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(12) United States Patent (10) Patent No.: US 8,124.387 B2 (51) Int. Cl.

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(12) United States Patent (10) Patent No.: US 8,124.387 B2 (51) Int. Cl. USOO8124387B2 (12) United States Patent (10) Patent No.: US 8,124.387 B2 Stuermer et al. (45) Date of Patent: Feb. 28, 2012 (54) PROCESS FOR THE PRODUCTION OF FOREIGN PATENT DOCUMENTS CTRONELLAL EP 0000315 A1 1, 1979 GB 1476818 6, 1977 (75) Inventors: Rainer Stuermer, Roedersheim-Gronau OTHER PUBLICATIONS (DE); Thomas Friedrich, Darmstadt (DE); Andre Mueller, Vienna (AU): hastiller, A.,et et and al., “Enzymatic J TR Reduction of thes:2. O.B. Unsaturate d Bernhard Hauer, Fussgoenheim (DE): Carbon Bond in Citral”, Journal of Molecular Catalyst B: Enzymatic, Bettina Rosche, Randwick (AU) 2006, vol. 38, pp. 126-130. Williams, R. E., et al., “New Uses for an Old Enzyme'. The Old (73) Assignee: BASFSE, Ludwigshafen (DE) Yellow Enzyme Family of Flavoenzymes'. Microbiology, 2002, vol. 148, pp. 1607-1614. (*) Notice: Subject to any disclaimer, the term of this Vaz, A. D.N. et al., “Old Yellow Enzyme: Aromatization of Cyclic atent is extended or adiusted under 35 Enones and the Mechanism of a Novel Dismutation Reaction'. Bio p chemistry, 1995, vol. 34, pp. 4246-4256. U.S.C. 154(b) by 958 days. Kitzing, K., et al., “The 13 A Crystal Structure of the Flavoprotein YoM reveals a Novel Class of Old Yellow Enzymes'. The Journal of (21) Appl. No.: 12/093,796 Biological Chemistry, 2005, vol. 280, No. 30, 27904-27913. Stott, K., et al., “Old Yellow Enzyme'. The Journal of Biological (22) PCT Filed: Nov. 10, 2006 Chemistry, 1993, vol. 268, No. 9, pp. 6097-6106. Seo, J., et al., “The genome sequence of the ethanologenic bacterium (86). PCT No.: PCT/EP2006/068338 Zymomonas mobilis ZM4”. Nature Biotechnology, 2005, vol. 23, No. 1, p. 63. S371 (c)(1), * cited by examiner (2), (4) Date: May 15, 2008 Primary Examiner — Susan Hanley (87) PCT Pub. No.: WO2007/057354 (74) Attorney, Agent, or Firm — Connolly Bove Lodge & PCT Pub. Date: May 24, 2007 Huitz LLP (57) ABSTRACT (65) Prior Publication Data The invention relates to a process for the production of opti cally active Citronellal by enzymatic reduction of Citral with US 2008/O28O337 A1 Nov. 13, 2008 a reductase from Zymomonas mobilis. Related U.S. Application Data (60) Provisional application No. 60/737,500, filed on Nov. 17, 2005. S S n O tral reductaseE (30) Foreign Application Priority Data Citral trans – Geranial Nov. 17, 2005 (EP) ..................................... 051 10867 cis = Neral (51) Int.CI2P Cl. 7/24 (2006.01) ----N No (52) U.S. CI. ... 435/147; 435/179; 435/171; 435/252.35: (R)-(+)-Citronellal 435/252.4; 435/252.5 (58) Field of Classification Search .................. 435/147, E 435/179, 171,252.35 s See application file for complete search history. N No (56) References Cited (S)-(-)-Citronellal U.S. PATENT DOCUMENTS 4,237,072 A 12/1980 Aviron-Violet et al. 6 Claims, 4 Drawing Sheets U.S. Patent Feb. 28, 2012 Sheet 1 of 4 US 8,124.387 B2 1s--- -s-s-sS. N1s O +2(H) (R)-(+)-Citronellai Citra Citra reductase trans a Geranial cis Nera N No (S)-(-)-Citronelial Figure 1 U.S. Patent Feb. 28, 2012 Sheet 2 of 4 US 8,124.387 B2 § -C. **** œ §§ Figure 2 U.S. Patent Feb. 28, 2012 Sheet 3 of 4 US 8,124.387 B2 a É 2 : 3. 2323. É 3.3, OO 6.9 2 É 0. 3 %3 É3. &3. Figure 3 U.S. Patent Feb. 28, 2012 Sheet 4 of 4 US 8,124.387 B2 3. 15 1.2 Toluene - 1.0 12 is e E. is 0.8 9 is 0.6 9,us 6 5 d O2 3 : 2. OO O b 12 1.O O.8 O6 0.4 0.2 O.O O 30 60 90 120 150 18O Time min) Citronella X Geraniol D Neral A Geranial Figure 4 US 8, 124,387 B2 1. 2 PROCESS FOR THE PRODUCTION OF A valuable use for the product (R)-(+)-citronellal is the CITRONELLAL Subsequent ring closure via a Prins reaction into isopulegol followed by hydration to (IR,2S.5R)-(-)-menthol 5. Non RELATED APPLICATIONS biological strategies are still challenged by their limited Ste reo-selectivity (citral has three double bonds) and enantio This application is a national stage application (under 35 selectivity 6 (see FIG. 1) U.S.C. S371) of PCT/EP2006/068338, filed Nov. 10, 2006, Enzymes which reduce the carbon double bond of other which claims benefit of European application 05110867.8, C.B-unsaturated carbonyls have been reported in the litera filed Nov. 17, 2005, and U.S. Provisional Application Ser. No. ture. They predominantly belong to the Old Yellow Enzyme 60/737,500, filed Nov. 17, 2005. 10 family of flavin and NADPH dependant reductases, reviewed by Williams and Bruce 7 with regards to possible biotech SUBMISSION OF SEQUENCE LISTING nological applications. Another example is carvone reductase from Rhodococcus The Sequence Listing associated with this application is erythropolis, which used an unidentified heat stable cofactor filed in electronic format via EFS-Web and hereby incorpo 15 and was not dependant on added NADH or NADPH 8. rated by reference into the specification in its entirety. The In order to detect a bioconversion of citral into citronellal, name of the text file containing the Sequence Listing is the corresponding enzyme must be active, electrons for Sequence Listing 12810 00663 US. The size of the text file reduction must be available, the very hydrophobic substrate is 1 KB, and the text file was created on Jul. 12, 2011. citral must reach the enzyme in Sufficient concentrations and Citral is an antimicrobial terpene, which imparts the char the citronellal formation must be faster than any Subsequent acteristic lemon scent to plants like lemon grass and the conversion. Accordingly, a screening strategy was developed Australian lemon myrtle. It is also readily available as an to test various microorganisms for citral conversion. industrial intermediate e.g. in the synthesis of the vitamins. A A first embodiment of the invention is a process for the and E. Several bioconversions of citral have been reported, production of optically active Citronellal by enzymatic reduc viz. reduction or oxidation of the aldehyde group 1, acyloin 25 tion of Citral with a reductase which is selected from the formation 2 and lyase activity 1, 3. group consisting of the genera Zymomonas, Citrobacter; Can The objective of this study was to screen for enzyme activi dida, Saccharomyces, Kluyveromyces, Candida, Issatchen ties which reduce the C.B-unsaturated carbon bond in citral to kia, Rhizopus wherein the reduction is accomplished in a yield the chiral product citronellal (FIG.1). Citral is a mixture two-phase liquid system. of the trans-isomer geranial and the cis-isomer neral, but 30 A preferred embodiment of this process uses a reductase Substrate specificity for either isomer might not be crucial as selected from the species Zymomonas mobilis, Citrobacter amino acids can catalyze the isomerization 4. freundii, Candida rugosa, Saccharomyces bavanus, Saccha romyces cerevisiae, Kluyveromyces marxianus, Candida uti DESCRIPTION OF THE FIGURES lis, Issatchenkia Orientalis, Rhizopus javanicus. 35 The microorganisms mentioned above are well known in FIG.1: Biotransformation of citral (geranial and neral) into the art and can be isolated by known procedures or from citronellal. public depositories such as ATCC and DSMZ. FIG. 2: Biotransformation of citral by Zymomonas mobilis Zymomonas mobilis has been deposited i.a. as ATCC cells in the presence of a NADPH regenerating system and 10998, ATCC 2.9192, ATCC 31821, ATCC 35001, ATCC various solvents: a) product citronellalb) sum of by-products 40 3.9985. Citrobacter freundii has been deposited i.a. as ATCC geraniol, nerol and citronellol. Initial conditions: 20% V/v 8090D, ATCC 11811. Candida rugosa has been deposited i.a. organic solvent, 20 mM citral, 5 mM dithiothreitol, 3.3 mM as DSM 70761. Issatchenkia Orientalis has been deposited MgCl2, 1.5 mM NADP+, 10 mM glucose-6-phosphate, 0.4 i.a. as DSM 3433, DSM 6128, DSM 11956, DSM 70075, U/ml glucose-6-phosphate dehydrogenase, approx. 14 g/1 70079. DCM Z. mobilis, 50 mMMOPS/KOH, pH 7.0, 3 hat 30° C. 45 The reductase can be used in an isolated and purified form *Solvents marked with asterisk dissolved in water, all other or as a “whole-cell-enzyme” which shall mean, that the solvents formed emulsions. MTBE-methyl tertiary enzyme together with the microorganism is used for the pro butylether, nd not detected. AU-Farbitrary units: GC area of cess according to the invention. The microorganism can also compound divided by the GC area of internal standard. Aver be permeabilized in order to improve the substrate, product, age values of three replicates are given and error bars indicate 50 cofactor transfer in and out of the cell. highest and lowest results. For toluene the ratio of areas The term “reductase' shall mean not only the isolated corresponded to a cov-centration of 1.4 mM citronellal. enzyme but also extracts, Solutions or Suspensions compris FIG. 3: Comparison of citronellal formation by bacteria, ing the enzyme, carrier where the enzyme has been immobi yeasts and a filamentous fungus in the a) aqueous/toluene lized and whole cells containing the enzyme. two-phase system and b) aqueous/methyl tertiary butylether 55 An improved embodiment of the invention is the use of a (MTBE) two-phase system (3h incubation at 30°C., compo cofactor which is oxidized by the simultaneous reduction of sition as in FIG. 2 at a biomass concentration of approxi Citral. As a cofactor every substance which can be oxidized mately 12 g DCM/I). Average values of two replicates are under the conditions of the process according to the invention given and error bars indicate highest and lowest results, is suitable.
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