Control of Fluxes Towards Antibiotics and the Role of Primary Metabolism in Production of Antibiotics

Gunnarsson, Nina; Eliasson, Anna; Nielsen, Linda

doi:10.1007/b99260

Cited by 28 publications

(30 citation statements)

References 96 publications

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“…The product selectivity shown in this study to arise from the oleA gene would be unusual if the OleA protein was in the middle of the biosynthetic pathway, as proposed by Beller et al (8). Biosynthetic pathways are typically controlled at the first committed step in the pathway (26,41). The mechanism proposed by Beller et al requires additional enzymes to generate the 1,3-diketone that is proposed to undergo OleA-catalyzed condensation with a second fatty acyl chain.…”

Section: Vol 76 2010supporting

confidence: 54%

Widespread Head-to-Head Hydrocarbon Biosynthesis in Bacteria and Role of OleA

Sukovich¹,

Seffernick

Richman

et al. 2010

Appl Environ Microbiol

109

138

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Previous studies identified the oleABCD genes involved in head-to-head olefinic hydrocarbon biosynthesis. The present study more fully defined the OleABCD protein families within the thiolase, ␣/␤-hydrolase, AMPdependent ligase/synthase, and short-chain dehydrogenase superfamilies, respectively. Only 0.1 to 1% of each superfamily represents likely Ole proteins. Sequence analysis based on structural alignments and gene context was used to identify highly likely ole genes. Selected microorganisms from the phyla Verucomicrobia, Planctomyces, Chloroflexi, Proteobacteria, and Actinobacteria were tested experimentally and shown to produce longchain olefinic hydrocarbons. However, different species from the same genera sometimes lack the ole genes and fail to produce olefinic hydrocarbons. Overall, only 1.9% of 3,558 genomes analyzed showed clear evidence for containing ole genes. The type of olefins produced by different bacteria differed greatly with respect to the number of carbon-carbon double bonds. The greatest number of organisms surveyed biosynthesized a single long-chain olefin, 3,6,9,12,15,19,22,25,28-hentriacontanonaene, that contains nine double bonds. Xanthomonas campestris produced the greatest number of distinct olefin products, 15 compounds ranging in length from C 28 to C 31 and containing one to three double bonds. The type of long-chain product formed was shown to be dependent on the oleA gene in experiments with Shewanella oneidensis MR-1 ole gene deletion mutants containing native or heterologous oleA genes expressed in trans. A strain deleted in oleABCD and containing oleA in trans produced only ketones. Based on these observations, it was proposed that OleA catalyzes a nondecarboxylative thiolytic condensation of fatty acyl chains to generate a ␤-ketoacyl intermediate that can decarboxylate spontaneously to generate ketones.

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Section: Vol 76 2010supporting

confidence: 54%

Widespread Head-to-Head Hydrocarbon Biosynthesis in Bacteria and Role of OleA

Sukovich¹,

Seffernick

Richman

et al. 2010

Appl Environ Microbiol

109

138

View full text Add to dashboard Cite

show abstract

“…It is generally accepted that the flux through central carbon metabolism is much higher than the flux towards the branches represented by the biosynthetic pathways [11,13]. In yeast cultured in medium with high glucose concentrations, de novo synthesis of 2-OG is performed in mitochondria by the first enzymatic reactions of the Krebs cycle enzymes [27] (Fig.…”

Section: Physiological Implications Of the High Control By 2-og Supplmentioning

confidence: 99%

“…For example, increases in precursor availability have positive effects on the synthesis of several commercially valuable amino acids such as tryptophan [4,5], phenylalanine [6], lysine [7,8] and glutamate [9] in Corynebacterium glutamicum and Escherichia coli, as well as in the synthesis of oil in Chlamydomonas reinhardtii [10] and antibiotics in Penicillium [11].…”

Section: Introductionmentioning

confidence: 99%

The 2‐oxoglutarate supply exerts significant control on the lysine synthesis flux in Saccharomyces cerevisiae

et al. 2013

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To determine the extent to which the supply of the precursor 2-oxoglutarate (2-OG) controls the synthesis of lysine in Saccharomyces cerevisiae growing exponentially in high glucose, top-down elasticity analysis was used. Three groups of reactions linked by 2-OG were defined. The 2-OG supply group comprised all metabolic steps leading to its formation, and the two 2-OG consumer groups comprised the enzymes and transporters involved in 2-OG transformation into lysine and glutamate and their further utilization for protein synthesis and storage. Various 2-OG steadystate concentrations that produced different fluxes to lysine and glutamate were attained using yeast mutants with increasing activities of Krebs cycle enzymes and decreased activities of Lys synthesis enzymes. The elasticity coefficients of the three enzyme groups were determined from the dependence of the amino acid fluxes on the 2-OG concentration. The respective degrees of control on the flux towards lysine (flux control coefficients) were determined from their elasticities, and were 1.1, 0.41 and À0.52 for the 2-OG producer group and the Lys and Glu branches, respectively. Thus, the predominant control exerted by the 2-OG supply on the rate of lysine synthesis suggests that over-expression of 2-OG producer enzymes may be a highly effective strategy to enhance Lys production.

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“…However, not every enzyme in the pathway exerts the same control on the flux and in some cases the flux is dominated by the activity of a single enzyme, the so-called rate-limiting enzyme (Gunnarsson et al, 2004). Nielsen and Jørgensen, (1995) concluded from a metabolic control analysis of the penicillin biosynthesis pathway in a high producing strain of P. chrysogenum that the rate-limiting step resides either at ACVS or at IPNS (Nielsen and Jørgensen, 1995).…”

Section: Introductionmentioning

confidence: 99%

Dynamic gene expression regulation model for growth and penicillin production in Penicillium chrysogenum

Douma

Verheijen

Laat

et al. 2010

Biotech & Bioengineering

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As is often the case for microbial product formation, the penicillin production rate of Penicillium chrysogenum has been observed to be a function of the growth rate of the organism. The relation between the biomass specific rate of penicillin formation (q(p)) and growth rate (mu) has been measured under steady state conditions in carbon limited chemostats resulting in a steady state q(p)(mu) relation. Direct application of such a relation to predict the rate of product formation during dynamic conditions, as they occur, for example, in fed-batch experiments, leads to errors in the prediction, because q(p) is not an instantaneous function of the growth rate but rather lags behind because of adaptational and regulatory processes. In this paper a dynamic gene regulation model is presented, in which the specific rate of penicillin production is assumed to be a linear function of the amount of a rate-limiting enzyme in the penicillin production pathway. Enzyme activity assays were performed and strongly indicated that isopenicillin-N synthase (IPNS) was the main rate-limiting enzyme for penicillin-G biosynthesis in our strain. The developed gene regulation model predicts the expression of this rate limiting enzyme based on glucose repression, fast decay of the mRNA encoding for the enzyme as well as the decay of the enzyme itself. The gene regulation model was combined with a stoichiometric model and appeared to accurately describe the biomass and penicillin concentrations for both chemostat steady-state as well as the dynamics during chemostat start-up and fed-batch cultivation.

show abstract

Control of Fluxes Towards Antibiotics and the Role of Primary Metabolism in Production of Antibiotics

Cited by 28 publications

References 96 publications

Widespread Head-to-Head Hydrocarbon Biosynthesis in Bacteria and Role of OleA

Widespread Head-to-Head Hydrocarbon Biosynthesis in Bacteria and Role of OleA

The 2‐oxoglutarate supply exerts significant control on the lysine synthesis flux in Saccharomyces cerevisiae

Dynamic gene expression regulation model for growth and penicillin production in Penicillium chrysogenum

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