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Bulletin of Chinese Academy of Sciences (Chinese Version)

Keywords

feed amino acid; bio-manufacturing; soybean meal reduction and substitution; strain; synthetic biology

Document Type

Biomanufacturing: Retrospect and Prospects

Abstract

With the promotion of soybean meal reduction and substitution as well as lower-protein diet technologies, China has become a leading global producer of feed amino acids. However, the amino acid industry faces significant challenges due to its relatively late start in independently developing industrial strains, resulting in relatively lagging key economic and technical parameters and a less robust intellectual property framework. The rapid progress of synthetic biology has provided promising avenues for the design and optimization of industrial amino acid-producing strains, offering new opportunities for the amino acid fermentation industry to enhance the global competitiveness. This study offers an in-depth analysis of the domestic and international market demand for feed amino acids, systematically reviews key technological breakthroughs in microbial amino acid production, and identifies the primary challenges confronting the domestic amino acid industry. Additionally, it further explores future development trends and challenges in microbial amino acid production, and proposes a series of targeted and comprehensive solutions to provide in-depth insights and guidance for the stable and accelerated growth of the microbial amino acid industry.

First page

25

Last Page

35

Language

Chinese

Publisher

Bulletin of Chinese Academy of Sciences

References

1 Wu L T, Zhang X X, Tang Z R, et al. Low-protein diets decrease porcine nitrogen excretion but with restrictive effects on amino acid utilization. Journal of Agricultural and Food Chemistry, 2018, 66(31): 8262-8271.

2 张丽明. 低蛋白日粮调整氨基酸平衡对肉鸡氮代谢及肠道氨基酸转运载体相关基因表达的影响. 长春: 吉林大学, 2017.

Zhang L M. Effects of Amino acid Balance in Low Protein Diets on Nitrogen Metabolism and Intestinal Amino Acid Transporter Related Genes Expression in Broilers. Changchun: Jilin University, 2017. (in Chinese)

3 Liao Y J, Ren M C, Liu B, et al. Dietary methionine requirement of juvenile blunt snout bream (Megalobrama amblycephala) at a constant dietary cystine level. Aquaculture Nutrition, 2014, 20(6): 741-752.

4 Mahouachi M, Rekik M, Lassoued N, et al. The effect of constant dietary energy supply during late gestation and early lactation on performances of prolific D’man ewes. Animal Research, 2004, 53(6): 515-525.

5 Heo J M, Kim J C, Hansen C F, et al. Feeding a diet with decreased protein content reduces indices of protein fermentation and the incidence of postweaning diarrhea in weaned pigs challenged with an enterotoxigenic strain of Escherichia coli. Journal of Animal Science, 2009, 87(9): 2833-2843.

6 Yue L Y, Qiao S Y. Effects of low-protein diets supplemented with crystalline amino acids on performance and intestinal development in piglets over the first 2 weeks after weaning. Livestock Science, 2008, 115(2-3): 144-152.

7 Chai M, Deng C, Chen Q, et al. Synthetic biology toolkits and metabolic engineering applied in Corynebacterium glutamicum for biomanufacturing. ACS Synthetic Biology, 2021, 10(12): 3237-3250.

8 Wang J Y, Doudna J A. CRISPR technology: A decade of genome editing is only the beginning. Science, 2023, 379: eadd8643.

9 Wang Y, Liu Y, Li J W, et al. Expanding targeting scope, editing window, and base transition capability of base editing in Corynebacterium glutamicum. Biotechnology and Bioengineering, 2019, 116(11): 3016-3029.

10 Huang C Y, Guo L W, Wang J G, et al. Efficient long fragment editing technique enables large-scale and scarless bacterial genome engineering. Applied Microbiology and Biotechnology, 2020, 104(18): 7943-7956.

11 O’Brien E J, Monk J M, Palsson B O. Using genome-scale models to predict biological capabilities. Cell, 2015, 161(5): 971-987.

12 Ye C, Xu N, Dong C, et al. IMGMD: A platform for the integration and standardisation of in silico Microbial Genome-Scale Metabolic Models. Scientific Reports, 2017, 7(1): 727.

13 叶超, 徐楠, 陈修来, 等. 应用代谢网络模型解析工业微生物胞内代谢. 生物工程学报, 2019, 35(10): 1901-1913.

Ye C, Xu N, Chen X L, et al. Application of metabolic network model to analyze intracellular metabolism of industrial microorganisms. Chinese Journal of Biotechnology, 2019, 35(10): 1901-1913. (in Chinese)

14 Chen X L, Zhang B, Tang L, et al. Expression and characterization of ArgR, an arginine regulatory protein in Corynebacterium crenatum. Biomedical and Environmental Sciences, 2014, 27(6): 436-443.

15 Li C Y, Zhang R H, Wang J, et al. Protein engineering for improving and diversifying natural product biosynthesis. Trends in Biotechnology, 2020, 38(7): 729-744.

16 Chen C, Li Y Y, Hu J Y, et al. Metabolic engineering of Corynebacterium glutamicum ATCC13869 for L-valine production. Metabolic Engineering, 2015, 29: 66-75.

17 Dong X Y, Zhao Y, Hu J Y, et al. Attenuating L-lysine production by deletion of ddh and lysE and their effect on L-threonine and L-isoleucine production in Corynebacterium glutamicum. Enzyme and Microbial Technology, 2016, 93: 70-78.

18 Dong X Y, Zhao Y, Zhao J X, et al. Characterization of aspartate kinase and homoserine dehydrogenase from Corynebacterium glutamicum IWJ001 and systematic investigation of L-isoleucine biosynthesis. Journal of Industrial Microbiology & Biotechnology, 2016, 43(6): 873-885.

19 Liu J H, Li H L, Xiong H, et al. Two-stage carbon distribution and cofactor generation for improving L-threonine production of Escherichia coli. Biotechnology and Bioengineering, 2019, 116(1): 110-120.

20 Zhou L B, Zeng A P. Exploring lysine riboswitch for metabolic flux control and improvement of L-Lysine synthesis in Corynebacterium glutamicum. ACS Synthetic Biology, 2015, 4(6): 729-734.

21 Mahr R, von Boeselager R F, Wiechert J, et al. Screening of an Escherichia coli promoter library for a phenylalanine biosensor. Applied Microbiology and Biotechnology, 2016, 100(15): 6739-6753.

22 Yang J N, Seo S W, Jang S, et al. Synthetic RNA devices to expedite the evolution of metabolite-producing microbes. Nature Communications, 2013, 4: 1413.

23 Ghosh A, Mustafiz A, Pareek A, et al. Glyoxalase III enhances salinity tolerance through reactive oxygen species scavenging and reduced glycation. Physiologia Plantarum, 2022, 174(3): e13693.

24 Subedi K P, Choi D, Kim I, et al. Hsp31 of Escherichia coli K-12 is glyoxalase Ⅲ. Molecular Microbiology, 2011, 81(4): 926-936.

25 Geng F, Chen Z, Zheng P, et al. Exploring the allosteric mechanism of dihydrodipicolinate synthase by reverse engineering of the allosteric inhibitor binding sites and its application for lysine production. Applied Microbiology and Biotechnology, 2013, 97(5): 1963-1971.

26 Xu J Z, Han M, Ren X D, et al. Modification of aspartokinase Ⅲ and dihydrodipicolinate synthetase increases the production of L-lysine in Escherichia coli. Biochemical Engineering Journal, 2016, 114: 79-86.

27 许雪晨, 王浩淼, 陈修来, 等. 代谢工程改造大肠杆菌底物利用途径促进L-赖氨酸生产. 生物工程学报, 2024, 40(8): 2513-2527.

Xu X C, Wang H M, Chen X L, et al. Metabolic engineering of the substrate utilization pathway in Escherichia coli increases L-lysine production. Chinese Journal of Biotechnology, 2024, 40(8): 2513-2527. (in Chinese)

28 Ye C, Luo Q L, Guo L, et al. Improving lysine production through construction of an Escherichia coli enzyme-constrained model. Biotechnology and Bioengineering, 2020, 117(11): 3533-3544.

29 Liu J, Ou Y, Xu J Z, et al. L-lysine production by systems metabolic engineering of an NADPH auto-regulated Corynebacterium glutamicum. Bioresource Technology, 2023, 387: 129701.

30 Willke T. Methionine production—A critical review. Applied Microbiology and Biotechnology, 2014, 98(24): 9893-9914.

31 Li Z C, Liu Q, Sun J H, et al. Multivariate modular metabolic engineering for enhanced L-methionine biosynthesis in Escherichia coli. Biotechnology for Biofuels and Bioproducts, 2023, 16(1): 101.

32 Chen Y Y, Huang L G, Yu T, et al. Balancing the AspC and AspA pathways of Escherichia coli by systematic metabolic engineering strategy for high-efficient L-homoserine production. ACS Synthetic Biology, 2024, 13(8): 2457-2469.

33 Zhu W Y, Niu K, Liu P, et al. Enhanced O-succinyl-l-homoserine production by recombinant Escherichia coli ΔIJBB*TrcmetL/pTrc-metAfbr-Trc-thrAfbr-yjeH via multilevel fermentation optimization. Journal of Applied Microbiology, 2021, 130(6): 1960-1971.

34 Tang X L, Li N, Liu Y L, et al. Engineering O-succinyl-L-homoserine mercaptotransferase for efficient L-methionine biosynthesis by fermentation-enzymatic coupling route. Advanced Synthesis & Catalysis, 2023, 365(7): 1048-1057.

35 Fang Y, Wang J L, Ma W J, et al. Rebalancing microbial carbon distribution for L-threonine maximization using a thermal switch system. Metabolic Engineering, 2020, 61: 33-46.

36 Lee S Y, Park J H. Integration of systems biology with bioprocess engineering: L-threonine production by systems metabolic engineering of Escherichia coli. Advances in Biochemical Engineering/Biotechnology. 2010, 120: 1-19.

37 赵磊. 大肠杆菌L-苏氨酸生产菌代谢工程改造优化. 无锡: 江南大学, 2020.

Zhao L. Metabolic Engineering Modification of an Escherichia coli L-threonine Production Strain. Wuxi: Jiangnan University, 2020. (in Chinese)

38 Zhao Z Q, You J J, Shi X P, et al. Engineering Escherichia coli for L-threonine hyperproduction based on multidimensional optimization strategies. Journal of Agricultural and Food Chemistry, 2024, 72(41): 22682-22691.

39 Liu J, Zhao X J, Cheng H J, et al. Comprehensive screening of industrially relevant components at genome scale using a high-quality gene overexpression collection of Corynebacterium glutamicum. Trends in Biotechnology, 2025, 43(1): 220-247.

40 Liu S, Wang B B, Xu J Z, et al. Engineering of shikimate pathway and terminal branch for efficient production of L-tryptophan in Escherichia coli. International Journal of Molecular Sciences, 2023, 24(14): 11866.

41 Li Z, Ding D Q, Wang H Y, et al. Engineering Escherichia coli to improve tryptophan production via genetic manipulation of precursor and cofactor pathways. Synthetic and Systems Biotechnology, 2020, 5(3): 200-205.

42 Tang M, Pan X W, Yang T J, et al. Multidimensional engineering of Escherichia coli for efficient synthesis of L-tryptophan. Bioresource Technology, 2023, 386: 129475.

43 Guo L, Ding S, Liu Y D, et al. Enhancing tryptophan production by balancing precursors in Escherichia coli. Biotechnology and Bioengineering, 2022, 119(3): 983-993.

44 Bartek T, Blombach B, Zönnchen Eet al. Importance of NADPH supply for improved L-valine formation in Corynebacterium glutamicum. Biotechnology Progress, 2010, 26(2): 361-371.

45 Blombach B, Schreiner M E, Bartek T, et al. Corynebacterium glutamicum tailored for high-yield L-valine production. Applied Microbiology and Biotechnology, 2008, 79(3): 471-479.

46 Hao Y N, Ma Q, Liu X Q, et al. High-yield production of L-valine in engineered Escherichia coli by a novel two-stage fermentation. Metabolic Engineering, 2020, 62: 198-206.

47 Hao Y N, Pan X W, Xing R F, et al. High-level production of L-valine in Escherichia coli using multi-modular engineering. Bioresource Technology, 2022, 359: 127461.

48 赵阔, 程金宇, 郭亮, 等. 谷氨酸棒杆菌代谢工程高效生产L-缬氨酸. 生物工程学报, 2023, 39(8): 3253-3272.

Zhao K, Cheng J Y, Guo L, et al. Highly efficient production of L-valine by multiplex metabolic engineering of Corynebacterium glutamicum. Chinese Journal of Biotechnology, 2023, 39(8): 3253-3272. (in Chinese)

49 Man Z W, Xu M J, Rao Z M, et al. Systems pathway engineering of Corynebacterium crenatum for improved L-arginine production. Scientific Reports, 2016, 6: 28629.

50 Wang H D, Xu J Z, Zhang W G. Reduction of acetate synthesis, enhanced arginine export, and supply of precursors, cofactors, and energy for improved synthesis of L-arginine by Escherichia coli. Applied Microbiology and Biotechnology, 2023, 107(11): 3593-3603.

51 Jiang S, Wang R R, Wang D H, et al. Metabolic reprogramming and biosensor-assisted mutagenesis screening for high-level production of L-arginine in Escherichia coli. Metabolic Engineering, 2023, 76: 146-157.

52 Park S H, Kim H U, Kim T Y, et al. Metabolic engineering of Corynebacterium glutamicum for L-arginine production. Nature Communications, 2014, 5: 4618.

53 Wendisch V F. Amino Acid Biosynthesis—Pathways, Regulation and Metabolic Engineering. Berlin, Heidelberg: Springer, 2007.

54 周文娟, 刘娇, 李庆刚, 等. 赖氨酸工业发展的机遇与挑战. 生物产业技术, 2019, (1): 84-90.

Zhou W J, Liu J, Li Q G, et al. Opportunities and challenges in the development of lysine industry. Biotechnology & Business, 2019, (1): 84-90. (in Chinese)

55 Ma J Y, Wen T Y, Chen J L, et al. L-lysine generation method by fermenting bacteria having modified aconitase gene and/or regulatory element: PCT, CN2014, 070228. 2014-08-14.

56 Bendt A K, Burkovski A, Schaffer S, et al. Towards a phosphoproteome map of Corynebacterium glutamicum. Proteomics, 2003, 3(8): 1637-1646.

57 Kalinowski J, Bathe B, Bartels D, et al. The complete Corynebacterium glutamicum ATCC 13032 genome sequence and its impact on the production of L-aspartate-derived amino acids and vitamins. Journal of Biotechnology, 2003, 104(1-3): 5-25.

58 Shi F, Li K, Li Y F. Comparative proteome analysis of global effect of POS5 and zwf-ppnK overexpression in L-isoleucine producing Corynebacterium glutamicum ssp. lactofermentum. Biotechnology Letters, 2015, 37(5): 1063-1071.

59 Gleizer S, Ben-Nissan R, Bar-On Y M, et al. Conversion of Escherichia coli to generate all biomass carbon from CO2. Cell, 2019, 179(6): 1255-1263.

60 Wenk S, Rainaldi V, Schann K, et al. Evolution-assisted engineering of E. coli enables growth on formic acid at ambient CO2 via the Serine Threonine Cycle. Metabolic Engineering, 2025, 88: 14-24.

61 Vo T M, Park J Y, Kim D, et al. Use of acetate as substrate for sustainable production of homoserine and threonine by Escherichia coli W3110: A modular metabolic engineering approach. Metabolic Engineering, 2024, 84: 13-22.

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62 Hu G P, Li Z H, Ma D L, et al. Light-driven CO2 sequestration in Escherichia coli to achieve theoretical yield of chemicals. Nature Catalysis, 2021, 4: 395-406.

63 Tröndle J, Trachtmann N, Sprenger G A, et al. Fed‐batch production of L-tryptophan from glycerol using recombinant Escherichia coli. Biotechnology and Bioengineering, 2018, 115(12): 2881-2892.

64 张周利. 玉米秸秆水解液发酵生产L-赖氨酸的研究. 郑州: 河南农业大学, 2021. Zhang Z L. A Study on the Fermentation of L-lysine Utilizing Corn Stover Hydrolysate. Zhengzhou: Henan Agricultural University, 2021. (in Chinese)

65 Li H, Chen J J, Li X Y, et al. Artificial neural network and genetic algorithm coupled fermentation kinetics to regulate L-lysine fermentation. Bioresource Technology, 2024, 393: 130151.

66 Khamwachirapithak P, Sae-Tang K, Mhuantong W, et al. Optimizing ethanol production in Saccharomyces cerevisiae at ambient and elevated temperatures through machine learning-guided combinatorial promoter modifications. ACS Synthetic Biology, 2023, 12(10): 2897-2908.

67 Li G L, Chen K Q, Wei Y P, et al. Mass transfer, gas holdup, and kinetic models of batch and continuous fermentation in a novel rectangular dynamic membrane airlift bioreactor. Engineering, 2022, 13: 153-163.

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