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Table 1 Metabolic engineering for overproduction of RF by gene manipulation

From: Production of riboflavin and related cofactors by biotechnological processes

Organism

GOIa and Manipulationb

Riboflavin titersc

Improvement

References

Overexpression of the RF synthesis pathway

 B. subtilis

ribA +

c−1

25%

[40]

 B. subtilis

rib operon +

0.4–0.7

Tenfold

[52]

 B. subtilis

rib operon +

4.3

27%

[87]

 A. gossypii

RIB genes +

0.327

3.1-fold

[53]

 E. coli

ribABDEC +

0.229

–

[54]

 C. ammoniagenes

rib genes +

15.3

16-fold

[88]

 C. famata

RIB1 +, RIB7 +

16.4

62-fold

[30]

 E. ashbyi

RIB1 +, RIB3 +

0.331

1.44-fold

[89]

 L. lactis

ribGBAH

0.024

–

[90]

Overexpression of the purine biosynthesis pathway

 B. subtilis

purF +

~ 5.1

31%

[91]

 B. subtilis

ΔpurR, purF*

0.827

Threefold

[92]

 A. gossypii

prs + , AGR371C +, AGL080C +

0.05

80%

[93]

 A. gossypii

AER117W+

~ 0.12c−2

40%

[94]

 A. gossypii

ADE4 + , SHM+

24.28 mg/gc−3

12-fold

[95]

 A. gossypii

AgADE4*+

0.228

Tenfold

[96]

 A. gossypii

ΔAgURA3

7.5 mg/gc−4

6.5

[97]

 E. coli

(ndk, gmk, purA, purF and prs) +

0.388

72%

[98]

 L. fermentum

ΔfolE

3.49 mg/L

50%

[99]

Optimization of the central carbon metabolism

 B. subtilis

zwf+

~ 0.8

25%

[100]

 B. subtilis

zwf + , gnd+

15.7

39%

[101]

 B. subtilis

fbp + , pckA + , gapB+

13.36

27.8%

[102]

 B. subtilis

ΔccpN

~ 13

~ 28%

[103]

 E. coli

Δpgi, Δedd, Δeda

0.56

–

[54]

Enhanced synthesis of glycine

 A. gossypii

GLY1+

~ 16 mg/gc−4

Ninefold

[104]

 A. gossypii

ΔSHM2

9.6 mg/gc−4

Tenfold

[105]

 A. gossypii

AGX1+

~ 0.15

30%

[106]

Other strategies

 B. subtilis

ΔcydC

12.3

38%

[107]

 B. subtilis

HSPs+

~ 0.3–0.35

23–66%

[108]

  1. aGOI represents the gene of interest. ribA, DHPB synthase; RIB1, GTP cyclohydrolase II; RIB7, RF synthase; RIB3, DHPB synthase; purF, PRPP amidotransferase; purR, purine repressor PurR; AGR371C and AGL080C, PRPP synthetases; prs, PRPP synthetase; purF, PRPP amidotransferase; AER117W, IMP dehydrogenase; ADE4, PRPP amidotransferase; SHM1 and SHM2, serine hydroxymethyltransferase; AgURA3, orotidine-5′-phosphate decarboxylase; zwf, glucose-6-phosphate dehydrogenase; gnd, 6-phosphogluconate dehydrogenase; fbp, fructose-1,6-bisphosphatase; pckA, phosphoenolpyruvate carboxykinase; gapB, glyceraldehyde-3-phosphate dehydrogenase; ccpN, gluconeogenic repressor CcpN; pgi, glucose-6-phosphate isomerase; edd, phosphogluconate dehydratase; eda, multifunctional 2-keto-3-deoxygluconate 6-phosphate aldolase and 2-keto-4-hydroxyglutarate aldolase and oxaloacetate decarboxylase; GLY1, threonine aldolase; SHM2, serine hydroxymethyltransferase; AGX1, alanine-glyoxylate aminotransferase; cydC, cytochrome bd oxidase; HSPs, heat shock proteins; folE, GTP cyclohydrolase I
  2. b“+”indicates gene over-expression; “−” indicates gene downregulation; “Δ” indicates gene knockout; “*” indicates gene mutation
  3. cThe maximum RF titer of the engineered strains. Unit: g/L unless otherwise specified; c−1, Strain VB2XL1 produced up to 25% more RF as compared to its parent strain RB50::[pRF69]n::[pRF93]m Ade; c−2, total (intracellular +extracellular) RF concentration; c−3, mg/g of biomass; c−4, mg/g mycelium
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Microbial Cell Factories

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