5-氨基乙酰丙酸生物合成技术的发展及展望

陈久洲; 王钰; 蒲伟; 郑平; 孙际宾

doi:10.12211/2096-8280.2021-010

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5-氨基乙酰丙酸生物合成技术的发展及展望

特约评述 | 更新时间：2025-03-20

- 5-氨基乙酰丙酸生物合成技术的发展及展望
- Advances and perspective on bioproduction of 5-aminolevulinic acid
- 合成生物学 2021年2卷第6期页码：1000-1016
- 作者机构：
  
  中国科学院天津工业生物技术研究所，中国科学院系统微生物工程重点实验室，天津 300308
- 作者简介：
  
  [ "陈久洲（1986—），男，硕士，高级工程师。研究方向为代谢工程、合成生物学。E-mail：chen_jz@tib.cas.cn" ]
  [ "郑平（1972—），女，博士，研究员，博士生导师。研究方向为代谢工程、系统生物学、合成生物学。E-mail：zheng_p@tib.cas.cn" ]
- 基金信息：
  
  国家重点研发计划(2018YFA0901400);国家自然科学基金(32000023)
- DOI：10.12211/2096-8280.2021-010
  中图分类号： Q81
- 收稿：2021-01-24，
  
  修回：2021-03-30，
  
  纸质出版：2021-12-31
- 稿件说明：
移动端阅览
陈久洲，王钰，蒲伟，郑平，孙际宾. 5-氨基乙酰丙酸生物合成技术的发展及展望［J］. 合成生物学， 2021， 2（6）： 1000-1016

CHEN Jiuzhou， WANG Yu， PU Wei， ZHENG Ping， SUN Jibin. Advances and perspective on bioproduction of 5-aminolevulinic acid［J］. Synthetic Biology Journal， 2021， 2（6）： 1000-1016
陈久洲，王钰，蒲伟，郑平，孙际宾. 5-氨基乙酰丙酸生物合成技术的发展及展望［J］. 合成生物学， 2021， 2（6）： 1000-1016 DOI： 10.12211/2096-8280.2021-010.

CHEN Jiuzhou， WANG Yu， PU Wei， ZHENG Ping， SUN Jibin. Advances and perspective on bioproduction of 5-aminolevulinic acid［J］. Synthetic Biology Journal， 2021， 2（6）： 1000-1016 DOI： 10.12211/2096-8280.2021-010.

摘要

5-氨基乙酰丙酸（5-ALA）是生物体内天然存在的一种功能性非蛋白质氨基酸，在医药保健和农牧领域具有重要的应用价值。尽管化学合成技术率先打通了5-ALA的制备路线，但工艺的复杂性和高成本问题，限制了其生产规模和应用推广。随着生物技术的兴起，生物合成作为一种绿色替代技术成为解决上述问题的突破口。本文回顾了近50年来5-ALA生物合成技术的发展历程，综述了5-ALA生物合成的3种主要策略，即天然菌株诱变筛选、利用重组外源C

途径的工程菌株催化合成以及基于代谢工程的高效细胞工厂构建，总结了每种策略的技术特点和主要问题，重点介绍了代谢工程改造策略和合成生物技术在5-ALA微生物细胞工厂开发中的应用和研究进展。在此基础上，本文进一步分析了限制5-ALA生物合成的瓶颈，阐述了血红素合成代谢的复杂调控作用和多底物的协同供给在5-ALA生物合成中的重要作用，并从新靶点、新底盘和新技术策略的角度，对合成生物学时代5-ALA生物合成技术未来的发展进行了展望。

Abstract

As a functional non-proteinogenic amino acid

5-aminolevulinic acid (5-ALA) is naturally synthesized by microbes

plants

and animals. It is a precursor for biosynthesis of tetrapyrrole compounds

such as heme

porphyrin

chlorophyll

and vitamin B

. Because of the critical roles of tetrapyrrole compounds in cellular metabolism

5-ALA has gained increasing attention in the fields of medicine

health care

agriculture

and animal husbandry. Methods for chemical synthesis of 5-ALA have been established for decades and are the primary routes for industrial production of 5-ALA. However

the high complexity and relatively low yield of the synthesis process lead to the high price of 5-ALA

which seriously limits the production scale and its widespread applications

especially in the fields of agriculture and animal feed. As an alternative technology

bioproduction of 5-ALA from renewable resources holds great promise to simplify the production process and lower the production cost

and thus has received increasing attentions worldwide. Although some algae and photosynthetic bacteria are capable of synthesizing 5-ALA naturally

the production levels cannot meet the requirement of industrialization and comm

ercialization. Moreover

these microorganisms are usually difficult to engineer due to lack of advanced genome editing tools. With the development of systems biology and synthetic biology approaches

intensive studies have focused on engineering platform microorganisms such as

Escherichia coli

and

Corynebacterium glutamicum

for 5-ALA bioproduction. Despite many successes in engineering synthetic 5-ALA producing strains

challenges remain in improving the production indices (titer

yield

and productivity) to levels as high as those for some proteinogenic amino acids

such as lysine and glutamate. In this paper

we review the development history of 5-ALA bioproduction technologies in the last half century and summarize the three key strategies for strain development and improvement

including mutagenesis and screening of natural strains

production by

Escherichia coli

expressing heterogenous 5-aminolevulinic acid synthases

and microbial cell factories constructed by metabolic engineering strategies. Recent advances on engineering synthetic 5-ALA producers using metabolic engineering and synthetic biotechnology are focused in this review. Furthermore

the bottlenecks of 5-ALA biosynthesis

such as the complex regulation of heme biosynthesis and the combined supply of multiple substrates

are also discussed in this review. Finally

the future development of 5-ALA biosynthesis technology in the era of synthetic biology is prospected from the perspectives of new gene targets

more suitable platform microorganisms and novel technical strategies.

关键词

Keywords

references

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