Please wait a minute...

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  2022, Vol. 42 Issue (3): 99-109    DOI: 10.13523/j.cb.2109020
综述     
微生物以5-氨基乙酰丙酸为唯一前体物合成血红素的研究进展*
刘佳萌1,李雪莹1,刘业学1,王稳航2,李庆刚1,路福平1,李玉1,**()
1 工业发酵微生物教育部重点实验室 天津科技大学生物工程学院 天津 300457
2 天津科技大学食品科学与工程学院 天津 300457
Research Progress on Microbial Synthesis of Heme Using 5-Aminolevulinic Acid as the Sole Precursor
LIU Jia-meng1,LI Xue-ying1,LIU Ye-xue1,WANG Wen-hang2,LI Qing-gang1,LU Fu-ping1,LI Yu1,**()
1 Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
2 College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China
 全文: PDF(3629 KB)   HTML
摘要：

随着人造肉热潮的兴起,血红素作为其呈色物质也愈发引起研究者的兴趣。血红素是一种含Fe2+的卟啉类化合物,以5-氨基乙酰丙酸为唯一前体物,在生物体中分别通过粪卟啉依赖性、原卟啉依赖性和西罗血红素依赖性三个途径合成,被认为是一种理想的补铁剂和着色剂。与化学合成法和生物提取法相比,微生物合成法具有操作方便、环境友好等优点,因此是一种非常有前景的血红素生产方法。介绍血红素的合成途径,总结微生物以5-氨基乙酰丙酸为唯一前体物合成血红素的最新进展,并简要分析其面临的挑战和前景。
关键词： 5-氨基乙酰丙酸;  血红素;  合成途径    
Abstract:

With the rise of the artificial meat craze, heme, which is the coloring substance of artificial meat, has increasingly attracted the interest of researchers. As a porphyrin compound containing iron, it takes 5-aminolevulinic acid as the only precursor, and is synthesized in organisms through three pathways, namely, coproporphyrin-dependent, protoporphyrin-dependent, and siroheme-dependent, which is considered to be an ideal iron supplement and colorant. Compared with chemical synthesis and biological extraction, microbial synthesis is the promising method to make mass product of heme due to its convenient operation, environmental-friendly and so on. This article introduces the synthetic pathway of heme in detail, and summarizes the latest progress in the production of heme using 5-aminolevulinic acid as the sole precursor by microorganisms. In addition, the challenges and prospects of synthetic microorganisms were briefly analyzed.
Key words: Microorganism    5-aminolevulinic acid    Heme    Synthetic pathway
收稿日期: 2021-09-08 出版日期: 2022-04-07
ZTFLH:  Q812  
基金资助: * 天津市合成生物技术创新能力提升行动专项(TSBICIP-KJGG-004);天津市研究生科研创新项目资助项目(2020YJSB128)
通讯作者: 李玉     E-mail: liyu@tust.edu.cn
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
刘佳萌
李雪莹
刘业学
王稳航
李庆刚
路福平
李玉

引用本文:

刘佳萌,李雪莹,刘业学,王稳航,李庆刚,路福平,李玉. 微生物以5-氨基乙酰丙酸为唯一前体物合成血红素的研究进展*[J]. 中国生物工程杂志, 2022, 42(3): 99-109.

LIU Jia-meng,LI Xue-ying,LIU Ye-xue,WANG Wen-hang,LI Qing-gang,LU Fu-ping,LI Yu. Research Progress on Microbial Synthesis of Heme Using 5-Aminolevulinic Acid as the Sole Precursor. China Biotechnology, 2022, 42(3): 99-109.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2109020    或    https://manu60.magtech.com.cn/biotech/CN/Y2022/V42/I3/99

图1  血红素的结构
图2  微生物血红素合成途径
图3  微生物中5-氨基乙酰丙酸的合成途径
Strains Key genes and sources Main substrates Pathway Titer/
(g·L-1)		 References
C. glutamicum hemA(R. palustris) Cassava bagasse
hydrolysate, glycine		 C4 18.50 [22]
E. coli hemA(R. capsulatus) Glucose C4 2.81 [23]
C. glutamicum hemA(R. capsulatus) Glucose, glycine C4 14.70 [24]
C. glutamicum hemA(R. sphaeroides) Glucose, glycine C4 3.40 [25]
C. glutamicum hemA(R. sphaeroides) Glucose, glycine C4 7.53 [31]
E. coli hemA(R. sphaeroides) Glycerol C4 6.93 [32]
E. coli hemA(R. palustris) Glucose, succinate, glycine C4 11.50 [34]
C. glutamicum hemA(S. arizona), hemL(E. coli) Glucose C5 3.16 [41]
E. coli hemA1 and pgr7(A. thaliana), hemL(E. coli) Glucose, Glutamate C5 7.64 [39]
E. coli hemA(S. typhimurium), hemL(E. coli) Glucose C5 3.40 [42]
E. coli hemA(S. arizona), hemL(E. coli) Glucose C5 4.05 [43]
C. glutamicum hemA(S.typhimurium), hemL(E. coli) Glucose C5 2.90 [46]
E. coli hemA(S. arizona), hemL(E. coli) Glucose C5 5.25 [47]
表1  近五年ALA的合成情况总结
图4  微生物中5-氨基乙酰丙酸到血红素的合成途径
Strains and optimization strategies Heme titer References
E. coli
Overpressed hemA,maeB and dctA 6.4 mg/L [48]
Overpressed coaA,hemA,maeB and dctA 0.49 μmol/g DCW [49]
Overpressed seven genes of hemA,hemB,hemC,hemD,hemE,hemF,hemY and hemH firstly (3.3 ± 0.3) μmol/L [51]
Overpressed hemAM,hemB,hemC,hemD,hemE,hemF,hemG and hemH modularly 0.954 μmol/(L·OD) [52]
Overpressed hemAM,hemB,hemC,hemD,hemE,hemF,hemG and hemH modularly,knocked out pta,ldhA and yfex,overpresseed ccmABC (115.5 ± 2.3) mg/L [60]
Overpressed hemA and coaA 9.1 μmol/g [61]
C. glutamicum
Overpressed hemAM,hemL and dtxR - [56]
Overpressed hemAM,hemL,hemY,hemH and hemQ (27.22 ± 0.65) mg/L [62]
表2  血红素合成途径优化小结
[1] Layer G. Heme biosynthesis in prokaryotes. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2021, 1868(1):118861.
doi: 10.1016/j.bbamcr.2020.118861
[2] 陈丹园. 大肠杆菌血红素合成途径关键酶基因的表达与调控. 无锡: 江南大学, 2018.
Chen D Y. Expression and regulation of genes coding for the key enzyme in heme synthstic pathway in E. coli. Wuxi: Jiangnan University, 2018.
[3] 汪学荣, 王飞. 生物态补铁剂-血红素铁的研究进展. 中国食品添加剂, 2007(3):82-87.
Wang X R, Wang F. Biology iron supplement-heme iron and its progress. China Food Additives, 2007(3):82-87.
[4] Skolmowska D, Głᶏbska D. Analysis of heme and non-heme iron intake and iron dietary sources in adolescent menstruating females in a national polish sample. Nutrients, 2019, 11(5):1049.
doi: 10.3390/nu11051049
[5] Hoppe M, Brün B, Larsson M P, et al. Heme iron-based dietary intervention for improvement of iron status in young women. Nutrition, 2013, 29(1):89-95.
doi: 10.1016/j.nut.2012.04.013
[6] 曹稳根, 李卫华. 亚硝基血红色素食品着色剂的研究. 信阳师范学院学报(自然科学版), 1996, 9(1):75-78.
Cao W G, Li W H. Study on the nitroso blood red pigmet colouring agent for food. Journal of Xinyang Teachers College (Natural Science Edition), 1996, 9(1):75-78.
[7] Jin Y, He X Y, Andoh-Kumi K, et al. Evaluating potential risks of food allergy and toxicity of soy leghemoglobin expressed in Pichia pastoris. Molecular Nutrition & Food Research, 2018, 62(1):1700297.
[8] Fraser R Z, Shitut M, Agrawal P, et al. Safety evaluation of soy leghemoglobin protein preparation derived from Pichia pastoris, intended for use as a flavor catalyst in plant-based meat. International Journal of Toxicology, 2018, 37(3):241-262.
doi: 10.1177/1091581818766318
[9] Zhao X R, Zhou J W, Du G C, et al. Recent advances in the microbial synthesis of hemoglobin. Trends in Biotechnology, 2021, 39(3):286-297.
doi: 10.1016/j.tibtech.2020.08.004
[10] Anderson K E, Collins S D. 192 Hemin treatment for acute porphyria: implications for clinical practice of an open-label study of 130 patients. Journal of Investigative Medicine, 2006, 54(1):S290.
[11] 卫乐红, 时亚文, 陈石良, 等. 血红素铁的制备及应用研究进展. 食品与药品, 2013, 15(5):357-360.
Wei L H, Shi Y W, Chen S L, et al. Progress on preparation and application of heme iron. Food and Drug, 2013, 15(5):357-360.
[12] 朱媛媛, 庄红, 张婷, 等. 血红素铁研究进展. 肉类研究, 2010, 24(5):18-23.
Zhu Y Y, Zhuang H, Zhang T, et al. Study process on heme iron. Meat Research, 2010, 24(5):18-23.
[13] Carlsson M L R, Kanagarajan S, Bülow L, et al. Plant based production of myoglobin - a novel source of the muscle heme-protein. Scientific Reports, 2020, 10(1):920.
doi: 10.1038/s41598-020-57565-y pmid: 31969582
[14] Zhou W J, Cen J W, Hu Q R, et al. Study on extractiing of heme from tilapias blood by enzymatic method. Advanced Materials Research, 2014,941- 944:2641-2645.
[15] Panek H, O’Brian M R. A whole genome view of prokaryotic haem biosynthesis. Microbiology (Reading, England), 2002, 148(Pt 8):2273-2282.
doi: 10.1099/00221287-148-8-2273
[16] Kang Z, Ding W W, Gong X, et al. Recent advances in production of 5-aminolevulinic acid using biological strategies. World Journal of Microbiology and Biotechnology, 2017, 33(11):200.
doi: 10.1007/s11274-017-2366-7
[17] Choi H P, Lee Y M, Yun C W, et al. Extracellular 5-aminolevulinic acid production by Escherichia coli containing the Rhodopseudomonas palustris KUGB306 hemA gene. Journal of Microbiology and Biotechnology, 2008, 18(6):1136-1140.
[18] Zhang L L, Chen J Z, Chen N, et al. Cloning of two 5-aminolevulinic acid synthase isozymes HemA and HemO from Rhodopseudomonas palustris with favorable characteristics for 5-aminolevulinic acid production. Biotechnology Letters, 2013, 35(5):763-768.
doi: 10.1007/s10529-013-1143-4 pmid: 23338702
[19] Lin J P, Fu W Q, Cen P L. Characterization of 5-aminolevulinate synthase from Agrobacterium radiobacter, screening new inhibitors for 5-aminolevulinate dehydratase from Escherichia coli and their potential use for high 5-aminolevulinate production. Bioresource Technology, 2009, 100(7):2293-2297.
doi: 10.1016/j.biortech.2008.11.008
[20] Lou J W, Zhu L, Wu M B, et al. High-level soluble expression of the hemA gene from Rhodobacter capsulatus and comparative study of its enzymatic properties. Journal of Zhejiang University-Science B, 2014, 15(5):491-499.
doi: 10.1631/jzus.B1300283
[21] Fu W Q, Lin J P, Cen P L. Enhancement of 5-aminolevulinate production with recombinant Escherichia coli using batch and fed-batch culture system. Bioresource Technology, 2008, 99(11):4864-4870.
doi: 10.1016/j.biortech.2007.09.039
[22] Chen J Z, Wang Y, Guo X, et al. Efficient bioproduction of 5-aminolevulinic acid, a promising biostimulant and nutrient, from renewable bioresources by engineered Corynebacterium glutamicum. Biotechnology for Biofuels, 2020, 13:41.
doi: 10.1186/s13068-020-01685-0
[23] Ding W W, Weng H J, Du G C, et al. 5-Aminolevulinic acid production from inexpensive glucose by engineering the C4 pathway in Escherichia coli. Journal of Industrial Microbiology & Biotechnology, 2017, 44(8):1127-1135.
[24] Yang P, Liu W J, Cheng X L, et al. A new strategy for production of 5-aminolevulinic acid in recombinant Corynebacterium glutamicum with high yield. Applied and Environmental Microbiology, 2016, 82(9):2709-2717.
doi: 10.1128/AEM.00224-16
[25] Zou Y L, Chen T, Feng L L, et al. Enhancement of 5-aminolevulinic acid production by metabolic engineering of the glycine biosynthesis pathway in Corynebacterium glutamicum. Biotechnology Letters, 2017, 39(9):1369-1374.
doi: 10.1007/s10529-017-2362-x
[26] Li T, Guo Y Y, Qiao G Q, et al. Microbial synthesis of 5-aminolevulinic acid and its coproduction with polyhydroxybutyrate. ACS Synthetic Biology, 2016, 5(11):1264-1274.
doi: 10.1021/acssynbio.6b00105
[27] Meng Q L, Zhang Y F, Ma C L, et al. Purification and functional characterization of thermostable 5-aminolevulinic acid synthases. Biotechnology Letters, 2015, 37(11):2247-2253.
doi: 10.1007/s10529-015-1903-4
[28] Meng Q L, Zhang Y F, Ju X Z, et al. Production of 5-aminolevulinic acid by cell free multi-enzyme catalysis. Journal of Biotechnology, 2016, 226:8-13.
doi: 10.1016/j.jbiotec.2016.03.024
[29] van der Werf M J, Zeikus J G. 5-Aminolevulinate production by Escherichia coli containing the Rhodobacter sphaeroides hemA gene. Applied and Environmental Microbiology, 1996, 62(10):3560-3566.
doi: 10.1128/aem.62.10.3560-3566.1996 pmid: 8837411
[30] Shin J A, Kwon Y D, Kwon O H, et al. 5-Aminolevulinic acid biosynthesis in Escherichia coli coexpressing NADP-dependent malic enzyme and 5-aminolevulinate synthase. Journal of Microbiology and Biotechnology, 2007, 17(9):1579-1584.
[31] Feng L L, Zhang Y, Fu J, et al. Metabolic engineering of Corynebacterium glutamicum for efficient production of 5-aminolevulinic acid. Biotechnology and Bioengineering, 2016, 113(6):1284-1293.
doi: 10.1002/bit.25886
[32] Miscevic D, Mao J Y, Kefale T, et al. Strain engineering for high-level 5-aminolevulinic acid production in Escherichia coli. Biotechnology and Bioengineering, 2021, 118(1):30-42.
doi: 10.1002/bit.v118.1
[33] Zhu C C, Chen J Z, Wang Y, et al. Enhancing 5-aminolevulinic acid tolerance and production by engineering the antioxidant defense system of Escherichia coli. Biotechnology and Bioengineering, 2019, 116(8):2018-2028.
doi: 10.1002/bit.v116.8
[34] Lanéelle M A, Tropis M, Daffé M. Current knowledge on mycolic acids in Corynebacterium glutamicum and their relevance for biotechnological processes. Applied Microbiology and Biotechnology, 2013, 97(23):9923-9930.
doi: 10.1007/s00253-013-5265-3
[35] 沈观宇. 外向转运蛋白对重组大肠杆菌5-氨基乙酰丙酸发酵的影响. 杭州: 浙江大学, 2018.
Shen G Y. Effect of exporters on 5-aminolevulinic acid fermentation by recombinant Escherichia coli. Hangzhou: Zhejiang University, 2018.
[36] Kang Z, Gao C J, Wang Q, et al. A novel strategy for succinate and polyhydroxybutyrate co-production in Escherichia coli. Bioresource Technology, 2010, 101(19):7675-7678.
doi: 10.1016/j.biortech.2010.04.084
[37] Layer G, Reichelt J, Jahn D, et al. Structure and function of enzymes in heme biosynthesis. Protein Science, 2010, 19(6):1137-1161.
doi: 10.1002/pro.405
[38] Kang Z, Wang Y, Gu P F, et al. Engineering Escherichia coli for efficient production of 5-aminolevulinic acid from glucose. Metabolic Engineering, 2011, 13(5):492-498.
doi: 10.1016/j.ymben.2011.05.003
[39] Zhao A G, Zhai M Z. Production of 5-aminolevulinic acid from glutamate by overexpressing HemA1 and pgr7 from Arabidopsis thaliana in Escherichia coli. World Journal of Microbiology and Biotechnology, 2019, 35(11):1-9.
doi: 10.1007/s11274-018-2566-9
[40] Zhang J L, Weng H J, Zhou Z X, et al. Engineering of multiple modular pathways for high-yield production of 5-aminolevulinic acid in Escherichia coli. Bioresource Technology, 2019, 274:353-360.
doi: 10.1016/j.biortech.2018.12.004
[41] Zhang C L, Li Y J, Zhu F Z, et al. Metabolic engineering of an auto-regulated Corynebacterium glutamicum chassis for biosynthesis of 5-aminolevulinic acid. Bioresource Technology, 2020, 318:124064.
doi: 10.1016/j.biortech.2020.124064
[42] Noh M H, Lim H G, Park S, et al. Precise flux redistribution to glyoxylate cycle for 5-aminolevulinic acid production in Escherichia coli. Metabolic Engineering, 2017, 43:1-8.
doi: 10.1016/j.ymben.2017.07.006
[43] Zhang J L, Kang Z, Ding W W, et al. Integrated optimization of the in vivo heme biosynthesis pathway and the in vitro iron concentration for 5-aminolevulinate production. Applied Biochemistry and Biotechnology, 2016, 178(6):1252-1262.
doi: 10.1007/s12010-015-1942-2
[44] Yu X L, Jin H Y, Liu W J, et al. Engineering Corynebacterium glutamicum to produce 5-aminolevulinic acid from glucose. Microbial Cell Factories, 2015, 14:183.
doi: 10.1186/s12934-015-0364-8
[45] Ramzi A B, Hyeon J E, Kim S W, et al. 5-Aminolevulinic acid production in engineered Corynebacterium glutamicum via C5 biosynthesis pathway. Enzyme and Microbial Technology, 2015, 81:1-7.
doi: 10.1016/j.enzmictec.2015.07.004
[46] Ko Y J, You S K, Kim M, et al. Enhanced production of 5-aminolevulinic acid via flux redistribution of TCA cycle toward l-glutamate in Corynebacterium glutamicum. Biotechnology and Bioprocess Engineering, 2019, 24(6):915-923.
doi: 10.1007/s12257-019-0376-z
[47] Zhang J, Wang Z G, Su T Y, et al. Tuning the binding affinity of heme-responsive biosensor for precise and dynamic pathway regulation. iScience, 2020, 23(5):101067.
doi: 10.1016/j.isci.2020.101067
[48] Kwon O H, Kim S, Hahm D H, et al. Potential application of the recombinant Escherichia coli-synthesized heme as a bioavailable iron source. Journal of Microbiology and Biotechnology, 2009, 19(6):604-609.
[49] Lee M J, Kim H J, Lee J Y, et al. Effect of gene amplifications in porphyrin pathway on heme biosynthesis in a recombinant Escherichia coli. Journal of Microbiology and Biotechnology, 2013, 23(5):668-673.
doi: 10.4014/jmb
[50] Dailey H A, Dailey T A, Gerdes S, et al. Prokaryotic heme biosynthesis: multiple pathways to a common essential product. Microbiology and Molecular Biology Reviews, 2017, 81(1):e00048-16.
[51] Kwon S J, de Boer A L, Petri R, et al. High-level production of porphyrins in metabolically engineered Escherichia coli: systematic extension of a pathway assembled from overexpressed genes involved in heme biosynthesis. Applied and Environmental Microbiology, 2003, 69(8):4875-4883.
doi: 10.1128/AEM.69.8.4875-4883.2003
[52] 翁焕娇, 丁雯雯, 石雅南, 等. 基于模块化优化策略强化大肠杆菌合成血红素. 食品与生物技术学报, 2019, 38(6):86-94.
Weng H J, Ding W W, Shi Y N, et al. Enhancement of heme synthesis pathway in Escherichia coli via a modular optimization strategy. Journal of Food Science and Biotechnology, 2019, 38(6):86-94.
[53] Troxell B, Hassan H M. Transcriptional regulation by ferric uptake regulator (Fur) in pathogenic bacteria. Frontiers in Cellular and Infection Microbiology, 2013, 3:59.
doi: 10.3389/fcimb.2013.00059 pmid: 24106689
[54] 李蒙蒙. 铁摄取调节子与亚铁鳌合酶基因表达对大肠杆菌血红素合成的调控. 无锡: 江南大学, 2019.
Li M M. Regulation of iron uptake regulator and ferrochelatase gene expression on heme synthesis of Escherichia coli. Wuxi: Jiangnan University, 2019.
[55] 于晓丽. 利用谷氨酸棒杆菌中血红素合成途径积累5-氨基乙酰丙酸的研究. 济南: 山东大学, 2016.
Yu X L. Accumulation of 5-aminolevulinic acid by Corynebaererium glutamicum using heme biosynthesis pathway. Jinan: Shandong University, 2016.
[56] Ko Y J, Joo Y C, Hyeon J E, et al. Biosynthesis of organic photosensitizer Zn-porphyrin by diphtheria toxin repressor (DtxR)-mediated global upregulation of engineered heme biosynthesis pathway in Corynebacterium glutamicum. Scientific Reports, 2018, 8(1):14460.
doi: 10.1038/s41598-018-32854-9
[57] Turlin E, Heuck G, Simões Brandão M I, et al. Protoporphyrin (PPIX) efflux by the MacAB-TolC pump in Escherichia coli. Microbiology Open, 2014, 3(6):849-859.
doi: 10.1002/mbo3.2014.3.issue-6
[58] 杨燕. rhtA与tolC的表达对大肠杆菌血红素合成的影响. 无锡: 江南大学, 2019.
Yang Y. Effect of expression of rhtA and tolC on heme synthesis in Escherichia coli. Wuxi: Jiangnan University, 2019.
[59] Feissner R E, Richard-Fogal C L, Frawley E R, et al. ABC transporter-mediated release of a haem chaperone allows cytochrome c biogenesis. Molecular Microbiology, 2006, 61(1):219-231.
pmid: 16824107
[60] Zhao X R, Choi K R, Lee S Y. Metabolic engineering of Escherichia coli for secretory production of free haem. Nature Catalysis, 2018, 1(9):720-728.
doi: 10.1038/s41929-018-0126-1
[61] Pranawidjaja S, Choi S I, Lay B W, et al. Analysis of heme biosynthetic pathways in a recombinant Escherichia coli. Journal of Microbiology and Biotechnology, 2015, 25(6):880-886.
pmid: 25537720
[62] Seok J, Ko Y J, Lee M E, et al. Systems metabolic engineering of Corynebacterium glutamicum for the bioproduction of biliverdin via protoporphyrin independent pathway. Journal of Biological Engineering, 2019, 13:28.
doi: 10.1186/s13036-019-0156-5
[63] Lee M J, Chun S J, Kim H J, et al. Porphyrin derivatives from a recombinant Escherichia coli grown on chemically defined medium. Journal of Microbiology and Biotechnology, 2012, 22(12):1653-1658.
doi: 10.4014/jmb
[64] 陈丹园, 沈云杰, 杨燕, 等. 关键酶基因的过表达与环境因素对大肠杆菌血红素合成的调控. 食品与发酵工业, 2018, 44(11):7-14.
Chen D Y, Shen Y J, Yang Y, et al. Regulation of heme synthesis in Escherichia coli by overexpression of genes for the key enzymes and environmental factors. Food and Fermentation Industries, 2018, 44(11):7-14.
[65] 赵鑫锐, 张国强, 李雪良, 等. 人造肉大规模生产的商品化技术. 食品与发酵工业, 2019, 45(11):248-253.
Zhao X R, Zhang G Q, Li X L, et al. Commercial production of artificial meat. Food and Fermentation Industries, 2019, 45(11):248-253.
[1] 王光路, 王梦园, 周忆菲, 马科, 张帆, 杨雪鹏. 吡咯喹啉醌生物合成研究进展 *[J]. 中国生物工程杂志, 2021, 41(1): 103-113.
[2] 宇光海, 彭海芬, 王翱宇. 阿维拉霉素生物合成研究进展 *[J]. 中国生物工程杂志, 2021, 41(1): 94-102.
[3] 饶海密,梁冬梅,李伟国,乔建军,财音青格乐. 真菌芳香聚酮化合物的合成生物学研究进展*[J]. 中国生物工程杂志, 2020, 40(9): 52-61.
[4] 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.
[5] 刘晓骅, 吉彩霞, 徐丽, 董超群, 罗进勇. Hmox1促进BMP9诱导C3H10T1/2细胞向成骨分化[J]. 中国生物工程杂志, 2017, 37(4): 33-39.
[6] 陈娟, 杨慧林, 黄运红, 龙中儿. 炭样小单孢菌中抗生素生物合成相关蛋白的筛选[J]. 中国生物工程杂志, 2016, 36(7): 55-63.
[7] 冯亚斌, 庄欣晨, 沈晓霞, 江建铭, 王忠华. 药用植物甾体生物碱的药理作用及合成途径[J]. 中国生物工程杂志, 2016, 36(1): 101-107.
[8] 王永成, 陈涛, 石婷, 王智文, 赵学明. 嘌呤核苷及其衍生物的代谢工程[J]. 中国生物工程杂志, 2015, 35(5): 87-95.
[9] 王翠翠, 许蕙金兰, 傅达奇. 茄属生物碱的研究进展[J]. 中国生物工程杂志, 2015, 35(2): 99-104.
[10] 蒋延超, 蒋世云, 傅凤鸣, 黄凯, 康星欣, 徐丹. 透明质酸生物合成途径及基因工程研究进展[J]. 中国生物工程杂志, 2015, 35(1): 104-110.
[11] 高燕会, 黄春红, 朱玉球, 童再康. 植物花青素苷生物合成及调控的研究进展[J]. 中国生物工程杂志, 2012, 32(08): 94-99.
[12] 陆庆宇,王其海,张占钰,袁道鹏,高伟,仓怀兴,毕汝昌. 福氏痢疾杆菌组氨酸合成中双功能焦磷酸水解酶和磷酸核糖环化水解酶双功能蛋白的初步研究[J]. 中国生物工程杂志, 2009, 29(04): 56-60.
[13] 杨鹤,郜玉钢,李璠瑛,张连学. 人参皂苷等萜类化合物生物合成途径及HMGR的研究进展[J]. 中国生物工程杂志, 2008, 28(10): 130-135.
[14] 蒋世云,余龙江. 微生物CoQ合成途径及CoQ10生产菌株的分子生物学改造[J]. 中国生物工程杂志, 2007, 27(10): 103-112.
[15] 李晔,袁其朋. 产番茄红素基因工程菌的研究进展[J]. 中国生物工程杂志, 2006, 26(11): 81-86.
主管：中国科学院 　主办：中国科学院文献情报中心 　中国生物技术发展中心 　中国生物工程学会