or by 35 ways. Also, in describing the exemplary embodiments, spe Friedel–Crafts acylation of phenols with dihydrocinammic cific terminology will be resorted to for the sake of clarity. acids. The disadvantage of this method is that food additives, It must also be noted that, as used in the specification and flavourings or aromatic Substances produced in this way can the appended claims, the singular forms “a,” “an and “the not be described as natural. In addition, dihydrochalcones, include plural references unless the context clearly dictates especially phloretin, can be obtained by extraction of for 40 otherwise. For example, reference to a component is intended example the corresponding glycoside (E.g. from Malus spp. also to include composition of a plurality of components. raw materials) with Subsequent generation of the aglycone. References to a composition containing “a” constituent is This process is time-consuming and cost-intensive, however, intended to include other constituents in addition to the one named. and is also dependent on the season. Also, in describing the exemplary embodiments, terminol Important flavourings and aromatic Substances with a dihy 45 ogy will be resorted to for the sake of clarity.
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