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Enzymatic Menthol Production Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES Article Enzymatic Menthol Production: One-pot Approach Using Engineered Escherichia coli Helen Toogood, Aisling Ni Cheallaigh, Shirley Tait, David J Mansell, Adrian Jervis, Antonios Lygidakis, Luke D Humphreys, Eriko Takano, John M Gardiner, and Nigel S. Scrutton ACS Synth. Biol., Just Accepted Manuscript • DOI: 10.1021/acssynbio.5b00092 • Publication Date (Web): 27 May 2015 Downloaded from http://pubs.acs.org on June 2, 2015 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. ACS Synthetic Biology is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 30 ACS Synthetic Biology 1 2 Enzymatic Menthol Production: One-pot Approach Using 3 4 5 Engineered Escherichia coli 6 7 8 9 a b a b a 10 Helen S. Toogood , Aisling Ní Cheallaigh , Shirley Tait , David J Mansell , Adrian Jervis , Antonios 11 12 Lygidakis a, Luke Humphreys c, Eriko Takano a, John M. Gardiner b, Nigel S. Scrutton a* 13 14 SYNBIOCHEM, Manchester Institute of Biotechnology, aFaculty of Life Sciences and bSchool of 15 16 Chemistry, University of Manchester, Manchester M1 7DN, UK. 17 18 cGlaxoSmithKline, Medicines Research Centre, Gunnel's Wood Road, Stevenage, Herts SG1 2NY, UK. 19 20 21 22 Corresponding authors: Nigel S. Scrutton and Helen S. Toogood: Manchester Institute of 23 24 Biotechnology, Faculty of Life Sciences, University of Manchester, Manchester M1 7DN, UK. 25 26 Phone: +44 161 3065152; Fax: +44 161 3068918; E-mail addresses: [email protected] 27 28 29 and [email protected] 30 31 Present address: David J. Mansell: Glythera Ltd. Herschel Annex, King’s Road, Newcastle-upon- 32 33 Tyne, NE1 7RU 34 35 36 E-mail addresses: [email protected]; [email protected]; 37 38 [email protected]; [email protected]; 39 40 [email protected]; [email protected]; 41 42 43 [email protected]; [email protected] 44 45 46 47 Abbreviations: 48 49 50 NtDBR: double bond reductase from Nicotiana tabacum ; MMR = (-)-menthone:(-)menthol 51 reductase from Mentha piperita ; MNMR = (-)-menthone:(-)neomenthol reductase from M. 52 piperita ; GDH = glucose dehydrogenase; DTT = dithiothreitol; SD = Shine-Dalgarno sequence; IPTG 53 = isopropyl-β-D-1-thiogalactopyranoside; TB = Terrific broth; TBAIM = Terrific broth auto induction 54 medium. Expression gene clusters: DM = NtDBR and MMR; DN = NtDBR and MNMR; DMN = 55 56 NtDBR, MMR and MNMR. 57 58 59 60 1 ACS Paragon Plus Environment ACS Synthetic Biology Page 2 of 30 1 2 ABSTRACT 3 4 5 Menthol isomers are high-value monoterpenoid commodity chemicals, produced naturally 6 7 by mint plants, Mentha spp. Alternative clean biosynthetic routes to these compounds are 8 9 10 commercially attractive. Optimization strategies for biocatalytic terpenoid production are mainly 11 12 focused on metabolic engineering of the biosynthesis pathway within an expression host. We 13 14 circumvent this bottleneck by combining pathway assembly techniques with classical biocatalysis 15 16 17 methods to engineer and optimize cell-free one-pot biotransformation systems and apply this 18 19 strategy to the mint biosynthesis pathway. Our approach allows optimization of each pathway 20 21 enzyme and avoidance of monoterpenoid toxicity issues to the host cell. We have developed a 22 23 24 one-pot (bio)synthesis of (1 R,2 S,5R)-(-)-menthol and (1 S,2 S,5 R)-(+)-neomenthol from pulegone, 25 26 using recombinant Escherichia coli extracts containing the biosynthetic genes for an ‘ene’- 27 28 29 reductase (NtDBR from Nicotiana tabacum ) and two menthone dehydrogenases (MMR and 30 31 MNMR from M. piperita ). Our modular engineering strategy allowed each step to be optimized to 32 33 improve the final production level. Moderate to highly pure menthol (79.1 %) and neomenthol 34 35 36 (89.9 %) were obtained when E. coli strains co-expressed NtDBR with only MMR or MNMR, 37 38 respectively. This one-pot biocatalytic method allows easier optimization of each enzymatic step 39 40 and easier modular combination of reactions to ultimately generate libraries of pure compounds 41 42 43 for use in high throughput screening. It will, therefore, be a valuable addition to the arsenal of 44 45 biocatalysis strategies, especially when applied for (semi)-toxic chemical compounds. 46 47 48 49 50 Keywords: 51 52 53 Menthol production; one-pot biosynthesis; recombinant biosynthetic pathways; Escherichia coli . 54 55 56 57 58 59 60 2 ACS Paragon Plus Environment Page 3 of 30 ACS Synthetic Biology 1 2 INTRODUCTION 3 4 5 Limonene biosynthesis MEP 6 OPP glyceraldehyde-3-phosphate Dimethylallyl diphosphate pathway + 7 OPP pyruvate GPPS 8 IDI 9 Geranyl OH diphosphate Mevalonate 'Mint' biosynthesis acetyl-CoA 10 OPP Monoterpenoid pathway (+)-Neomenthol Isopentyl diphosphate MNMR 11 Precursor Eukaryotes only 12 LimS MMR PP Peppermint pathway 13 (-)-Menthone O OH NADP+ 14 For L3H/CPR IPDH IPR (-)-Menthol IPGI PGR both 15 NADPH NADPH NADP+ OH NAD+ NADH O NADPH NADP+ O O NADPH NADP+ + H O MNMR 16 + O2 2 LIMONENE (-)- trans-Isopiperitenol (-)-Isopiperitenone (+)- cis-Isopulegone (+)-Pulegone O OH 17 MMR NADPH + O2 NADPH + O2 (+)-Isomenthone (+)-Isomenthol 18 MFS- + NADP + H2O NAD + Spearmint pathway CPR 19 L6H/CPR P + H2O 20 HO CDH O Methanofuran OH AD+ ADH biosynthesis 21 N N O (+)-Neoisomenthol 22 Menthol (-)- trans-Carveol (-)-Carvone (+)-Menthofuran Isomers 23 24 1 25 Scheme 1. Monoterpenoid biosynthesis pathways in different Mentha species. IDI = Isopentenyl-diphosphate Delta- 26 isomerase; GPPS = geranyl diphosphate synthase; LimS = (-)-limonene synthase; L3H = (-)-limonene-3-hydroxylase; 27 CPR = cytochrome P450 reductase; IPDH = (-)-trans -isopiperitenol dehydrogenase; IPR = (-)-isopiperitenone reductase; 28 IPGI = (+)-cis -isopulegone isomerase; PGR = (+)-pulegone reductase; MMR = (-)-menthone:(-)menthol reductase; 29 MNMR = menthone:(+)-neomenthol reductase; MFS = (+)-menthofuran synthase; L6H = (-)-limonene-6-hydroxylase; 30 CDH = (-)-trans -carveol dehydrogenase. 31 32 33 34 Limonene enantiomers are the most abundant monocyclic monoterpenoids in nature; (-)- 35 36 limonene is found in herbs such as Mentha spp. (e.g., peppermint and spearmint), while the (+)- 37 38 enantiomer is the major oil constituent of orange and lemon peel.2 Natural limonene derivatives 39 40 41 are known to be important precursors in the production of several pharmaceutical and commodity 42 43 chemicals, such as fragrances, perfumes and flavors. For example, essential oils of mint contain a 44 45 variety of limonene derivatives (Scheme 1), such as menthol isomers, pulegone and methanofuran 46 47 48 in peppermint ( Mentha piperita ) and carveol/carvone in spearmint ( Mentha spicata ). Menthol 49 50 isomers, (1 R,2 S,5 R)-(-)-menthol, (1 R,2 S,5 S)-(+)-isomenthol, (1 S,2 S,5 R)-(+)-neomenthol and 51 52 53 (1 R,2 R,5 R)-(+)-neoisomenthol, and carvone are used as additives in oral hygiene products, and 54 55 flavors in food and beverages. Carveol is found in cosmetics, while pulegone is commonly found as 56 57 a flavor in perfumery and aromatherapy products. Carvone and carveol are also known to have 58 59 60 3 ACS Paragon Plus Environment ACS Synthetic Biology Page 4 of 30 1 2 anticancer properties, while menthol has antibacterial activity against Staphylococcus aureus and 3 4 Escherichia coli .3 5 6 7 There is a high demand for limonene and derivatives (e.g., menthol oil ca 3,000 t/$373–401 8 9 US million pa), which are traditionally obtained from natural sources (Mentha spp.) due to the 10 11 flavor/fragrance industries demanding so-called ‘natural’ sources that are compatible with use in 12 13 14 food products. However, the production of natural menthol relies heavily on ca 0.29 million 15 16 hectares of arable land, and requires expensive steam distillation and filtration processes.4 Given 17 18 the volatility of mint crop prices due to unpredictable harvest yields and the environmental 19 20 21 footprint of intensive mint cultivation, alternative clean (bio)synthetic routes to these compounds 22 23 are commercially attractive.5 24 25 An alternative ‘natural’ route to highly pure complex organic compounds utilizes 26 27 28 microorganisms as biological factories. They are built from existing or de novo biosynthetic 29 30 pathways, incorporated into rapidly growing, cost effective and even food compatible 31 32 microorganisms grown on non-petroleum based renewable feedstock.
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