CN104962593A - Fermentation culture medium for producing diterpene compound through Eutypella sp. - Google Patents
Fermentation culture medium for producing diterpene compound through Eutypella sp. Download PDFInfo
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- CN104962593A CN104962593A CN201510408258.XA CN201510408258A CN104962593A CN 104962593 A CN104962593 A CN 104962593A CN 201510408258 A CN201510408258 A CN 201510408258A CN 104962593 A CN104962593 A CN 104962593A
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Abstract
The invention relates to fermentation culture medium for producing a diterpene compound through Eutypella sp. The culture medium provided by the invention is suitable for the growth of Eutypella sp. and can greatly improve the yield of the diterpene compound Libertellenone H.
Description
Technical field
The invention belongs to biological technical field; More specifically, the present invention relates to the fermention medium composition producing diterpene-kind compound Libertellenone H for arctic filamentous fungus Eutypella sp., improved the output of Libertellenone H by the method for medium optimization.
Background technology
Because pathogenic agent is to the reinforcement of various drug resistance and the serious and long-term side effect of some common drugs, develop new medicine particularly urgent.Arctic regions is because long-term low temperature, dry, multigelation, strong uv-radiation, light application time are long and the nutrition growth seriously limiting plant and animal such as poor, and the microorganism that tolerance is strong but plays an important role in Polar ecosystems.In recent years, because polar microorganism can produce the secondary metabolites of novel structure, become the important potential resources of developing new drug thing gradually.
Curved spore gathers shell bacterium D-1 (Eutypella sp.D-1, China typical culture collection center, deposit number is CCTCC M2013144) be separated the strain filamentous fungus from arctic high latitude (78 ° of 55 ' N) fairy maiden wood foundation soil, this genus fungi is comparatively extensive in distribution on global, and the secondary metabolites of many novel structures, function uniqueness can be produced, such as eudesmane type sesquiterpene, pimarane type diterpene, triterpene, cytochalasins, polyketone class and CYCLIC DIPEPTIDES compounds.From this bacterium tunning, two kinds of isolation identification novel isopimarane type diterpene-kind compound Libertellenone G and Libertellenone H all have certain inhibit activities to these 7 kinds of tumor cell lines of human lung carcinoma cell line H460, human glioma cells strain U251, human stomach cancer cell line SG7901, human pancreas cancer cell strain SW1990, human cervical carcinoma cell strain Hela and human hepatoma cell strain Huh-7.Wherein Libertellenone H is the strongest to the restraining effect of Mcf-7 mammary cancer, IC
50reach 3.31 μm of ol/L, and the IC of positive control Taxol
50quite, there is development prospect.
But the original output of Libertellenone H extremely low (lower than HPLC detection limit), seriously limit follow-up pharmacological effect and clinical study, therefore need the output being improved Libertellenone H by fermention medium optimization, lay the foundation for its follow-up large scale fermentation and as anticancer drug candidate exploitation.
Summary of the invention
The object of the present invention is to provide the fermention medium composition and the preparation method that produce diterpene-kind compound Libertellenone H for arctic filamentous fungus Eutypella sp..
In a first aspect of the present invention, provide the substratum of a kind of arctic filamentous fungus (Eutypella sp.), described substratum comprises following component:
In a preference of the present invention, described substratum comprises following component:
In another preference of the present invention, described substratum comprises following component:
In another preference of the present invention, described substratum comprises following component:
Wherein, each component content in the medium can float in ± 10% (more preferably ± 5%) scope.
In another preference of the present invention, in described substratum, each component is formulated in water; Described water is preferably deionized water.
In another preference of the present invention, the pH value 5.8 ± 0.5 of described substratum.
In another preference of the present invention, described arctic filamentous fungus Eutypella sp. is Eutypellasp.D-1.
In another aspect of this invention, providing the purposes of described substratum, for cultivating arctic filamentous fungus (Eutypella sp.), producing diterpene-kind compound Libertellenone H.
In another aspect of this invention, provide the method for the substratum of the arctic filamentous fungus (Eutypella sp.) described in preparation, described method comprises:
(1) mother liquor of CoCL2 6H2O and calcium chloride is prepared;
(2) by sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, the appropriate water dissolution of urea; The CoCL2 6H2O prepared with (1) and the mother liquor of calcium chloride mix; Wherein, the consumption of each component is according to described in arbitrary above.
In a preference of the present invention, described method also comprises: pH is adjusted to 5.8 ± 0.5, at 15 DEG C of sterilizing 20min.
In another aspect of this invention, one is provided to utilize arctic filamentous fungus (Eutypella sp.) to produce the method for Libertellenone H, described method comprises: the culture medium culturing arctic filamentous fungus (Eutypella sp.) described in utilization, thus produces Libertellenone H.
In another preference of the present invention, the inoculum size of the seed liquor of arctic filamentous fungus (Eutypella sp.) 5-10% is by volume inoculated into arbitrary described substratum above, be placed in 20 DEG C, 180r/min shaking table cultivation 8-12 days, obtain fermented liquid, wherein containing diterpene-kind compound Libertellenone H.
In another aspect of this invention, provide a kind of for cultivating the test kit of arctic filamentous fungus (Eutypella sp.), described test kit comprises the foregoing substratum of the present invention.
Other side of the present invention, due to disclosure herein, is apparent to those skilled in the art.
Embodiment
The present inventor, through long-term and deep research, has researched and developed a kind of culture medium prescription being suitable for arctic filamentous fungus Eutypella sp. High-efficient Production diterpene-kind compound Libertellenone H newly.Substratum of the present invention, is suitable for the growth of arctic filamentous fungus Eutypella sp., and significantly can improve the output of Libertellenone H.
As used herein, described " containing ", " having " or " comprising " include " comprising ", " primarily of ... form ", " substantially by ... form " and " by ... form "; " primarily of ... form ", " substantially by ... form " and " by ... formation " belong to the subordinate concept of " containing ", " having " or " comprising ".
Term " substratum of the arctic of the present invention filamentous fungus (Eutypella sp.) " refers to containing sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, urea, and the composition of optional CoCL2 6H2O and calcium chloride; Or substantially by sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, urea, and the composition of optional CoCL2 6H2O and calcium chloride composition.In the composition, described sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, urea and optional CoCL2 6H2O, calcium chloride account for the 80-100% of substratum gross weight, preferably account for 90-100%, more preferably account for 95-100%, as 98%, 99%.
As optimal way of the present invention, also add CoCL2 6H2O and calcium chloride in described substratum, the addition of CoCL2 6H2O and calcium chloride is advisable to improve needed for thalli growth and production, and those skilled in the art can empirically add.
As optimal way of the present invention, the consumption for each component preparing the arctic of the present invention filamentous fungus (Eutypella sp.) (more preferably Eutypella sp.D-1) substratum is as shown in table 1.
Table 1
According to announcement of the present invention, after obtaining the cicada arctic of the present invention filamentous fungus (Eutypella sp.) (more preferably Eutypella sp.D-1) substratum component used and formula thereof, those skilled in the art can prepare described substratum easily.
The component (raw material) of the application of substratum of the present invention is business-like general chemistry product, price comparison is low, prepare also very simple, compared with the substratum of prior art, novel culture medium of the present invention significantly can promote arctic filamentous fungus (Eutypella sp.) fermentative production Libertellenone H, the output of LibertellenoneH is significantly improved, and is conducive to large-scale industrial production.
As optimal way of the present invention, when arctic filamentous fungus (Eutypella sp.) (the more preferably Eutypella sp.D-1) substratum described in preparing, first accurately take each component respectively, they are mixed in water.Described water is preferably deionized water.Preferred, a kind of method for the preparation of above-mentioned substratum is provided, comprises step:
A () prepares high density (1000 times) mother liquor of micro-CoCL2 6H2O and calcium chloride;
B () is by described sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, the appropriate water dissolution of urea;
C () adds the mother liquor of CoCL2 6H2O and calcium chloride trace element in above-mentioned solution;
As optimal way of the present invention, after step (c), comprise further: pH is adjusted to 5.8 ± 0.5, at 115 DEG C of sterilizing 20min.
In a particular embodiment of the present invention, additionally provide the fermentation process using described culture medium culturing arctic filamentous fungus (Eutypella sp.) (more preferably Eutypella sp.D-1) fermentative production Libertellenone H, comprise step:
A () vertically inserts solid medium central authorities with the mycelia in transfering loop picking conservation pipe, under 28 DEG C of conditions, cultivate 7 ~ 8d;
B () adopts plain taper bottle to cultivate seed liquor, 8 layers of gauze ensure aseptic ventilative.Punch on solid plate with the punch tool of diameter 1cm, with inoculation shovel, agar nahlock is evenly cut into 4 pieces, be inoculated in the Erlenmeyer flask that 100ml seed culture medium is housed, be placed in 28 DEG C, 180r/min shaking table cultivates 3.5d (the concrete growing state depending on seed), identical seed culture medium is accessed according to 5% (v/v) inoculum size, in 28 DEG C, 180r/min shaking table cultivation 2.5d, obtain fresh secondary seed solution, for fermentation culture;
C () adopts plain taper bottle fermentation culture, be the inoculum size access fresh seeds liquid according to 5% (v/v) in the Erlenmeyer flask of 50ml at liquid amount, is placed in 20 DEG C, 180r/min shaking table cultivation 10d acquisition fermented liquid.
Preferably, after the bacterial classification that-80 DEG C are preserved is thawed, with aseptic inoculation ring picking mycelia, vertical insertion solid medium central authorities, be placed in 28 DEG C of constant incubators, activation culture 7 ~ 8d, obtain fresh solid dull and stereotyped, then be placed in 4 DEG C of Refrigerator stores stand-by, later solid plate reactivates once every 30d.
Preferably, often liter of activation medium includes glucose 20g/L, and potato leaches powder 10g/L, and all the other are deionized water, at 121 DEG C of sterilizing 20-30min.Preferably, often liter of solid plate activation medium adds agar powder 15-20g on the basis of activation medium.
Present invention also offers the detection method of the Libertellenone H that a kind of above-mentioned fermentation process is produced, its operation steps comprises:
Get the fermented liquid 10ml being cultured to 10d, add equal-volume ethyl acetate, and add 30 granulated glass spherees (diameter is 3-5mm), after sealing, in shaking table 20 DEG C, 36h is extracted under 180r/min condition, it is all transferred in 50ml centrifuge tube, after the centrifugal 10min of 4500r/min, get upper organic phase and carry out rotary evaporation in vacuo (37 DEG C), after being spin-dried for, the methyl alcohol of 1.5ml is added in eggplant type flask, ultrasonic dissolution assisting, washings is transferred in 1.5ml centrifuge tube, supernatant is got after the centrifugal 10min of 13400g, be placed in 4 DEG C of preservations, and the detection of product is carried out with HPLC.
Beneficial effect of the present invention is specific as follows:
1. novel culture medium composition of the present invention comprises sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, urea, and optional CoCL2 6H2O, calcium chloride, be common agents, raw material is easy to get, consumption is few, and cost is low;
2. when preparing novel culture medium of the present invention, first sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, urea appropriate amount of deionized water are dissolved, add a small amount of liquid microelement again, constant volume, preparation is simple;
3. adopt novel fermentation culture medium culturing arctic filamentous fungus Eutypella sp.D-1 of the present invention, during fermentation ends, the output of the Libertellenone H detected from this strain fermentation extract is significantly increased, ultimate capacity brings up to 10.7mg/L from original 0.18mg/L, is approximately 59 times of original level.This invention has important directive significance for the large scale fermentation cultivation of follow-up arctic filamentous fungus Eutypella sp.D-1 and the pharmacological effect research of Libertellenone H.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, conveniently condition such as J. Pehanorm Brooker etc. is write usually, Molecular Cloning: A Laboratory guide, the third edition, Science Press, the condition described in 2002, or according to the condition that manufacturer advises.
Embodiment 1, substratum 1
1.1 experimental strains and method for preserving
Curved spore gathers shell bacterium D-1, and (Eutypella sp.D-1, culture presevation is numbered: CCTCC M2013144) provided by Second Military Medical University, PLA.Inoculation obtains fresh seeds liquid cultivate 3.5d in seed culture fluid after, and 50% glycerine and fresh seeds liquid are mixed in conservation pipe in 2:3 ratio ,-80 DEG C of freezings, and gets fresh seeds liquid and preserve through vacuum freezedrying in ampoul tube.
The preparation of 1.2 solid plates, seed culture medium and fermention medium 1
Solid plate and seed liquid nutrient medium:
The pH of substratum is adjusted to 5.8.Solid plate substratum be then add on this basis 2% agar powder, sterilizing 20min under 121 DEG C of conditions.
Fermention medium 1:
PH is adjusted to 5.8, sterilizing 20min under 115 DEG C of conditions.
1.3 fermentative production diterpene-kind compound Libertellenone H
Solid plate is cultivated: vertically insert solid medium central authorities with the mycelia in transfering loop picking conservation pipe, under 28 DEG C of conditions, cultivate 7 ~ 8d.
Seed culture: seed liquor all adopts 500ml plain taper bottle to cultivate, 8 layers of gauze ensure aseptic ventilative.Punch on solid plate with the punch tool of diameter 1cm, with inoculation shovel, agar nahlock is evenly cut into 4 pieces, be inoculated in the Erlenmeyer flask that 100ml seed culture medium is housed, be placed in 28 DEG C, 180r/min shaking table cultivates 3.5d (the concrete growing state depending on seed), identical seed culture medium is accessed according to 5% (v/v) inoculum size, in 28 DEG C, 180r/min shaking table cultivation 2.5d, obtain fresh secondary seed solution, for fermentation culture.
Shake flask fermentation is cultivated: fermentation culture all adopts the plain taper bottle of 250ml to cultivate, is to access fresh seeds liquid according to the inoculum size of 5% (v/v) in the Erlenmeyer flask of 50ml at liquid amount, is placed in 20 ± 1 DEG C, 180 ± 20r/min shaking table cultivates 10 days.
The mensuration of 1.4 diterpene-kind compound Libertellenone H output
Get fermented liquid 10ml prepared by previous step, add equal-volume ethyl acetate, and add 30 granulated glass spherees (diameter is 3-5mm), after sealing, in shaking table 20 DEG C, 36h is extracted under 180r/min condition, it is all transferred in 50ml centrifuge tube, after the centrifugal 10min of 4500r/min, get upper organic phase and carry out rotary evaporation in vacuo (37 DEG C), after being spin-dried for, the methyl alcohol of 1.5ml is added in eggplant type flask, ultrasonic dissolution assisting, washings is transferred in 1.5ml centrifuge tube, supernatant is got after the centrifugal 10min of 13400g, be placed in 4 DEG C of preservations, and the detection of product is carried out with HPLC.
HPLC testing conditions: high performance liquid chromatograph (Agilent 1200), liquid-phase chromatographic column be Kromasil-C18 (250mm × 4.6mm,
), column temperature 25 DEG C, determined wavelength 332nm, flow velocity 1ml/min, sample size is 20 μ l, and moving phase is 0.1% acetic acid (A phase) and acetonitrile (B phase), and gradient is: 0 ~ 10min, 5 ~ 60%B phase; 10 ~ 30min, 60%B phase; 30.1 ~ 35min, 100%B phase.The residence time of Libertellenone H standard substance is 26-27min.Peak area is calculated, then according to typical curve (y=24.369x+1.6144, R to gained liquid phase peak integration
2=0.9999) conversion obtains Product yields, and wherein y is peak area, and x is sample introduction concentration (mg/L).
In fermention medium 1, the output of the Libertellenone H that Eutypella sp.D-1 produces is 0.18mg/L.
Embodiment 2, substratum 2 (glucose is as carbon source)
The preparation of 2.1 solid plates, seed culture medium and fermention medium 2
The preparation of solid plate and seed liquid nutrient medium is with the step 1.2 of embodiment 1.
Fermention medium 2:
PH is adjusted to 5.8, sterilizing 20min under 115 DEG C of conditions.
2.2 fermentative production diterpene-kind compound Libertellenone H
Application of fermentation substratum 2 is produced, and method is with the step 1.3 of embodiment 1.
The mensuration of 2.3 thalli growths and Libertellenone H output
With the step 1.4 of embodiment 1, the output recording Libertellenone H reaches 0.21mg/L.
Embodiment 3, substratum 3 (sucrose is as carbon source)
The preparation of 3.1 solid plates, seed culture medium and fermention medium 3
The preparation of solid plate and seed liquid nutrient medium is with the step 1.2 of embodiment 1.
Fermention medium 3:
PH is adjusted to 5.8, sterilizing 20min under 115 DEG C of conditions.
3.2 fermentative production diterpene-kind compound Libertellenone H
Application of fermentation substratum 3 is produced, and method is with the step 1.3 of embodiment 1.
The mensuration of 3.3 diterpene-kind compound Libertellenone H output
With the step 1.4 of embodiment 1, the output recording Libertellenone H reaches 0.52mg/L.
Embodiment 4, substratum 4
The preparation of 4.1 solid plates, seed culture medium and fermention medium 4
The comparatively suitable concentration of experiment of single factor determination SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate, Repone K, yeast extract, L-ornithine hydrochloride.The preparation of solid plate and seed liquid nutrient medium is with the step 1.2 of embodiment 1.
Fermention medium 4:
PH is adjusted to 5.8, sterilizing 20min under 115 DEG C of conditions.
4.2 fermentative production diterpene-kind compound Libertellenone H
Application of fermentation substratum 4 is produced, and method is with the step 1.3 of embodiment 1.
The mensuration of 4.3 diterpene-kind compound Libertellenone H output
With the step 1.4 of embodiment 1, the output recording Libertellenone H reaches 0.75mg/L.
Embodiment 5, substratum 5 (taking urea as nitrogenous source)
The preparation of 5.1 solid plates, seed culture medium and fermention medium 5
The preparation of solid plate and seed liquid nutrient medium is with the step 1.2 of embodiment 1.
Fermention medium 5:
PH is adjusted to 5.8, sterilizing 20min under 115 DEG C of conditions.
5.2 fermentative production diterpene-kind compound Libertellenone H
Application of fermentation substratum 5 is produced, and method is with the step 1.3 of embodiment 1.
The mensuration of 5.3 diterpene-kind compound Libertellenone H output
With the step 1.4 of embodiment 1, the output recording Libertellenone H reaches 2.35mg/L.
Embodiment 6, substratum 6 (checking of urea preferred concentration)
The preparation of 6.1 solid plates, seed culture medium and fermention medium 6
The preparation of solid plate and seed liquid nutrient medium is with the step 1.2 of embodiment 1.
Fermention medium 6:
PH is adjusted to 5.8, sterilizing 20min under 115 DEG C of conditions.
6.2 fermentative production diterpene-kind compound Libertellenone H
Application of fermentation substratum 6 is produced, and method is with the step 1.3 of embodiment 1.
The mensuration of 6.3 diterpene-kind compound Libertellenone H output
With the step 1.4 of embodiment 1, the output recording Libertellenone H reaches 10.7mg/L.
Should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. a substratum for arctic filamentous fungus (Eutypella sp.), it is characterized in that, described substratum comprises following component:
2. substratum as claimed in claim 1, it is characterized in that, described substratum comprises following component:
3. substratum as claimed in claim 2, it is characterized in that, described substratum comprises following component:
4. the substratum as described in as arbitrary in claim 1-3, it is characterized in that, in described substratum, each component is formulated in water; And/or the pH value 5.8 ± 0.5 of described substratum.
5. the purposes of the arbitrary described substratum of claim 1-4, for cultivating arctic filamentous fungus, produces diterpene-kind compound Libertellenone H.
6. prepare a method for the substratum of the arbitrary described arctic filamentous fungus of claim 1-4, described method comprises:
(1) mother liquor of CoCL2 6H2O and calcium chloride is prepared;
(2) by sucrose, SODIUMNITRATE, three water dipotassium hydrogen phosphates, magnesium sulfate heptahydrate, Repone K, yeast extract, ferrous sulfate, the appropriate water dissolution of urea; The CoCL2 6H2O prepared with (1) and the mother liquor of calcium chloride mix;
Wherein, the consumption of each component arbitrary according to claim 1-4 described in.
7. method as claimed in claim 6, is characterized in that, also comprise: pH is adjusted to 5.8 ± 0.5, at 15 DEG C of sterilizing 20min.
8. utilize arctic filamentous fungus to produce a method of Libertellenone H, it is characterized in that, described method comprises: utilize the arbitrary described culture medium culturing arctic filamentous fungus of claim 1-4, thus produce Libertellenone H.
9. method as claimed in claim 8, it is characterized in that, the inoculum size of the seed liquor of arctic filamentous fungus 5-10% is by volume inoculated into arbitrary described substratum above, be placed in 20 DEG C, 180r/min shaking table cultivation 8-12 days, obtain fermented liquid, wherein containing diterpene-kind compound Libertellenone H.
10. for cultivating a test kit for arctic filamentous fungus, it is characterized in that, described test kit comprises: the arbitrary described substratum of claim 1-4.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6080543A (en) * | 1997-12-08 | 2000-06-27 | E. & J. Gallo Winery | Detection of fungal pathogens |
| CN103274915A (en) * | 2013-05-30 | 2013-09-04 | 中国人民解放军第二军医大学 | Diterpenoid compounds libertellenone G and libertellenone H with antineoplastic activities and application thereof |
-
2015
- 2015-07-13 CN CN201510408258.XA patent/CN104962593B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6080543A (en) * | 1997-12-08 | 2000-06-27 | E. & J. Gallo Winery | Detection of fungal pathogens |
| CN103274915A (en) * | 2013-05-30 | 2013-09-04 | 中国人民解放军第二军医大学 | Diterpenoid compounds libertellenone G and libertellenone H with antineoplastic activities and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| XIAO-LING LU ET AL.: "Pimarane diterpenes from the Arctic fungus Eutypella sp.D-1", 《THE JOURNAL OF ANTIBIOTICS》 * |
| 上海市轻工业局，复旦大学工业微生物学习班: "《工业微生物》", 31 December 1971, 上海人民出版社 * |
| 刘靖堂等: "北极真菌Eutypella sp．D-1中海松烷二萜类化合物的研究", 《天然产物研究与开发》 * |
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