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Table 2 The systems metabolic engineering strategies on phenylalanine pathway for the microbial production of aromatic compounds

From: Metabolic engineering of microorganisms for production of aromatic compounds

Product

Precursor

Carbon source

Host

Titer

Time (h)

Bioprocess strategy

Systems metabolic engineering strategies

References

Phenylpyruvate derivatives

 d-PHG

S-MA

Glucose

E. coli

0.036 g/L

24

Batch (shake-flask)

Integrating genes encoding feedback resistant DAHP and bifunctional chorismate mutase/prephenete dehydratase; Deleting three genes in competing pathway using PPA and CHA; Construction 3-step artificial pathway from CHA to d-PHG

[84]

 l-PHG

S-MA

Glucose

E. coli

–

48

Batch (shake-flask)

Screening better HpgT activity from different sources; Deleting genes in competing pathway using PPA; Construction 3-step artificial pathway from CHA to l-PHG

[86]

 S-MA

PPA

Glucose

E. coli

0.74 g/L

24

Batch (shake-flask)

Integrating genes encoding feedback resistant DAHP and bifunctional chorismate mutase/prephenete dehydratase; Their overexpression with S-MA; Deleting genes responsible for synthesis of l-TRP, l-TYR and l-PHE in competing pathways using CHA; Construction 3-step artificial pathway from CHA to R-MA

[87]

 R-MA

S-MA

1.02 g/L

84

 S-MA

PPA

Glucose

S. cerevisiae

0.236 g/L

120

Batch (shake-flask)

Screening better HmaS activity from different microorganisms; Overexpressing genes (encoding pentafunctional protein and feedback two isozyme of resistant DAHP synthase); Deleting genes phenylpyruvate decarboxylase to reduce flux towards Ehrlich pathway

[88]

 d-PHE

PPA

Glucose

E. coli

1.72 g/L

60

Fed-batch (fermenter, 15 L)

Screening and homology based modeling of d-aminoacid transferase (Dat) from three Bacillus species; Constructing artificial d-PHE synthetic operon including each Dat gene

[89]

 l-PhLA

PPA

Glucose

E. coli

1.9 g/L

24

Batch (shake-flask)

Integration feedback-resistant allel of gene involved in SHK and l-PHE amino acid pathway; Deleting genes in competing pathway using CHA. Introducing lactate dehydrogenase with heterologous phenylpyruvate reductase

[91]

 Poly-(3HB-co-d-PhLA)

PPA

Glucose

E. coli

13.9 g/L

96

Fed-batch (fermenter, 6.6 L)

Identifying and introducing the gene encoding CoA transferase; integrating gene of enzyme responsible conversion from glucose to d-PhLA. Modulating flux under different promoters

[92]

 Cinnamic acid

d-PhLA

Glucose

E. coli

1.7 g/L

30 (aerobic phase)

Batch coculture (shake-flask)

Integrating phenylpyruvate reductase-coding pprA from Wickerhamia fluorescens in d-PhLA producer strain; Integrating phenyllactate dehydratase-coding fldABCI from Clostridium sporogens in CA producer strain; Performing stepwise process; Optimizing cultivation time of aerobic phase followed by anaerobic one

[105]

Phenylalanine derivatives

 Pinosylvin

Cinnamoyl-CoA

Glucose + CA

C. glutamicum

0.121 g/L

72

Batch (shake-flask)

Deleting three gene cluster; Integrating 4CL and STS-coding genes from plant sources; Supplying cerulenin to inhibit activity of enzymes in fatty acid synthesis using malonyl-CoA

[116]

Cinnamoyl-CoA

Glucose

E. coli

0.281 g/L

48

Batch (shake-flask)

Constructing two expression modules; Optimizing expression levels by combining promoter type and copy number in these expression modules; Designing upstream pathway module to direct carbon flux towards precursor; Designing downstream pathway module to produce the molecule of interest

[117]

 Chrysin

Pinocembrin

Galactose + acetate

S. cerevisiae

0.001 g/L

92

Batch (shake-flask)

Introducing and overexpressing parsley FSI gene into biosynthetic pinocembrin pathway

[162]

Galactose + raffinose

0.002 g/L

92

Batch (shake-flask)

Introducing and overexpressing snapdragon gene (encoding flavone synthase II) and yeast gene (encoding P450 reductase) into biosynthetic pinocembrin pathway

 

Pinocembrin

Glucose + l-PHE

E. coli

0.0094 g/L

36

Batch (shake-flask)

Introducing FNS1 gene from Petroselinum crispum into biosynthetic pinocembrin metabolic pathway comprising PAL/TAL, 4CL, CHS, CHI and ACC (encoded by dtsR1 and accBC)

[164]

 Cinnamic acid

l-PHE

Glucose + casaminoacids

E. coli

6.9 g/L

86

Fed-batch (fermenter, 2 L)

Screening appropriate promoter to express Streptomyces maritimus PAL gene; Investigating the effect of different supplements in feeding solution on pH-stat fed-batch fermentation

[106]

Styrene

CA

Glucose

E. coli

0.26 g/L

29

Batch (shake-flask)

Introducing genes encoding plant phenylalanine ammonia lyase and yeast trans-cinnamate decarboxylase into l-PHE overproducer strain lacking multiple genes and expressing genes encoding feedback resistant enzymes in SHK pathway

[107]

 Pinocembrin

Cinnamyl-CoA

Glucose

E. coli

0.710 g/L

36

Batch (shake-flask)

Overexpressing malonate carrier- and malonate synthase-coding genes involved in the malonate assimilation pathway; Repressing activity of two genes in fatty acid pathway by the addition of cerulenin

[159]

 Galangin

Pinocembrin

Glucose + l-PHE

E. coli

0.001 g/L

36

Batch (shake-flask)

Introducing F3H and FLS gene from Citrus species into biosynthetic pinocembrin metabolic pathway comprising PAL/TAL, 4CL, CHS, CHI and ACC (encoded by dtsR1 and accBC)

[164]