A case study in flux balance analysis: Lysine, a cephamycin C precursor, can also increase clavulanic acid production

Cavallieri, André Pastrelo; Baptista, Amanda Salvador; Leite, Carla Andréa; Araujo, Maria Lucia Gonsales da Costa

doi:10.1016/j.bej.2016.03.012

Cited by 7 publications

(7 citation statements)

References 39 publications

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“…Defined media was used to study the influence of nutrients on carbon flux distribution during CA biosynthesis [ 10 , 27 ]. Previous studies also have suggested that amino acid supplementation could affect the specialized metabolite accumulation in S. clavuligerus given their connections with amino acid biosynthesis and degradation pathways [ 27 , 28 ]. In this case a defined medium was used for fed-batch cultivations of S. clavuligerus in a stirred tank and single-use 2-D rocking-motion bioreactors.…”

Section: Introductionmentioning

confidence: 99%

A Genome-Scale Insight into the Effect of Shear Stress During the Fed-Batch Production of Clavulanic Acid by Streptomyces Clavuligerus

et al. 2020

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Streptomyces clavuligerus is a filamentous Gram-positive bacterial producer of the β-lactamase inhibitor clavulanic acid. Antibiotics biosynthesis in the Streptomyces genus is usually triggered by nutritional and environmental perturbations. In this work, a new genome scale metabolic network of Streptomyces clavuligerus was reconstructed and used to study the experimentally observed effect of oxygen and phosphate concentrations on clavulanic acid biosynthesis under high and low shear stress. A flux balance analysis based on experimental evidence revealed that clavulanic acid biosynthetic reaction fluxes are favored in conditions of phosphate limitation, and this is correlated with enhanced activity of central and amino acid metabolism, as well as with enhanced oxygen uptake. In silico and experimental results show a possible slowing down of tricarboxylic acid (TCA) due to reduced oxygen availability in low shear stress conditions. In contrast, high shear stress conditions are connected with high intracellular oxygen availability favoring TCA activity, precursors availability and clavulanic acid (CA) production.

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Section: Introductionmentioning

confidence: 99%

A Genome-Scale Insight into the Effect of Shear Stress During the Fed-Batch Production of Clavulanic Acid by Streptomyces Clavuligerus

et al. 2020

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“…In addition, multicopy expression of ccaR under glpFp resulted in significantly improved industrial high-titer CA producer S. clavuligerus strains [39]. Thus, the increased expression of biosynthetic genes in S. clavuligerus pCOlysA might be Cavallieri et al [19] showed by flux balance analysis that lysine and maltose addition to chemically defined media increased both CephC and CA productions in S. clavuligerus. It was also shown that the addition of glycerol or other vegetable oils promotes CA production [40,41].…”

Section: Discussionmentioning

confidence: 99%

“…In S. clavuligerus, CephC and CA are synthesized simultaneously through different metabolic pathways [18]. Several reports indicated the positive impact of inducers and precursors as well as carbon or nitrogen sources in the fermentation media for the production of either compound, CephC or CA [19]. For instance, the culture supplemented with soluble starch as carbon source or cottonseed extract as complex nitrogen source enhanced CephC production while the glycerol feeding did not cause an increase in maximum CephC production [20].…”

Section: Introductionmentioning

confidence: 99%

Homologous expression of lysA encoding diaminopimelic acid (DAP) decarboxylase reveals increased antibiotic production in Streptomyces clavuligerus

Otur

Kurt‐Kızıldoğan

2019

Braz J Microbiol

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lysA gene encoding meso-diaminopimelic acid (DAP) decarboxylase enzyme that catalyzes L-lysine biosynthesis in the aspartate pathway in Streptomyces clavuligerus was overexpressed, and its effects on cephamycin C (CephC), clavulanic acid (CA), and tunicamycin productions were investigated. Multicopy expression of lysA gene under the control of glpF promoter (glpFp) in S. clavuligerus pCOlysA led to higher expression levels ranging from 2-to 6-fold increase at both lysA gene and CephC biosynthetic gene cluster at T 36 and T 48 of TSBG fermentation. These results accorded well with CephC production. Thus, 1.86-and 3.14-fold higher volumetric as well as 1.26-and 1.71-fold increased specific CephC yields were recorded in S. clavuligerus pCOlysA in comparison with the wild-type and its control strain, respectively, at 48th h. Increasing the expression of lysA provided 4.3 times more tunicamycin yields in the recombinant strain. These findings suggested that lysA overexpression in S. clavuligerus made the strain more productive for CephC and tunicamycin. The results also supported the presence of complex interactions among antibiotic biosynthesis pathways in S. clavuligerus.

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“…Glycerol is the main substrate in the CA production by S. clavuligerus as it has direct incorporation into the glycolytic pathway by forming glyceraldehyde 3-phosphate, the first C-3 precursor of CA [ 42 , 43 ]. Then, the carbon flux splits into three pathways, two of them belonging to the primary metabolism: glycolysis and gluconeogenesis, and one belonging to the secondary metabolism: the clavam pathway [ 43 , 44 , 45 ]. In addition to glyceraldehyde 3-phosphate, the need for a C-5 precursor implies the constant demand for L-arginine.…”

Section: Overview Of Ca Biosynthesis In S Clavuligerus mentioning

confidence: 99%

Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

2021

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Clavulanic acid (CA) is an irreversible β-lactamase enzyme inhibitor with a weak antibacterial activity produced by Streptomyces clavuligerus (S. clavuligerus). CA is typically co-formulated with broad-spectrum β‑lactam antibiotics such as amoxicillin, conferring them high potential to treat diseases caused by bacteria that possess β‑lactam resistance. The clinical importance of CA and the complexity of the production process motivate improvements from an interdisciplinary standpoint by integrating metabolic engineering strategies and knowledge on metabolic and regulatory events through systems biology and multi-omics approaches. In the large-scale bioprocessing, optimization of culture conditions, bioreactor design, agitation regime, as well as advances in CA separation and purification are required to improve the cost structure associated to CA production. This review presents the recent insights in CA production by S. clavuligerus, emphasizing on systems biology approaches, strain engineering, and downstream processing.

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A case study in flux balance analysis: Lysine, a cephamycin C precursor, can also increase clavulanic acid production

Cited by 7 publications

References 39 publications

A Genome-Scale Insight into the Effect of Shear Stress During the Fed-Batch Production of Clavulanic Acid by Streptomyces Clavuligerus

A Genome-Scale Insight into the Effect of Shear Stress During the Fed-Batch Production of Clavulanic Acid by Streptomyces Clavuligerus

Homologous expression of lysA encoding diaminopimelic acid (DAP) decarboxylase reveals increased antibiotic production in Streptomyces clavuligerus

Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

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