CN101777094B - Metabolic network analysis method for streptomyces roseosporus as daptomycin producing thalli - Google Patents
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Abstract
The present invention relates to a metabolic network analysis method for streptomyces roseosporus as adaptomycin producing thalli, which comprises the following steps of: (1) constructing a central metabolic network pattern according to a glucolysis pathway, a pentose phosphate pathway, a citric acid cycle, an anaplerotic reaction, and a daptomycin synthesis reaction belonging to a cell synthesis reaction; (2) converting the metabolic network pattern into a matrix S (m*n), collecting a fermented liquid, measuring the cell dry weight, the glucose consumption rate, the daptomycin growth rate and the cell growth rate, and calculating an unknown flux according to know fluxes. In the present invention, the metabolic network analysis method is applied to the metabolic flux analysis of streptomyces roseosporus,the metabolic fluxes of intracellular reactions are calculated by measuring the metabolic flux of extracellular substances, and the distribution condition of glucose utilized by thalli to the glucolysis pathway, the pentose phosphate pathway, the citric acid cycle and the anaplerotic reaction is reflected. The present invention provides a new method for quantitatively researching the intracellular metabolic properties of streptomyces roseosporus.
Description
Technical field
The invention belongs to the metabolic engineering field, particularly Daptomycin is produced the metabolism network analysis method of bacterium Streptomyces roseosporus.
Background technology
" Streptomyces roseosporus " (latin name is: " Streptomyces roseosporus ") is a kind of actinomyces of streptomyces, it is N-caprinoyl-L-tryptophanyl-altheine acyl-L-aspartoyl-L-threonyl-glycyl-L-ornithyl-L-aspartoyl-D-alanyl-L-aspartoyl-glycyl-D-seryl-L-threo-3-methyl-glutamy-L-dog urinary ammonia acyl ε 1-lactone that its growth index increases the Daptomycin (English name " daptomycin ") that synthesizes later stage to stationary phase, being to be formed by connecting by-individual decane side chain the tryptophane with-individual ring-type beta amino acids peptide chain N-end, is a kind of novel lipopeptide microbiotic.
Daptomycin is a kind of microbiotic of calcium ion dependent form, under the condition that calcium ion exists, Daptomycin is attached on the epicyte protein with the form of non-covalent bond, Daptomycin on the cell membrane is its target site in conjunction with albumen, Daptomycin can be upset cell membrane to amino acid whose transhipment, thereby hinder the biosynthesizing of the LTA lipid of bacteria cell wall peptide glycan, change the character of cytoplasma membrane; In addition, it can also be by destroying the cell membrane of bacterium, its content is leaked and reaches the purpose of kill bacteria.Report is also arranged is it and the combining of cell membrane, and causes the reduction of film potential, thereby destroys the synthetic of RNA and DNA in the born of the same parents, finally bacteria growing inhibiting.Daptomycin is because the particular structure feature and the mechanism of action, for drug-fast bacteria, as the enterococcus of vancomycin resistance, the golden Portugal bacterium of methicillin-resistant, the golden Portugal bacterium of glycopeptide class sensitivity, the staphylococcus of coagulase-negative and the infection of penicillin-fast streptococcus pneumonia have notable therapeutic effect.Be a kind of novel microbiotic after vancomycin, aspect treatment skin infection and the heart film inflammation significant curative effect arranged.Daptomycin became the first lipopeptide antibiotic that first is gone on the market by drugs approved by FDA in 2003.2006, Daptomycin obtained the authentication that European medicine evaluation is deployed in whole Europe once more.
Research to the biological metabolism network is subject to people's attention day by day, the function that mainly is each the component composition in the biology all is to embody by the interaction with other parts, and therefore only on system level all the components being carried out holistic approach could have correct understanding comprehensively to the physiological function of biology.Utilize constructed Metabolic Network Model, by the metabolic flux analysis, can be in the hope of the distribution situation of intracellular organic matter metabolism.For the production bacterium Streptomyces roseosporus of Daptomycin, also not to the report of its metabolism network analysis, therefore make up the Metabolic Network Model of Streptomyces roseosporus at present, the metabolic flux that calculates in its born of the same parents distributes, and can understand the metabolic characteristic of this bacterial classification better.
Summary of the invention
The Metabolic Network Model that the objective of the invention is the Streptomyces roseosporus of application build is calculated the method that the carbon metabolism distributes, and by measuring the flux of the outer reaction of born of the same parents, calculates the metabolic flux of each intramicellar reaction in the Metabolic Network Model.
The metabolism network analysis method of Daptomycin production bacterium Streptomyces roseosporus is as follows:
1) according to the Daptomycin synthetic reaction of glycolytic pathway, pentose phosphate pathway, citrate cycle, anaplerotic reaction and cell synthetic reaction, constructs the center Metabolic Network Model;
2) (m * n), wherein m is born of the same parents' intracellular metabolite thing, and n is reaction Metabolic Network Model to be converted into matrix S, S (m, the n) stoichiometric coefficient of expression metabolin m in reaction n, and have V to represent to react flux (n-dimensional vector), cumulative speed at steady state conditions lower eyelid intracellular metabolite thing is 0, and S is then arranged
CV
C+ S
KV
K=0, wherein subscript C represents unknown flux, and K represents known flux, and unknown flux is by formula
Obtain;
3) Streptomyces roseosporus is carried out the perseverance cultivation in fermentation tank, collect fermentation liquor, measure dry cell weight, glucose consumption speed, Daptomycin generating rate and cell growth rate;
4) with the glucose consumption speed, Daptomycin generating rate and the cell growth rate that record in the step 3 respectively divided by dry cell weight, obtain than glucose consumption speed, than Daptomycin generating rate with compare cell growth rate, then be 3 known flux, bring the formula in the step 2 into, obtain unknown flux.
The present invention is applied to the metabolism network analysis technique metabolic flux analysis of Streptomyces roseosporus, by measuring the metabolic flux of the outer material of born of the same parents, calculate the metabolic flux of intramicellar reaction, reflect glucose by the thalline utilization after in the distribution situation of glycolytic pathway, pentose phosphate pathway, citrate cycle and anaplerotic reaction, for the metabolic characteristic in the Quantitative study Streptomyces roseosporus born of the same parents provides a new method.
Description of drawings
Fig. 1 is the metabolism network diagram that makes up among the embodiment 1.
Fig. 2 is matrix S, S among the embodiment 1
CAnd S
KAnd vectorial V, V
CAnd V
KSynoptic diagram.
Embodiment
The present invention will be further described below in conjunction with specific embodiment:
Embodiment 1:
According in the biological chemistry about the knowledge of metabolic response, make up center carbon metabolism network, comprise glycolytic pathway, pentose phosphate pathway, citrate cycle, anaplerotic reaction, cell synthetic reaction and Daptomycin synthetic reaction; Form and synthetic these amino acid whose precursor substances according to the amino acid of Daptomycin, be expressed as by precursor substance Daptomycin synthetic, (Zhao Xueming etc. translate the synthetic precursor substance of amino acid with reference to " metabolic engineering-principle and methods " that the people showed such as Stephanopoulos, Chemical Industry Press, 1998); The precursor substance of cell is formed with reference to people such as Schilling at " Biotechnology andBioengineering " (Vol.71:286-306,2001) " the Combining pathway analysis with fluxbalance analysis for the comprehensive study of metabolic systems " that delivers, the metabolism network that obtains comprises 15 born of the same parents' intracellular metabolite things and 18 reactions.
Table 1 metabolism network reaction tabulation
In the table 1, " → " expression non-reversible reaction,
Expression expression reversible reaction, the unit of " cell " is 1/h in the reaction 18, the unit of all other reactants is mmol/ (g dry cell weight h); Reaction 1 is the glucose priming reaction, and reaction 2-6 is a glycolytic pathway, and reaction 7-11 is a pentose phosphate pathway, and reaction 12 is an anaplerotic reaction, and reaction 13-16 is a citrate cycle, and reaction 17 is the Daptomycin synthetic reaction, and reaction 18 is the cell synthetic reaction.
V1-V18 is respectively in the table 1 metabolic flux of reaction 1-18 among Fig. 1, " precursor substance " of V17 and V18 see Table reaction 17 and 18 in 1.
Table 2 is born of the same parents' intracellular metabolite thing tabulation of metabolism network among the embodiment 1.Wherein metabolin is the metabolite in the born of the same parents in the listed reaction of table 1, has 15.
Born of the same parents' intracellular metabolite thing tabulation in the table 2 metabolism network
2. the metabolism network that makes up is converted into matrix S (m * n), wherein m is born of the same parents' intracellular metabolite thing (15), n is reaction (18), S (m, n) stoichiometric coefficient of expression metabolin m in reaction n, the degree of freedom of matrix is n-m=3, respond totally 3 of 1,17 and 18 metabolic fluxs of known flux, degree of freedom=known flux number is positive definite matrix; Unknown flux is reaction 2,3 ... 16 metabolic flux is found the solution with following formula
Wherein V represents to react flux, and subscript T represents transposed matrix, and subscript C represents unknown flux, and K represents known flux.As shown in Figure 2, wherein figure (1)-(6) are represented S, S respectively
C, S
K, V, V
CAnd V
K, the horizontal ordinate 1-18 of (1)-(3) represents the reaction 1-18 in the table 1 respectively among the figure, ordinate 1-15 represents born of the same parents' intracellular metabolite thing 1-15 in the table 2 respectively.
3. at room temperature Streptomyces roseosporus is carried out the perseverance cultivation at 3 liters of automatic fermentation tanks, liquid amount is 2 liters, control pH 7.0,30 ℃ of temperature, rotating speed 400rpm, throughput 0.8vvm, speed stream in fermentation tank with 2ml/h adds capric acid: ammoniacal liquor (volume ratio 2: 1) solution, and adding fermentation medium with the velocity flow of 48ml/h, the speed with 50ml/h extracts fermentation liquor from fermentation tank simultaneously, keeps the stable of liquid measure in the fermentation tank.The composition of fermentation medium and mass content are: glucose 40g/l, MgSO
47H
2O 1g/l, K
2HPO
43H
2O 2g/l, CaCl
22H
2O 1g/l, FeSO
47H
2O 0.05g/l, pH 7.0.Glucose consumption speed, cell growth rate, Daptomycin generating rate and the dry cell weight measured are respectively 2.285mmol/ (1h), 0.251g/ (1h), 0.001mmol/ (1h) and 5.02g/l.
With the glucose consumption speed, cell growth rate and the Daptomycin generating rate that record in the step 3 respectively divided by dry cell weight, obtain than glucose consumption speed, be respectively 0.4552mmol/ (g dry cell weight h), 0.0002mmol/ (g dry cell weight h) and 0.051/h than Daptomycin generating rate with than cell growth rate, be respectively V1, V17 and V18, bring the formula in the step 2 into, obtain unknown flux V2, V3 ... V16.
The metabolic flux of table 3 for calculating among the embodiment 1 wherein reacts the reaction in the 1-18 difference corresponding tables 1, and the metabolic flux unit of reaction 1-17 is mmol/ (g dry cell weight h), and the metabolic flux unit of reaction 18 is 1/h.
The metabolic flux that calculates among table 3 embodiment 1 distributes
Claims (3)
1. Daptomycin is produced the metabolism network analysis method of bacterium Streptomyces roseosporus, it is characterized in that:
1) forms and the Daptomycin molecular composition according to metabolic response principle, cell in the biological chemistry, construct center metabolism network;
2) (m * n), wherein m is born of the same parents' intracellular metabolite thing, and n is reaction the metabolism network to be converted into matrix S, S (m, the n) stoichiometric coefficient of expression metabolin m in reaction n, and have V to represent to react flux, V is a n-dimensional vector, is 0 at the cumulative speed of steady state conditions lower eyelid intracellular metabolite thing, and S is then arranged
CV
C+ S
KV
K=0, wherein subscript C represents the subscript of unknown flux, and K represents the subscript of known flux, and Vc represents unknown flux, V
KRepresent known flux, unknown flux is by formula
Obtain;
3) Streptomyces roseosporus is carried out the perseverance cultivation in fermentation tank, collect fermentation liquor, measure dry cell weight, glucose consumption speed, Daptomycin generating rate and cell growth rate;
4) with the glucose consumption speed, Daptomycin generating rate and the cell growth rate that record in the step 3 respectively divided by dry cell weight, obtain than glucose consumption speed, than Daptomycin generating rate with compare cell growth rate, then be 3 known flux, bring the formula in the step 2 into, obtain unknown flux.
2. according to the described metabolism network analysis method of claim 1, it is characterized in that the Metabolic Network Model of structure comprises glycolytic pathway, pentose phosphate pathway, citrate cycle, anaplerotic reaction, cell synthetic reaction and Daptomycin synthetic reaction.
3. according to the described metabolism network analysis method of claim 1, it is characterized in that matrix S is made up of 15 born of the same parents' intracellular metabolite things and 18 reactions, the degree of freedom of matrix is 3.
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| CN1793356A (en) * | 2005-11-03 | 2006-06-28 | 天津大学 | Process for selecting cultivating high yield strain of datomycin by laser inducing rose sporestreptomycete |
| CN101240013A (en) * | 2000-01-20 | 2008-08-13 | 卡比斯特制药公司 | High purity lipopeptides, lipopeptide micelles, processes for preparing same |
| CN101550436A (en) * | 2008-04-01 | 2009-10-07 | 上海来益生物药物研究开发中心有限责任公司 | Method for enhancing output of antibacterial substance A21978C |
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| CN101240013A (en) * | 2000-01-20 | 2008-08-13 | 卡比斯特制药公司 | High purity lipopeptides, lipopeptide micelles, processes for preparing same |
| CN1793356A (en) * | 2005-11-03 | 2006-06-28 | 天津大学 | Process for selecting cultivating high yield strain of datomycin by laser inducing rose sporestreptomycete |
| CN101550436A (en) * | 2008-04-01 | 2009-10-07 | 上海来益生物药物研究开发中心有限责任公司 | Method for enhancing output of antibacterial substance A21978C |
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