Advances on (+)-nootkatone microbial biosynthesis and its related enzymes

Abstract (+)-Nootkatone is an important functional sesquiterpene and is comprehensively used in pharmaceutical, cosmetic, agricultural and food flavor industries. However, (+)-nootkatone is accumulated trace amounts in plants, and the demand for industry is mainly met by chemical methods which is harmful to the environment. The oxygen-containing sesquiterpenes prepared using microbial methods can be considered as “natural.” Microbial transformation has the advantages of mild reaction conditions, high efficiency, environmental protection, and strong stereoselectivity, and has become an important method for the production of natural spices. The microbial biosynthesis of (+)-nootkatone from the main precursor (+)-valencene is summarized in this paper. Whole-cell systems of fungi, bacteria, microalgae, and plant cells have been employed. It was described that the enzymes involved in the microbial biosynthesis of (+)-nootkatone, including cytochrome p450 enzymes, laccase, lipoxygenase, and so on. More recently, the related enzymes were expressed in microbial hosts to heterologous produce (+)-nootkatone, such as Escherichia coli, Pichia pastoris, Yarrowia lipolytica, and Saccharomyces cerevisiae. Finally, the development direction of research for realizing industrialization of microbial transformation was summarized and it provided many options for future improved bioprocesses.

[1]  G. Pastore,et al.  Recent advances in the microbial and enzymatic production of aroma compounds , 2021 .

[2]  Carla Nunes de Melo,et al.  Manganese complex catalyst for valencene oxidation: The first use of metalloporphyrins for the selective production of nootkatone , 2021 .

[3]  Siyi Pan,et al.  Catalytic condition optimization in the conversion of nootkatone from valencene by Yarrowia lipolytica , 2020 .

[4]  S. Baek,et al.  Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells , 2020, BMC Cancer.

[5]  Weerawat Runguphan,et al.  Metabolic engineering of Pichia pastoris for production of isopentanol (3-Methyl-1-butanol). , 2020, Enzyme and microbial technology.

[6]  H. Corke,et al.  Inhibition of multidrug-resistant foodborne Staphylococcus aureus biofilms by a natural terpenoid (+)-nootkatone and related molecular mechanism , 2020, Food Control.

[7]  Mohammad Zahirul Islam,et al.  Grape terpenoids: flavor importance, genetic regulation, and future potential , 2020, Critical reviews in food science and nutrition.

[8]  H. Coutinho,et al.  Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice , 2020, Molecules.

[9]  Siyi Pan,et al.  Genomic and Transcriptomic Study for Screening Genes Involved in the Limonene Biotransformation of Penicillium digitatum DSM 62840 , 2020, Frontiers in Microbiology.

[10]  Weifeng Liu,et al.  Metabolic engineering Saccharomyces cerevisiae for de novo production of the sesquiterpenoid (+)-nootkatone , 2020, Microbial Cell Factories.

[11]  J. Lutkenhaus,et al.  Escherichia coli , 2020, Definitions.

[12]  Xiangxiang Zhu,et al.  Inhibition of anticancer growth in Retinoblastoma cells by naturally occurring sesquiterpene nootkatone is mediated via autophagy, endogenous ROS production, cell cycle arrest and inhibition of NF-κB signalling pathway. , 2020, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[13]  Kaishun Bi,et al.  Comparative pharmacokinetic study of the components in Alpinia oxyphylla Miq.-Schisandra chinensis (Turcz.) Baill. herb pair and its single herb between normal and Alzheimer's disease rats by UPLC-MS/MS. , 2020, Journal of pharmaceutical and biomedical analysis.

[14]  J. Fan,et al.  Non-food bioactive products: Design and semisynthesis of novel (+)-nootkatone derivatives containing isoxazoline moiety as insecticide candidates , 2019, Industrial Crops and Products.

[15]  A. González-Coloma,et al.  Novel Insect Antifeedant and Ixodicidal Nootkatone Derivatives , 2019, Biomolecules.

[16]  S. Cho,et al.  Nootkatone, an AMPK activator derived from grapefruit, inhibits KRAS downstream pathway and sensitizes non-small-cell lung cancer A549 cells to adriamycin. , 2019, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[17]  Shaobin Huang,et al.  Stepwise engineering of Saccharomyces cerevisiae to produce (+)-valencene and its related sesquiterpenes , 2019, RSC advances.

[18]  Kaishun Bi,et al.  Combination of schisandrin and nootkatone exerts neuroprotective effect in Alzheimer’s disease mice model , 2019, Metabolic Brain Disease.

[19]  Takayoshi Yamaguchi.  Antibacterial Properties of Nootkatone Against Gram-Positive Bacteria , 2019, Natural Product Communications.

[20]  M. Wang,et al.  Discovery and Engineering of Cytochrome P450s for Terpenoid Biosynthesis. , 2019, Trends in biotechnology.

[21]  R. Bernhardt,et al.  A novel short chain dehydrogenase from Bacillus megaterium for the conversion of the sesquiterpene nootkatol to (+)-nootkatone. , 2019, Journal of biotechnology.

[22]  Wenyu Lu,et al.  Heterologous biosynthesis of (+)-nootkatone in unconventional yeast Yarrowia lipolytica , 2018, Biochemical Engineering Journal.

[23]  Mengjie Xu,et al.  Nootkatone, a neuroprotective agent from Alpiniae Oxyphyllae Fructus, improves cognitive impairment in lipopolysaccharide‐induced mouse model of Alzheimer's disease , 2018, International immunopharmacology.

[24]  S. Al-Salam,et al.  In Vivo Protective Effects of Nootkatone against Particles-Induced Lung Injury Caused by Diesel Exhaust Is Mediated via the NF-κB Pathway , 2018, Nutrients.

[25]  G. Pastore,et al.  Biogeneration of aroma compounds , 2018 .

[26]  M. Rajesh,et al.  Nootkatone confers hepatoprotective and anti‐fibrotic actions in a murine model of liver fibrosis by suppressing oxidative stress, inflammation, and apoptosis , 2018, Journal of biochemical and molecular toxicology.

[27]  U. Krings,et al.  Cell-free one-pot conversion of (+)-valencene to (+)-nootkatone by a unique dye-decolorizing peroxidase combined with a laccase from Funalia trogii , 2018, Journal of Industrial Microbiology & Biotechnology.

[28]  Fanxing Xu,et al.  Neuroprotective effects of nootkatone from Alpiniae oxyphyllae Fructus against amyloid-β-induced cognitive impairment , 2017, Metabolic Brain Disease.

[29]  A. Prado-Barragán,et al.  On the conceptual design of a partitioning technology for the bioconversion of (+)-valencene to (+)-nootkatone on whole cells: Experimentation and modelling , 2017 .

[30]  Sarma Mutturi,et al.  Progress in terpene synthesis strategies through engineering of Saccharomyces cerevisiae , 2017, Critical reviews in biotechnology.

[31]  V. Nardello‐Rataj,et al.  One-Pot Synthesis of (+)-Nootkatone via Dark Singlet Oxygenation of Valencene: The Triple Role of the Amphiphilic Molybdate Catalyst , 2016 .

[32]  K. Chang,et al.  Nootkatone from the Rhizomes of Cyperus rotundus Protects Against Ischemia-reperfusion Mediated Acute Myocardial Injury in the Rat , 2016 .

[33]  O. Rutiaga-Quiñones,et al.  Kinetic, oxygen mass transfer and hydrodynamic studies in a three-phase stirred tank bioreactor for the bioconversion of (+)-valencene on Yarrowia lipolytica 2.2ab , 2016 .

[34]  Siyi Pan,et al.  Proteins differentially expressed during limonene biotransformation by Penicillium digitatum DSM 62840 were examined using iTRAQ labeling coupled with 2D-LC–MS/MS , 2016, Journal of Industrial Microbiology & Biotechnology.

[35]  O. Rutiaga-Quiñones,et al.  Whole Cell Bioconversion of (+)-valencene to (+)-nootkatone in 100 % Organic Phase using Yarrowia lipolytica 2.2ab , 2016 .

[36]  Abhishek Dutta,et al.  Whole cell bioconversion of (+)‐valencene to (+)‐nootkatone by Yarrowia lipolytica using a three phase partitioning bioreactor , 2016 .

[37]  E. Leitner,et al.  Enhancing cytochrome P450-mediated conversions in P. pastoris through RAD52 over-expression and optimizing the cultivation conditions. , 2016, Fungal genetics and biology : FG & B.

[38]  Siyi Pan,et al.  Optimisation of α-terpineol production by limonene biotransformation using Penicillium digitatum DSM 62840. , 2016, Journal of the science of food and agriculture.

[39]  O. Rutiaga-Quiñones,et al.  Screening of microorganisms for bioconversion of (+)-valencene to (+)-nootkatone , 2015 .

[40]  E. Leitner,et al.  Over-expression of ICE2 stabilizes cytochrome P450 reductase in Saccharomyces cerevisiae and Pichia pastoris. , 2015, Biotechnology journal.

[41]  Vera D. Jäger,et al.  Selective Enzymatic Synthesis of the Grapefruit Flavor (+)‐Nootkatone , 2015 .

[42]  V. Wendisch,et al.  Production of the sesquiterpene (+)-valencene by metabolically engineered Corynebacterium glutamicum. , 2014, Journal of biotechnology.

[43]  U. Krings,et al.  Crosses between monokaryons of Pleurotus sapidus or Pleurotus florida show an improved biotransformation of (+)-valencene to (+)-nootkatone. , 2014, Bioresource technology.

[44]  M. Wyss,et al.  Yarrowia lipolytica: Safety assessment of an oleaginous yeast with a great industrial potential , 2014, Critical reviews in microbiology.

[45]  Zhitao Liang,et al.  Tissue-specific metabolite profiling of Cyperus rotundus L. rhizomes and (+)-nootkatone quantitation by laser microdissection, ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and gas chromatography-mass spectrometry techniques. , 2014, Journal of agricultural and food chemistry.

[46]  Erich Leitner,et al.  Production of the sesquiterpenoid (+)-nootkatone by metabolic engineering of Pichia pastoris. , 2014, Metabolic engineering.

[47]  M. Goedbloed,et al.  Valencene oxidase CYP706M1 from Alaska cedar (Callitropsis nootkatensis) , 2014, FEBS letters.

[48]  D. Bosch,et al.  Valencene synthase from the heartwood of Nootka cypress (Callitropsis nootkatensis) for biotechnological production of valencene. , 2014, Plant biotechnology journal.

[49]  M. Maffei,et al.  Engineering monoterpene production in yeast using a synthetic dominant negative geranyl diphosphate synthase. , 2014, ACS synthetic biology.

[50]  Y. Asakawa,et al.  Modification of Valencene by Bio- and Chemical Transformation , 2013, Natural product communications.

[51]  Fanny Lambert,et al.  Challenges and pitfalls of P450-dependent (+)-valencene bioconversion by Saccharomyces cerevisiae. , 2013, Metabolic engineering.

[52]  U. Krings,et al.  Functional expression of a valencene dioxygenase from Pleurotus sapidus in E. coli. , 2012, Bioresource technology.

[53]  T. Janeczko,et al.  Microbial transformation of (+)-nootkatone and the antiproliferative activity of its metabolites. , 2011, Bioorganic & medicinal chemistry.

[54]  D. Bosch,et al.  A chicory cytochrome P450 mono‐oxygenase CYP71AV8 for the oxidation of (+)‐valencene , 2011, FEBS letters.

[55]  B. Hamberger,et al.  Cytochromes P450 , 2011, The arabidopsis book.

[56]  Y. Gounaris.  Biotechnology for the production of essential oils, flavours and volatile isolates. A review.†‡ , 2010 .

[57]  U. Krings,et al.  A dioxygenase of Pleurotus sapidus transforms (+)-valencene regio-specifically to (+)-nootkatone via a stereo-specific allylic hydroperoxidation. , 2010, Bioresource technology.

[58]  Regina M. Stöber,et al.  A novel oxygenase from Pleurotus sapidus transforms valencene to nootkatone , 2009 .

[59]  Ulrich Krings,et al.  Enzymatische synthese von nootkaton , 2009 .

[60]  U. Krings,et al.  Autoxidation versus biotransformation of alpha-pinene to flavors with Pleurotus sapidus: regioselective hydroperoxidation of alpha-pinene and stereoselective dehydrogenation of verbenol. , 2009, Journal of agricultural and food chemistry.

[61]  V. Urlacher,et al.  Regioselective biooxidation of (+)-valencene by recombinant E. coli expressing CYP109B1 from Bacillus subtilis in a two-liquid-phase system , 2009, Microbial cell factories.

[62]  R. Berger,et al.  Nootkatone—a biotechnological challenge , 2009, Applied Microbiology and Biotechnology.

[63]  C. Galli,et al.  Phenolic compounds as likely natural mediators of laccase: A mechanistic assessment , 2008 .

[64]  Shunji Takahashi,et al.  Functional Characterization of Premnaspirodiene Oxygenase, a Cytochrome P450 Catalyzing Regio- and Stereo-specific Hydroxylations of Diverse Sesquiterpene Substrates* , 2007, Journal of Biological Chemistry.

[65]  J. Gershenzon,et al.  The function of terpene natural products in the natural world. , 2007, Nature chemical biology.

[66]  M. A. Fraatz.  Enzymatische Oxidation von Mono- und Sesquiterpenen , 2007 .

[67]  S. Bell,et al.  Biotransformation of the sesquiterpene (+)-valencene by cytochrome P450cam and P450BM-3. , 2005, Organic & biomolecular chemistry.

[68]  R. Berger,et al.  Laccases of Pleurotus sapidus: characterization and cloning. , 2005, Journal of agricultural and food chemistry.

[69]  Y. Asakawa,et al.  Highly efficient production of nootkatone, the grapefruit aroma from valencene, by biotransformation. , 2005, Chemical & pharmaceutical bulletin.

[70]  Y. Asakawa,et al.  Biotransformation of citrus aromatics nootkatone and valencene by microorganisms. , 2005, Chemical & pharmaceutical bulletin.

[71]  T. Taniai,et al.  Biotransformation of valencene by cultured cells of Gynostemma pentaphyllum , 2005 .

[72]  Anthony Clark,et al.  Microbial isoprenoid production: an example of green chemistry through metabolic engineering. , 2005, Advances in biochemical engineering/biotechnology.

[73]  U. Krings,et al.  Bioconversion of (+)-valencene in submerged cultures of the ascomycete Chaetomium globosum , 2005, Applied Microbiology and Biotechnology.

[74]  F. Chen,et al.  Nootkatone Is a Repellent for Formosan Subterranean Termite (Coptotermes formosanus) , 2001, Journal of Chemical Ecology.

[75]  J. Iborra,et al.  Accumulation of the sesquiterpenes nootkatone and valencene by callus cultures of Citrus paradisi, Citrus limonia and Citrus aurantium , 1991, Plant Cell Reports.

[76]  R. Berger,et al.  Regioselective biotransformation of valencene in cell suspension cultures of Citrus sp. , 1984, Plant Cell Reports.

[77]  Rüdiger Kaspera.  Oxyfunktionalisierung von Terpenkohlenwasserstoffen zu aromaaktiven Terpenoiden durch selektive Biokatalyse , 2004 .

[78]  E. Lewinsohn,et al.  Citrus fruit flavor and aroma biosynthesis: isolation, functional characterization, and developmental regulation of Cstps1, a key gene in the production of the sesquiterpene aroma compound valencene. , 2003, The Plant journal : for cell and molecular biology.

[79]  R. Laine,et al.  The sesquiterpenoid nootkatone and the absolute configuration of a dibromo derivative. , 2003, Acta crystallographica. Section C, Crystal structure communications.

[80]  J. Clark,et al.  The allylic oxidation of unsaturated steroids by tert-butyl hydroperoxide using surface functionalised silica supported metal catalysts , 2002 .

[81]  N. Durán,et al.  Potential applications of laccase in the food industry , 2002 .

[82]  三橋 勝久,et al.  Process for the preparation of nootkatone , 2002 .

[83]  G. Reil,et al.  Genesis of aroma compounds in photomixotrophic cell cultures of Grapefruit, Citrus paradisi cv. White March , 1996 .

[84]  K. Hull,et al.  A stereoselective synthesis of (±)-nootkatone and (±)-valencene via an intramolecular Sakurai reaction , 1985 .

[85]  T. Inokuchi,et al.  Functionalization of trans-Decalin. V. A Synthesis of (±)-Nootkatone and (±)-Valencene from 4β,4aβ-Dimethyl-Δ6,7-octalin-1-one Ethylene Acetal , 1982 .

[86]  Charles W. Wilson,et al.  Importance of nootkatone to the aroma of grapefruit oil and the flavor of grapefruit juice , 1981 .

[87]  M. Miyashita,et al.  Synthetic study of (+)-nootkatone from (-)-.beta.-pinene , 1980 .

[88]  R. Crawford,et al.  Microbial degradation of lignin , 1979 .

[89]  M. Miyashita,et al.  Stereocontrolled synthesis of (+)-nootkatone from (–)-β-pinene , 1979 .

[90]  Charles W. Wilson,et al.  Synthesis of nootkatone from valencene , 1978 .

[91]  K. Dastur.  Stereoselective approach to eremophilane sesquiterpenes. Synthesis of (+-)-nootkatone , 1973 .

[92]  A. D. Gen,et al.  Olfactory studies on enantiomeric eremophilane sesquiterpenoids , 1972 .

[93]  J. A. Marshall,et al.  Stereoselective total synthesis of racemic nootkatone , 1971 .

[94]  F. Drawert,et al.  Über die biogenese von aromastoffen bei pflanzen und früchten , 1970 .

[95]  M. Pesaro,et al.  The total synthesis of racemic nootkatone , 1968 .

[96]  M. Akhtar.  Microbial Transformation , 1968, Nature.

[97]  G. Hunter,et al.  Analysis of the Terpene and Sesquiterpene Hydrocarbons in Some Citrus Oils , 1965 .

[98]  W. D. Macleod,et al.  The constitution of nootkatone, nootkatene and valencene , 1965 .

[99]  W. D. Macleod,et al.  Sesquiterpenes. I. Nootkatone, A New Grapefruit Flavor Constituent , 1964 .