Research Progress of Key Enzymes in Terpene Biosynthesis

doi:10.13523/j.cb.2102032

China Biotechnology

2021, Vol. 41

Issue (6): 60-70 DOI: 10.13523/j.cb.2102032

Research Progress of Key Enzymes in Terpene Biosynthesis

MIAO Yi-nan¹,LI Jing-zhi¹,WANG Shuai¹,LI Chun^1,²,WANG Ying^1,^**(

)

1 Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
2 Department of Chemical Engineering, Tsinghua University, Beijing 100084, China

Download:

HTML

PDF(909KB) HTML
Export: BibTeX | EndNote (RIS)

Abstract

Terpenes are a large class of highly diverse natural products with various physiological activities such as anti-tumor, anti-oxidation and immune regulation. Therefore, they are widely used in the fields of medicine and health, food, cosmetics, and biofuels. However, obtaining terpene compounds directly from natural resources is low efficient, costly, and often has an adverse impact on the ecological environment, making it impossible to achieve green and sustainable production. Microbial synthesis of terpenes has attracted much attention in recent years. Researchers have conducted explorations from the construction and regulation of synthetic pathways, protein engineering, and fermentation process optimization, and have obtained fruitful results. Among them, the efficiency of key enzymes in the synthetic pathway plays an important role in the microbial production of terpenes. Research on key enzymes is of great significance for improving the ability of microorganisms to synthesize terpenes and thus accelerating the large-scale application of microbial production of such natural products. Here, four key enzymes in the synthetic pathway of terpenes including 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), 1-deoxy-D-xylulose-5-phosphate synthase (DXS), isoprenyl diphosphate synthase (IDS), and terpene synthase (TPS) were introduced. The regulation of catalytic activities of key enzymes via metabolic engineering, protein engineering and synthetic biology to improve the efficiency of microbial synthesis of terpenes as well as the prospects of using microorganisms to synthesize terpenes were also reviewed.

Key words： Terpenes Key enzymes Metabolic engineering Protein engineering Biosynthesis

Received: 24 February 2021 Published: 06 July 2021

ZTFLH:

Q819

Corresponding Authors: Ying WANG E-mail: wy2015@bit.edu.cn

	Service
	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors
	Yi-nan MIAO
	Jing-zhi LI
	Shuai WANG
	Chun LI
	Ying WANG

Cite this article:

MIAO Yi-nan,LI Jing-zhi,WANG Shuai,LI Chun,WANG Ying. Research Progress of Key Enzymes in Terpene Biosynthesis. China Biotechnology, 2021, 41(6): 60-70.

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2102032 OR https://manu60.magtech.com.cn/biotech/Y2021/V41/I6/60

Fig.1 The biosynthetic pathway of terpenes DXS. 1-deoxy-D-xylulose-5-phosphate synthase; DXR. 1-deoxy-D-xylulose-5-phosphate DXS reductoisomerase; AACT. Acetoacetyl-CoA thiolase; HMGS. HMG-CoA synthase; HMGR. HMG-CoA reductase; IDI. Isopentenyl diphosphate isomerase; GPPS. Geranyl diphosphate synthase; FPPS. Farnesyl diphosphate synthase; GFPPS. Geranylgeranyl diphosphate synthase; TPS. Terpenes synthase

Table 1 Key enzymes in terpene biosynthesis

Fig.2 The reaction pathways of trans- and cis- IDS

Table 2 Key enzymes and regulation strategies in the synthesis of terpenes


[1]	Chen M B, Chou W K W, Al-Lami N, et al. Probing the role of active site water in the sesquiterpene cyclization reaction catalyzed by aristolochene synthase. Biochemistry, 2016, 55(20):2864-2874. doi: 10.1021/acs.biochem.6b00343

[2]	Ansari M M, Ahmad A, Kumar A, et al. Aminocellulose-grafted-polycaprolactone coated gelatin nanoparticles alleviate inflammation in rheumatoid arthritis: A combinational therapeutic approach. Carbohydrate Polymers, 2021, 258:117600. doi: 10.1016/j.carbpol.2020.117600

[3]	Yang Y, Wei Y G, Guo X N, et al. Glycyrrhetic acid monoglucuronide: sweetness concentration-response and molecular mechanism as a naturally high-potency sweetener. Food Science and Biotechnology, 2019, 28(4):1187-1193. doi: 10.1007/s10068-019-00559-y

[4]	Benjamin K R, Silva I R, Cherubim J P, et al. Developing commercial production of semi-synthetic artemisinin, and of β-farnesene, an isoprenoid produced by fermentation of Brazilian sugar. Journal of the Brazilian Chemical Society, 2016, 27(8):1339-1345.

[5]	Zhang Y L, Long Y, Yu S, et al. Natural volatile oils derived from herbal medicines: A promising therapy way for treating depressive disorder. Pharmacological Research, 2021, 164:105376. doi: 10.1016/j.phrs.2020.105376

[6]	Ajikumar P K, Xiao W H, Tyo K E J, et al. Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Science, 2010, 330(6000):70-74. doi: 10.1126/science.1191652

[7]	Polakowski T, Stahl U, Lang C. Overexpression of a cytosolic hydroxymethylglutaryl-CoA reductase leads to squalene accumulation in yeast. Applied Microbiology and Biotechnology, 1998, 49(1):66-71. doi: 10.1007/s002530051138

[8]	Matthews P D, Wurtzel E T. Metabolic engineering of carotenoid accumulation in Escherichia coli by modulation of the isoprenoid precursor pool with expression of deoxyxylulose phosphate synthase. Applied Microbiology and Biotechnology, 2000, 53(4):396-400. doi: 10.1007/s002530051632

[9]	Ignea C, Pontini M, Maffei M E, et al. Engineering monoterpene production in yeast using a synthetic dominant negative geranyl diphosphate synthase. ACS Synthetic Biology, 2014, 3(5):298-306. doi: 10.1021/sb400115e

[10]	Navale G R, Sharma P, Said M S, et al. Enhancing epi-cedrol production in Escherichia coli by fusion expression of farnesyl pyrophosphate synthase and epi-cedrol synthase. Engineering in Life Sciences, 2019, 19(9):606-616. doi: 10.1002/elsc.v19.9

[11]	Yin J, Li Y, Li C X, et al. Cloning, expression characteristics of a new FPS gene from birch (Betula platyphylla Suk.) and functional identification in triterpenoid synthesis. Industrial Crops and Products, 2020, 154:112591. doi: 10.1016/j.indcrop.2020.112591

[12]	Wendt K U, Poralla K, Schulz G E. Structure and function of a squalene cyclase. Science, 1997, 277(5333):1811-1815. doi: 10.1126/science.277.5333.1811

[13]	Zhang G L, Cao Q, Liu J Z, et al. Refactoring β-amyrin synthesis in Saccharomyces cerevisiae. AIChE Journal, 2015, 61(10):3172-3179. doi: 10.1002/aic.v61.10

[14]	Bach T J. Hydroxymethylglutaryl-CoA reductase, a key enzyme in phytosterol synthesis? Lipids, 1986, 21(1):82-88. pmid: 3959769

[15]	Istvan E S, Palnitkar M, Buchanan S K, et al. Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. The EMBO Journal, 2000, 19(5):819-830. doi: 10.1093/emboj/19.5.819

[16]	Peng B Y, Plan M R, Chrysanthopoulos P, et al. A squalene synthase protein degradation method for improved sesquiterpene production in Saccharomyces cerevisiae. Metabolic Engineering, 2017, 39:209-219. doi: 10.1016/j.ymben.2016.12.003

[17]	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

[18]	Ignea C, Cvetkovic I, Loupassaki S, et al. Improving yeast strains using recyclable integration cassettes, for the production of plant terpenoids. Microbial Cell Factories, 2011, 10(1):1-18. doi: 10.1186/1475-2859-10-1

[19]	Meadows A L, Hawkins K M, Tsegaye Y, et al. Rewriting yeast central carbon metabolism for industrial isoprenoid production. Nature, 2016, 537(7622):694-697. doi: 10.1038/nature19769 pmid: 27654918

[20]	Estévez J M, Cantero A, Reindl A, et al. 1-deoxy-d-xylulose-5-phosphate synthase, a limiting enzyme for plastidic isoprenoid biosynthesis in plants. Journal of Biological Chemistry, 2001, 276(25):22901-22909. doi: 10.1074/jbc.M100854200

[21]	Diao J J, Song X Y, Zhang L, et al. Tailoring cyanobacteria as a new platform for highly efficient synthesis of astaxanthin. Metabolic Engineering, 2020, 61:275-287. doi: 10.1016/j.ymben.2020.07.003

[22]	Banerjee A, Wu Y, Banerjee R, et al. Feedback inhibition of deoxy-d-xylulose-5-phosphate synthase regulates the methylerythritol 4-phosphate pathway. Journal of Biological Chemistry, 2013, 288(23):16926-16936. doi: 10.1074/jbc.M113.464636

[23]	Banerjee A, Preiser A L, Sharkey T D. Engineering of recombinant poplar deoxy-D-xylulose-5-phosphate synthase (PtDXS) by site-directed mutagenesis improves its activity. PLoS One, 2016, 11(8):e0161534. doi: 10.1371/journal.pone.0161534

[24]	Chen C C, Zhang L L, Yu X J, et al. Versatile Cis-isoprenyl diphosphate synthase superfamily members in catalyzing carbon-carbon bond formation. ACS Catalysis, 2020, 10(8):4717-4725. doi: 10.1021/acscatal.0c00283

[25]	Kim S, Kim E J, Park J B, et al. Crystal structure of geranylgeranyl pyrophosphate synthase (crtE) from Nonlabens dokdonensis DSW-6. Biochemical and Biophysical Research Communications, 2019, 518(3):479-485. doi: 10.1016/j.bbrc.2019.08.071

[26]	Li M, Xu S, Lu W. Engineering Corynebacterium glutamicum for geraniol production. Transactions of Tianjin University, 2020, 27(4):1-8. doi: 10.1007/s12209-020-00274-4

[27]	Cao Y J, Zhang R B, Liu W, et al. Manipulation of the precursor supply for high-level production of longifolene by metabolically engineered Escherichia coli. Scientific Reports, 2019, 9(1):95. doi: 10.1038/s41598-018-36495-w

[28]	Ruiz-Sola M Á, Coman D, Beck G, et al. Arabidopsis geranylgeranyl diphosphate synthase 11 is a hub isozyme required for the production of most photosynthesis-related isoprenoids. New Phytologist, 2016, 209(1):252-264. doi: 10.1111/nph.2016.209.issue-1

[29]	Huang D Q, Liu W F, Li A G, et al. Discovery of geranylgeranyl pyrophosphate synthase (GGPPS) paralogs from Haematococcus pluvialis based on Iso-seq analysis and their function on astaxanthin biosynthesis. Marine Drugs, 2019, 17(12):E696.

[30]	Xie W P, Lv X, Ye L D, et al. Construction of lycopene-overproducing Saccharomyces cerevisiae by combining directed evolution and metabolic engineering. Metabolic Engineering, 2015, 30:69-78. doi: 10.1016/j.ymben.2015.04.009

[31]	Dong H, Chen S, Zhu J X, et al. Enhance production of diterpenoids in yeast by overexpression of the fused enzyme of ERG20 and its mutant mERG20. Journal of Biotechnology, 2020, 307:29-34. doi: S0168-1656(19)30907-1 pmid: 31689467

[32]	Tarshis L C, Proteau P J, Kellogg B A, et al. Regulation of product chain length by isoprenyl diphosphate synthases. Proceedings of the National Academy of Sciences of the United States of America, 1996, 93(26):15018-15023.

[33]	Rudolf J D, Chang C Y. Terpene synthases in disguise: enzymology, structure, and opportunities of non-canonical terpene synthases. Natural Product Reports, 2020, 37(3):425-463. doi: 10.1039/C9NP00051H

[34]	Christianson D W. Structural and chemical biology of terpenoid cyclases. Chemical Reviews, 2017, 117(17):11570-11648. doi: 10.1021/acs.chemrev.7b00287 pmid: 28841019

[35]	Jiang G Z, Yao M D, Wang Y, et al. Manipulation of GES and ERG20 for geraniol overproduction in Saccharomyces cerevisiae. Metabolic Engineering, 2017, 41:57-66. doi: 10.1016/j.ymben.2017.03.005

[36]	Tashiro M, Kiyota H, Kawai-Noma S, et al. Bacterial production of pinene by a laboratory-evolved pinene-synthase. ACS Synthetic Biology, 2016, 5(9):1011-1020. doi: 10.1021/acssynbio.6b00140 pmid: 27247193

[37]	Muangphrom P, Misaki M, Suzuki M, et al. Identification and characterization of (+)-α-bisabolol and 7-epi-silphiperfol-5-ene synthases fromArtemisia abrotanum. Phytochemistry, 2019, 164:144-153. doi: S0031-9422(19)30313-9 pmid: 31151061

[38]	Liu J M, Ni M Y, Fan Y F, et al. Structure and properties of artimisinin. Acta Chimica Sinica, 1979, 37:129-41.

[39]	Abdallah I I, van Merkerk R, Klumpenaar E, et al. Catalysis of Amorpha-4, 11-diene synthase unraveled and improved by mutability landscape guided engineering. Scientific Reports, 2018, 8:9961. doi: 10.1038/s41598-018-28177-4 pmid: 29967474

[40]	Zhang W X, Guo J Q, Wang Z, et al. Improved production of germacrene A, a direct precursor of β-elemene, in engineered Saccharomyces cerevisiae by expressing a cyanobacterial germacrene A synthase. Microbial Cell Factories, 2021, 20(1):7. doi: 10.1186/s12934-020-01500-3

[41]	Abdallah I I, Pramastya H, van Merkerk R, et al. Metabolic engineering of Bacillus subtilis toward taxadiene biosynthesis as the first committed step for taxol production. Frontiers in Microbiology, 2019, 10:218. doi: 10.3389/fmicb.2019.00218 pmid: 30842758

[42]	Leonard E, Ajikumar P K, Thayer K, et al. Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(31):13654-13659.

[43]	Abe I. Enzymatic synthesis of cyclic triterpenes. Natural Product Reports, 2007, 24(6):1311-1331. doi: 10.1039/b616857b

[44]	Thimmappa R, Geisler K, Louveau T, et al. Triterpene biosynthesis in plants. Annual Review of Plant Biology, 2014, 65:225-257. doi: 10.1146/annurev-arplant-050312-120229 pmid: 24498976

[45]	Zhou J W, Hu T Y, Gao L H, et al. Friedelane-type triterpene cyclase in celastrol biosynthesis from Tripterygium wilfordii and its application for triterpenes biosynthesis in yeast. The New Phytologist, 2019, 223(2):722-735. doi: 10.1111/nph.2019.223.issue-2

[46]	Yu Y, Rasool A, Liu H R, et al. Engineering Saccharomyces cerevisiae for high yield production of α-amyrin via synergistic remodeling of α-amyrin synthase and expanding the storage pool. Metabolic Engineering, 2020, 62:72-83. doi: 10.1016/j.ymben.2020.08.010

[47]	Yu Y, Chang P C, Yu H, et al. Productive amyrin synthases for efficient α-amyrin synthesis in engineered Saccharomyces cerevisiae. ACS Synthetic Biology, 2018, 7(10):2391-2402. doi: 10.1021/acssynbio.8b00176

[48]	Mansouri M, Mohammadi F. Transcriptome analysis to identify key genes involved in terpenoid and rosmarinic acid biosynthesis in lemon balm (Melissa officinalis). Gene, 2021, 773:145417. doi: 10.1016/j.gene.2021.145417

[49]	Lauersen K J, Wichmann J, Baier T, et al. Phototrophic production of heterologous diterpenoids and a hydroxy-functionalized derivative from Chlamydomonas reinhardtii. Metabolic Engineering, 2018, 49:116-127. doi: S1096-7176(18)30206-4 pmid: 30017797

[50]	Yin J, Sun L, Li Y, et al. Functional identification of BpMYB21 and BpMYB61 transcription factors responding to MeJA and SA in birch triterpenoid synthesis. BMC Plant Biology, 2020, 20(1):374. doi: 10.1186/s12870-020-02521-1

[51]	Xie Z X, Li B Z, Mitchell L A, et al. “Perfect” designer chromosome V and behavior of a ring derivative. Science, 2017, 355(6329): eaaf4704.

[52]	Li C Y, Gao X P, Peng X, et al. Intelligent microbial cell factory with genetic pH shooting (GPS) for cell self-responsive base/acid regulation. Microbial Cell Factories, 2020, 19(1):202. doi: 10.1186/s12934-020-01457-3

[1]	MA Ning,WANG Han-jie. Advances of Optogenetics in the Regulation of Bacterial Production[J]. China Biotechnology, 2021, 41(9): 101-109.

[2]	ZHANG Heng,LIU Hui-yan,PAN Lin,WANG Hong-yan,LI Xiao-fang,WANG Tong,FANG Hai-tian. Research Strategy for Biosynthesis of Gamma Aminobutyric Acid[J]. China Biotechnology, 2021, 41(8): 110-119.

[3]	LI Bing,ZHANG Chuan-bo,SONG Kai,LU Wen-yu. Research Progress in Biosynthesis of Rare Ginsenosides[J]. China Biotechnology, 2021, 41(6): 71-88.

[4]	ZHAI Jun-ye,CHENG Xu,SUN Ze-min,LI Chun,LV Bo. Current Advances in Biosynthesis of Acteoside[J]. China Biotechnology, 2021, 41(5): 94-104.

[5]	LI Yuan-yuan,LI Yan,CAO Ying-xiu,SONG Hao. Research and Strategies of Flavins-mediated Extracellular Electron Transfer[J]. China Biotechnology, 2021, 41(10): 89-99.

[6]	WANG Guang-lu, WANG Meng-yuan, ZHOU Yi-fei, MA Ke, ZHANG Fan, YANG Xue-peng. Research Progress in Pyrrologuinoline Quinone Biosynthesis[J]. China Biotechnology, 2021, 41(1): 103-113.

[7]	GUO Er-peng, ZHANG Jian-zhi, SI Tong. Recent Advances in the High-throughput Engineering of Lanthipeptides[J]. China Biotechnology, 2021, 41(1): 30-41.

[8]	LIU Xiao-chen, FAN Dai-di, YANG Fan, WU Zhan-sheng. Advances in Microbial Production of Ginsenoside and Its Derivatives[J]. China Biotechnology, 2021, 41(1): 80-93.

[9]	DUAN Hai-rong,WEI Sai-jin,LI Xun-hang. *Advances in Rhamnolipid Biosynthesis by Pseudomonas aeruginosa* Research**[J]. China Biotechnology, 2020, 40(9): 43-51.

[10]	DENG Ting-shan,WU Guo-gan,SUN Yu,TANG Xue-ming. Advances in Biosynthesis of Phenyllactic Acid[J]. China Biotechnology, 2020, 40(9): 62-68.

[11]	YAN Wei-huan,HUANG Tong,HONG Jie-fang,MA Yuan-yuan. Recent Advances in Butanol Biosynthesis of Escherichia coli[J]. China Biotechnology, 2020, 40(9): 69-76.

[12]	XUE Yan-ting,WU Sheng-bo,XU Cheng-yang,YUAN Bo-xin,YANG Shu-juan,LIU Jia-heng,QIAO Jian-jun,ZHU Hong-ji. Research Progress on the Quorum Sensing in the Dynamic Metabolic Regulation[J]. China Biotechnology, 2020, 40(6): 74-83.

[13]	LI Bing-juan,LIU Jin-ding,LIAO Yi-fang,HAN Wen-ying,LIU Ke,HOU Chen-lu,ZHANG Lei. Advances in Protein Engineering of the Old Yellow Enzyme OYE Family[J]. China Biotechnology, 2020, 40(3): 163-169.

[14]	LI Zhi-gang,CHEN Bao-feng,ZHANG Zhong-hua,CHANG Jing-ling. The Physiological Mechanism for Enhanced Cyclic Adenosine Monophosphate Biosynthesis by Auxiliary Energy Substance[J]. China Biotechnology, 2020, 40(1-2): 102-108.

[15]	LIU Jin-cong,LIU Xue,YU Hong-jian,ZHAO Guang-rong. Recent Advances in Microbial Production of Phloretin and Its Glycosides[J]. China Biotechnology, 2020, 40(10): 76-84.

Viewed

Full text

Abstract

Cited

Shared

Discussed