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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2018, Vol. 38 Issue (11): 92-102    DOI: 10.13523/j.cb.20181112
综述     
桉叶素生物合成研究进展
匙占库,文孟良,赵江源,李铭刚,韩秀林()
云南生物资源保护与利用国家重点实验室 西南微生物多样性教育部重点实验室 云南省微生物研究所 云南大学生命科学学院 昆明 650091
Recent Advances in Biosynthesis of 1,8-Cineole
Zhan-ku SHI,Meng-liang WEN,Jiang-yuan ZHAO,Ming-gang LI,Xiu-lin HAN()
State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan,Key Laboratory of Microbial Diversity in Southwest of China, Ministry of Education,Yunnan Institute of Microbiology, School of Life Sciences, Yunnan University, Kunming 650091, China
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摘要：

作为桉叶油的主要成分,桉叶素是具有多种生物活性的单萜化合物,被广泛应用于药品、食品及化妆品等领域。桉叶油主要从桉树叶提取,该过程耗费大量人力及自然资源,且容易污染环境。近年来,随着微生物代谢工程与合成生物学的快速发展,加上越来越多萜类生物合成途径得到解析,为桉叶素的绿色生产提供了新的途径。对桉叶素的生物合成途径、桉叶素合酶的结构与功能及近年来桉叶素的微生物合成进行了综述,并对利用微生物代谢工程合成桉叶素等单萜化合物的瓶颈问题及解决方案进行了探讨和归纳,为构建高产桉叶素等单萜微生物工程菌株提供参考。
关键词： 桉叶素;  桉叶素合酶;  生物合成途径;  合成生物学    
Abstract:

As the main component of eucalyptus oil, 1,8-cineole is a monoterpene compound exhibiting a wide range of bioactivities. It has been applied broadly in the fields of pharmaceuticals, food, and cosmetic industries. The commercially available eucalyptus oil is mainly extracted from eucalyptus leaves. The extraction process requires intensive labor and abundant natural resources, and is prone to contaminate the environment. 1,8-cineole will be produced greenly with the rapid development of microbial metabolic engineering and synthetic biology, and with more and more biosynthetic pathways of terpenoids have been deciphered in the future . The biosynthetic pathway of 1,8-cineole, the structures and functions of 1,8-cineole synthases, and the microbial biosynthesis of 1,8-cineole are reviewed. The bottleneck problems encountered in the production of 1,8-cineole with engineered microbial strains are summarized, and the corresponding solving strategies are proposed,that will provide references for the construction of engineered microbial strains with high yield of 1,8-cineole or other monoterpenes.
Key words: 1,8-cineole    Cineole synthase    Biosynthetic pathway    Synthetic biology
收稿日期: 2018-05-18 出版日期: 2018-12-06
ZTFLH:  TQ35  
通讯作者: 韩秀林     E-mail: xlhan@ynu.edu.cn
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匙占库
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引用本文:

匙占库,文孟良,赵江源,李铭刚,韩秀林. 桉叶素生物合成研究进展[J]. 中国生物工程杂志, 2018, 38(11): 92-102.

Zhan-ku SHI,Meng-liang WEN,Jiang-yuan ZHAO,Ming-gang LI,Xiu-lin HAN. Recent Advances in Biosynthesis of 1,8-Cineole. China Biotechnology, 2018, 38(11): 92-102.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20181112    或    https://manu60.magtech.com.cn/biotech/CN/Y2018/V38/I11/92

图1  植物体内萜类化合物合成示意图
图2  桉叶素合酶催化GPP到桉叶素的反应机制 [19]
Species Accession
No.		 Products Crystal
structure		 References
Nicotiana
suaveolens		 ABP88782 1,8-cineole (62%), myrcene, limonene, sabinene, cimene, α-terpineole, α-pinene, - [23]
Nicotiana
noctiflora		 AHK23027 1,8-cineole (50%), limonene, myrcene, β-pinene, α-pinene, sabinene, α-terpineol. - [25]
Nicotiana
mutabilis		 AFO59753 1,8-cineole(50%-80%), myrcene, limonene, sabinene, cimene, α-terpineole, α-pinene, - [24]
Nicotiana
forgetiana		 AFO63172 1,8-cineole(60%-67%), α-terpineol,pinene, sabinene, β-myrcene, limonene - [24]
Nicotiana
longiflora		 AFO59752 1,8-cineole (60%-67%), α-terpineol pinene, sabinene, β-myrcene, limonene - [24]
Lavandula
latifolia		 AFL03422 1,8-cineole (80%), sabinene, α-phellandrene, limonene, α-terpineol - [27]
Salvia
officinalis		 AAC26016 1,8-cineole (79%), α-terpineol, olefins - [20]
Salvia
fruticosa		 ABH07677 1,8-cineole (72.4%), α-terpineol, β-pinene, α-pinene, sabinene, myrcene, limonene + [18]
Artemisia
annua		 AIE41601 1,8-cineole (59.28%), sabinene, β-phellandrene, α-terpineol, trans-sabinene, (-)-α-pinene, cis-β-terpineol, β-myrcene, α-thujene - [29]
Arabidopsis
thaliana		 AAU01970 1,8-cineole(52%), α-thujene, α-pinene, sabinene, β-pinene, myrcene, limonene, (E)-β-ocimene, terpinolene, α-terpineol - [21]
Citrus unshiu BAD91045 1,8-cineole (>98%) - [22]
Streptomyces
clavuligerus
ATCC 27064		 EDY47508 1,8-cineole (>50%), 1,4-cineole, isoborneol, borneol α-terpinol, fenchol - [26]
Hypoxylon sp.
E7406B		 AHY23922 1,8-cineole (90%) D-limonene - [28]
表1  不同物种来源桉叶素合酶及其重组蛋白催化产物
图3  桉叶素合酶晶体结构 [18,19]
图4  不同物种来源的桉叶素合酶的氨基酸序列比对以及酶活性位点的关键氨基酸残基
[1] Viturro C I, Molina A C, Heit C I . Volatile components of Eucalyptus globulus Labill ssp. bicostata from Jujuy, Argentina. J Essent Oil Res, 2003,15(3):206-208.
doi: 10.1080/10412905.2003.9712115
[2] Tizianabaratta M, Damiendorman H J, Deans S , et al. Chemical composition, antimicrobial and antioxidative activity of laurel, sage, rosemary, oregano and coriander essential oils. J Essent Oil Res, 1998,10(6):618-627.
doi: 10.1080/10412905.1998.9700989
[3] Hussain A I, Anwar F, Nigam P S , et al. Antibacterial activity of some Lamiaceae essential oils using resazurin as an indicator of cell growth. LWT- Food Sci Technol, 2011,44(4):1199-1206.
doi: 10.1016/j.lwt.2010.10.005
[4] Wang K Y, Strobel G A, Yan D H . The production of 1,8-cineole, a potential biofuel, from an endophytic strain of Annulohypoxylon sp. FPYF3050 when grown on agricultural residues. J Sustain Bioenergy Syst, 2017,7(2):65-84.
doi: 10.4236/jsbs.2017.72006
[5] Hu Z, Chen Z, Yin Z , et al. In vitro acaricidal activity of 1,8-cineole against Sarcoptes scabiei var. cuniculi and regulating effects on enzyme activity. Parasitol Res, 2015,114(8):2959-2567.
doi: 10.1007/s00436-015-4498-8 pmid: 25924796
[6] Caldas G F R, Oliveira A R D S, Araújo A V , et al. Gastroprotective mechanisms of the monoterpene 1,8-cineole (eucalyptol). PLoS One, 2015,10(8):e0134558.
doi: 10.1371/journal.pone.0134558 pmid: 26244547
[7] Juergens U R . Anti-inflammatory properties of the monoterpene 1.8-cineole: current evidence for co-medication in inflammatory airway diseases. Drug Res (Stuttg), 2014,64(12):638-646.
doi: 10.1055/s-0034-1372609 pmid: 24831245
[8] Khan A, Vaibhav K, Javed H , et al. 1,8-cineole (eucalyptol) mitigates inflammation in amyloid beta toxicated PC12 cells: relevance to Alzheimer’s disease. Neurochem Res, 2014,39(2):344-352.
doi: 10.1007/s11064-013-1231-9 pmid: 24379109
[9] Moon H K, Kang P, Lee H S , et al. Effects of 1,8-cineole on hypertension induced by chronic exposure to nicotine in rats. J Pharm Pharmacol, 2014,66(5):688-693.
doi: 10.1111/jphp.12195
[10] Santos F A, Silva R M, Tome A R , et al. 1,8-Cineole protects against liver failure in an in-vivo murine model of endotoxemic shock. J Pharm Pharmacol, 2001,53(4):505-511.
doi: 10.1211/0022357011775604 pmid: 11341367
[11] Moteki H, Hibasami H, Yamada Y , et al. Specific induction of apoptosis by 1,8-cineole in two human leukemia cell lines, but not a in human stomach cancer cell line. Oncol Rep, 2002,9(4):757-760.
doi: 10.3892/or.9.4.757 pmid: 12066204
[12] Dhakad A K, Pandey V V, Beg S , et al. Biological, medicinal and toxicological significance of Eucalyptus leaf essential oil: a review. J Sci Food Agric, 2017,98(3):833-848.
doi: 10.1002/jsfa.8600 pmid: 28758221
[13] Lahlou S, Figueiredo A F, Magalh?es P J , et al. Cardiovascular effects of 1,8-cineole, a terpenoid oxide present in many plant essential oils, in normotensive rats. Can J Physiol Pharmacol, 2002,80(12):1125-1131.
doi: 10.1139/y02-142 pmid: 12564637
[14] Verma P, Sharma M P, Dwivedi G . Potential use of eucalyptus biodiesel in compressed ignition engine. Egypt J Pet, 2016,25(1):91-95.
doi: 10.1016/j.ejpe.2015.03.008
[15] Zebec Z, Wilkes J, Jervis A J , et al. Towards synthesis of monoterpenes and derivatives using synthetic biology. Curr Opin Chem Biol, 2016,34:37-43.
doi: 10.1016/j.cbpa.2016.06.002 pmid: 27315341
[16] Tholl D . Terpene synthases and the regulation, diversity and biological roles of terpene metabolism. Curr Opin Plant Biol, 2006,9(3):297-304.
doi: 10.1016/j.pbi.2006.03.014
[17] Croteau R, Alonso W R, Koepp A E , et al. Biosynthesis of monoterpenes: partial purification, characterization, and mechanism of action of 1,8-cineole synthase. Arch Biochem Biophys, 1994,309(1):184-192.
doi: 10.1006/abbi.1994.1101 pmid: 8117108
[18] Kampranis S C, Ioannidis D, Purvis A , et al. Rational conversion of substrate and product specificity in a Salvia monoterpene synthase: structural insights into the evolution of terpene synthase function. Plant Cell, 2007,19(6):1994-2005.
doi: 10.1105/tpc.106.047779
[19] Karuppiah V, Ranaghan K E ,Leferink N G H, , et al. Structural basis of catalysis in the bacterial monoterpenesynthases linalool synthase and 1,8-cineole synthase. ACS Catal, 2017,7(9):6268-6282.
doi: 10.1021/acscatal.7b01924 pmid: 5617326
[20] Wise M L, Savage T J, Katahira E , et al. Monoterpene synthases from common sage (Salvia officinalis). cDNA isolation, characterization, and functional expression of (+)-sabinene synthase, 1,8-cineole synthase, and (+)-bornyl diphosphate synthase. J Biol Chem, 1998,273(24):14891-14899.
doi: 10.1074/jbc.273.24.14891
[21] Chen F, Ro D K, Petri J , et al. Characterization of a root-specific Arabidopsis terpene synthase responsible for the formation of the volatile monoterpene 1,8-cineole. Plant Physiol, 2004,135(4):1956-1966.
doi: 10.1104/pp.104.044388 pmid: 15299125
[22] Shimada T, Endo T, Fujii H , et al. Isolation and characterization of (E)-beta-ocimene and 1,8 cineole synthases in Citrus unshiu Marc. Plant Sci, 2005,168(4):987-995.
doi: 10.1016/j.plantsci.2004.11.012
[23] Roeder S, Hartmann A M, Effmert U , et al. Regulation of simultaneous synthesis of floral scent terpenoids by the 1,8-cineole synthase of Nicotiana suaveolens. Plant Mol Biol, 2007,65(1-2):107-124.
doi: 10.1007/s11103-007-9202-7 pmid: 17611797
[24] Fahnrich A, Brosemann A, Teske L , et al. Synthesis of ‘cineole cassette’ monoterpenes in Nicotiana section Alatae: gene isolation, expression, functional characterization and phylogenetic analysis. Plant Mol Biol, 2012,79(6):537-553.
doi: 10.1007/s11103-012-9933-y
[25] Fahnrich A, Neumann M, Piechulla B . Characteristic alatoid ‘cineole cassette’ monoterpene synthase present in Nicotiana noctiflora. Plant Mol Biol, 2014,85(1-2):135-145.
doi: 10.1007/s11103-014-0176-y pmid: 24493662
[26] Nakano C, Kim H K, Ohnishi Y . Identification of the first bacterial monoterpene cyclase, a 1,8-cineole synthase, that catalyzes the direct conversion of geranyl diphosphate. Chembiochem, 2011,12(13):1988-1991.
doi: 10.1002/cbic.201100330 pmid: 21726035
[27] Demissie Z A, Cella M A, Sarker L S , et al. Cloning, functional characterization and genomic organization of 1,8-cineole synthases from Lavandula. Plant Mol Biol, 2012,79(4-5):393-411.
doi: 10.1007/s11103-012-9920-3 pmid: 22592779
[28] Shaw J J, Berbasova T, Sasaki T , et al. Identification of a fungal 1,8-cineole synthase from Hypoxylon sp. with specificity determinants in common with the plant synthases. J Biol Chem, 2015,290(13):8511-8526.
doi: 10.1074/jbc.M114.636159 pmid: 25648891
[29] Ruan J X, Li J X, Fang X , et al. Isolation and characterization of three new monoterpene synthases from Artemisia annua. Front Plant Sci, 2016,7(45):638.
doi: 10.3389/fpls.2016.00638 pmid: 4861830
[30] Keszei A, Brubaker C L, Carter R , et al. Functional and evolutionary relationships between terpene synthases from Australian Myrtaceae. Phytochemistry, 2010,71(8-9):844-852.
doi: 10.1016/j.phytochem.2010.03.013 pmid: 20399476
[31] Balacs T . Cineole-rich eucalyptus. Int J Aromather, 1997,8(8):15-21.
doi: 10.1016/S0962-4562(97)80020-3
[32] Williams D C, Mcgarvey D J, Katahira E J , et al. Truncation of limonene synthase preprotein provides a fully active ‘pseudomature’ form of this monoterpene cyclase and reveals the function of the amino-terminal arginine pair. Biochemistry, 1998,37(35):12213-12220.
doi: 10.1021/bi980854k pmid: 9724535
[33] Whittington D A, Wise M L, Urbansky M , et al. Bornyl diphosphate synthase: structure and strategy for carbocation manipulation by a terpenoid cyclase. Proc Natl Acad Sci USA, 2002,99(24):15375-15380.
doi: 10.1073/pnas.232591099
[34] Degenhardt J, Köllner T G, Gershenzon J . Monoterpene and sesquiterpene synthases and the origin of terpene skeletal diversity in plants. Phytochemistry, 2009,70(15):1621-1637.
doi: 10.1016/j.phytochem.2009.07.030
[35] Starks C M, Noel J P . Structural basis for cyclic terpene biosynthesis by tobacco 5-epi-aristolochene synthase. Science, 1997,277(5333):1815-1820.
doi: 10.1126/science.277.5333.1815
[36] Gao Y, Honzatko R B, Peters R J . Terpenoid synthase structures: A so far incomplete view of complex catalysis. Nat Prod Rep, 2012,29(10):1153-1175.
doi: 10.1039/c2np20059g pmid: 3448952
[37] Piechulla B, Bartelt R, Brosemann A , et al. The α-terpineol to 1,8-cineole cyclization reaction of tobacco terpene synthases. Plant Physiol, 2016,172(4):2120-2131.
doi: 10.1104/pp.16.01378 pmid: 27729471
[38] Tomsheck A R, Strobel G A, Booth E , et al. Hypoxylon sp. an endophyte of Persea indica producing 1,8-cineole and other bioactive volatiles with fuel potential. Microb Ecol, 2010,60(4):903-914.
doi: 10.1007/s00248-010-9759-6 pmid: 20953951
[39] Mends M T, Yu E, Strobel G A , et al. An endophytic Nodulisporium sp. producing volatile organic ccompounds having bioactivity and fuel potential. J Pet Environ Biotechnol, 2012,3(Supplement S1):S33-S47.
[40] Riyaz-Ul-Hassan S, Strobel G, Geary B , et al. An endophytic Nodulisporium sp. from central America producing volatile organic compounds with both biological and fuel potential. J Microbiol Biotechnol, 2013,23(1):29-35.
doi: 10.1051/jp4:1993112 pmid: 23314364
[41] Goldstein J L, Brown M S . Regulation of the mevalonate pathway. Nature, 1990,343(6257):425-430.
doi: 10.1038/343425a0
[42] Ignea C, Cvetkovic I, Loupassaki S , et al. Improving yeast strains using recyclable integration cassettes, for the production of plant terpenoids. Microb Cell Fact, 2011,10(1):4.
doi: 10.1186/1475-2859-10-4 pmid: 21276210
[43] Erhardt H, Dempwolff F, Pfreundschuh M , et al. Organization of the Escherichia coli aerobic enzyme complexes of oxidative phosphorylation in dynamic domains within the cytoplasmic membrane. Microbiologyopen, 2014,3(3):316-326.
doi: 10.1002/mbo3.163 pmid: 24729508
[44] Mendez-Perez D, Alonsogutierrez J, Hu Q , et al. Production of jet fuel precursor monoterpenoids from engineered Escherichia coli. Biotechnol Bioeng, 2017,114(8):1703-1712.
doi: 10.1002/bit.26296
[45] Martin V J, Pitera D J, Withers S T , et al. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol, 2003,21(7):796-802.
doi: 10.1038/nbt833 pmid: 12778056
[46] Guan Z, Xue D, Abdallah I I , et al. Metabolic engineering of Bacillus subtilis, for terpenoid production. Appl Microbiol Biotechnol, 2015,99(22):9395-9406.
doi: 10.1007/s00253-015-6950-1 pmid: 4628092
[47] Formighieri C, Melis A . Sustainable heterologous production of terpene hydrocarbons in cyanobacteria. Photosynth Res, 2016,130(1-3):1-13.
doi: 10.1007/s11120-015-0207-9 pmid: 26650229
[48] Paddon C J, Westfall P J, Pitera D J , et al. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature, 2013,496(7446):528-532.
doi: 10.1038/nature12051 pmid: 23575629
[49] Westfall P J, Pitera D J, Lenihan J R , et al. Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. Proc Natl Acad Sci USA, 2012,109(3):111-118.
doi: 10.1073/pnas.1110740109 pmid: 22247290
[50] Ro D K, Paradise E M, Ouellet M , et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature, 2006,440(7086):940-943.
doi: 10.1038/nature04640 pmid: 16612385
[51] Han G H, Kim S K, Yoon P K , et al. Fermentative production and direct extraction of (-)-α-bisabolol in metabolically engineered Escherichia coli. Microb Cell Fact, 2016,15(1):185.
doi: 10.1186/s12934-016-0588-2 pmid: 5282890
[52] You S, Yin Q, Zhang J , et al. Utilization of biodiesel by-product as substrate for high-production of β-farnesene via relatively balanced mevalonate pathway in Escherichia coli. Bioresour Technol, 2017,243:228.
doi: 10.1016/j.biortech.2017.06.058 pmid: 28672185
[53] Fischer M J, Meyer S, Claudel P , et al. Metabolic engineering of monoterpene synthesis in yeast. Biotechnol Bioeng, 2011,108(8):1883-1892.
doi: 10.1002/bit.23129 pmid: 21391209
[54] Carrau F M, Medina K, Boido E , et al. De novo synthesis of monoterpenes by Saccharomyces cerevisiae wine yeasts. FEMS Microbiol Lett, 2005,243(1):107-115.
doi: 10.1016/j.femsle.2004.11.050 pmid: 15668008
[55] Banerjee A, Sharkey T D . Methylerythritol 4-phosphate (MEP) pathway metabolic regulation. Nat Prod Rep, 2014,31(8):1043-1055.
doi: 10.1039/c3np70124g pmid: 24921065
[56] Rodwell V W, Nordstrom J L, Mitschelen J J . Regulation of HMG-CoA reductase. Adv Lipid Res, 1976,14:1-74.
doi: 10.1016/B978-0-12-024914-5.50008-5
[57] Fujisaki S, Hara H, Nishimura Y , et al. Cloning and nucleotide sequence of the ispA gene responsible for farnesyl diphosphate synthase activity in Escherichia coli. J Biochem, 1990,108(6):995-1000.
doi: 10.1016/0141-8130(90)90047-E pmid: 2089044
[58] Anderson M S, Yarger J G, Burck C L , et al. Farnesyl diphosphate synthetase. Molecular cloning, sequence, and expression of an essential gene from Saccharomyces cerevisiae. J Biol Chem, 1989,264(32):19176-19184.
doi: 10.1016/0006-291X(89)91832-9 pmid: 2681213
[59] Donald K A, Hampton R Y, Fritz I B . Effects of overproduction of the catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase on squalene synthesis in Saccharomyces cerevisiae. Appl Environ Microbiol, 1997,63(9):3341-3344.
doi: 10.1016/S0027-5107(97)00112-7 pmid: 168639
[60] Engels B, Dahm P, Jennewein S . Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production. Metab Eng, 2008,10(3-4):201-206.
doi: 10.1016/j.ymben.2008.03.001 pmid: 18485776
[61] Li Q, Sun Z, Li J , et al. Enhancing beta-carotene production in Saccharomyces cerevisiae by metabolic engineering. FEMS Microbiol Lett, 2013,345(2):94-101.
doi: 10.1111/1574-6968.12187 pmid: 23718229
[62] Fischer M J, Meyer S, Claudel P , et al. Metabolic engineering of monoterpene synthesis in yeast. Biotechnol Bioeng, 2011,108(8):1883-1892.
doi: 10.1002/bit.23129 pmid: 21391209
[63] Ignea C, Pontini M, Maffei M E , et al. Engineering monoterpene production in yeast using a synthetic dominant negative geranyl diphosphate synthase. ACS Synth Biol, 2014,3(5):298-306.
doi: 10.1021/sb400115e pmid: 24847684
[64] Tashiro M, Kiyota H, Kawainoma S , et al. Bacterial production of pinene by a laboratory-evolved pinene-synthase. ACS Synth Biol, 2016,5(9):1011-1120.
doi: 10.1021/acssynbio.6b00140 pmid: 27247193
[65] Brennan T C R, Turner C D, Krömer J O , et al. Alleviating monoterpene toxicity using a two-phase extractive fermentation for the bioproduction of jet fuel mixtures in Saccharomyces cerevisiae. Biotechnol Bioeng, 2012,109(10):2513-3522.
doi: 10.1002/bit.24536 pmid: 22539043
[66] Zhang L, Xiao W H, Wang Y , et al. Chassis and key enzymes engineering for monoterpenes production. Biotechnol Adv, 2017,35(8):1022-1031.
doi: 10.1016/j.biotechadv.2017.09.002 pmid: 28888552
[67] Denby C M, Li R A, Vu V T , et al. Industrial brewing yeast engineered for the production of primary flavor determinants in hopped beer. Nat Commun., 2018,9(1):965-974.
doi: 10.1038/s41467-018-03293-x pmid: 29559655
[68] Baadhe R R, Mekala N K, Parcha S R , et al. Combination of ERG9 repression and enzyme fusion technology for improved production of amorphadiene in Saccharomyces cerevisiae. J anal Methods Chem, 2013,2013(12):140469-140476.
doi: 10.1155/2013/140469 pmid: 24282652
[69] Jiang G Z, Yao M D, Wang Y , et al. Manipulation of GES and ERG20 for geraniol overproduction in Saccharomyces cerevisiae. Metab Eng, 2017,41:57-66.
doi: 10.1016/j.ymben.2017.03.005 pmid: 28359705
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