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中国生物工程杂志

China Biotechnology
China Biotechnology
China Biotechnology  2022, Vol. 42 Issue (3): 99-109    DOI: 10.13523/j.cb.2109020
    
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
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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     
Received: 08 September 2021      Published: 07 April 2022
ZTFLH:  Q812  
Corresponding Authors: Yu LI     E-mail: liyu@tust.edu.cn
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Cite this article:

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.

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

Fig.1 The structure of heme
Fig.2 The heme pathway of microorganism
Fig.3 Synthetic pathway of 5-aminolevulinic acid in microorganisms Red arrow: C4 pathway synthesizes 5-aminolevulinic acid; blue arrow: C5 pathway synthesizes 5-aminolevulinic acid;red font: overexpressed gene; green font:knocked out gene
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]
Table 1 Summary of the synthesis of ALA in the past five years
Fig.4 Synthetic pathway of 5-aminolevulinic acid to heme in microorganisms Blue arrow: PPD pathway synthesizes heme, presenting in eukaryotes and gram-negative bacteria;green arrow: CPD pathway synthesizes heme, presenting in eukaryotes and gram-positive bacteria;orange arrow: SHD pathway synthesizes heme, presenting in archaea and sulfate-reducing bacteria;red font: overexpressed gene; green font: knocked-out gene
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]
Table 2 Summary of optimization of heme synthesis pathway
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