CN108611278A - A kind of method and its bacterial strain preparing phenazocine by microbial fermentation - Google Patents
A kind of method and its bacterial strain preparing phenazocine by microbial fermentation Download PDFInfo
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- CN108611278A CN108611278A CN201810409352.0A CN201810409352A CN108611278A CN 108611278 A CN108611278 A CN 108611278A CN 201810409352 A CN201810409352 A CN 201810409352A CN 108611278 A CN108611278 A CN 108611278A
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- ethyl acetate
- phenazocine
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/14—Fungi; Culture media therefor
- C12N1/145—Fungal isolates
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
Abstract
The invention discloses a kind of methods and its bacterial strain preparing phenazocine by microbial fermentation.The present invention provides applications of the Pseudogymnoascus pannorum BJZ13 in preparing phenazocine；The Pseudogymnoascus pannorum BJZ13 are CGMCC No.15389 in the preservation registration number of China Committee for Culture Collection of Microorganisms's common micro-organisms center.Phenazocine can be obtained after Pseudogymnoascus pannorum BJZ13 fermented and cultureds, easy to operate, of low cost, with short production cycle, the application potential with industrial-scale production.The present invention provides new way for the development of resources of phenazocine class drug.
Description
Technical field
The present invention relates to biochemical fields, and in particular to it is a kind of by microbial fermentation prepare phenazocine method and
Its bacterial strain.
Background technology
Phenazocine is a kind of opium analgesics, has the function of similar pentazocine.Phenazocine has analgesic work(
Effect, effect is 4 times of morphine, and will not cause Oddi sphincterismus, is to be particularly suited for treatment biliary tract or pancreas than morphine
The drug of gland pain.
Phenazocine is presently mainly to be produced in chemically synthesized method.It, can using micro-organisms phenazocine
To obtain the higher phenazocine monomer of purity, to avoid the residual of chemical synthesis by-product, and microorganism is that live body is
Synthesizing site, using biology, the resource of itself generates phenazocine drug, can the waste to avoid resource and the destruction to environment.
Microorganism is easy to breeding and mass propgation, easy to operate, of low cost, with short production cycle, answering with industrial-scale production
It is the desirable route for producing phenazocine drug with potentiality.
Invention content
The object of the present invention is to provide a kind of methods preparing phenazocine by microbial fermentation.
In a first aspect, claimed Pseudogymnoascus pannorum BJZ13 are preparing phenazocine
In application.
Wherein, it is micro- to be preserved in China on March 8th, 2018 by the Pseudogymnoascus pannorum BJZ13
(abbreviation CGMCC, address are biological inoculum preservation administration committee common micro-organisms center：BeiChen West Road, Chaoyang District, BeiJing City 1
Institute 3, Institute of Microorganism, Academia Sinica), preservation registration number is CGMCC No.15389.
Second aspect, a kind of claimed method preparing phenazocine.
The method provided by the present invention for preparing phenazocine, it may include following steps：Described in fermented and cultured
Pseudogymnoascus pannorum BJZ13, obtain phenazocine.
Further, the solvent of the culture medium of the fermented and cultured is water, solute and a concentration of：Soluble starch 20g/L,
FeCl30.00065g/L, MgSO40.5g/L, KH2PO40.5g/L, (NH4)2SO40.65g/L, 1 μ l/ml of ammonia benzyl antibiotic；
PH to 7.2-7.4.
Further, the condition of the fermented and cultured is concretely：28 DEG C, 120r/min shaken cultivations 34 days.
Further, the method further includes the steps that the separation bacterium solution from the fermentation system that the fermented and cultured obtains.
Specifically filter paper can be used detaches bacterium solution from the fermentation system that the fermented and cultured obtains.The filter paper is concretely：Qualitative filter
Paper (102) middling speed.
Further, the method further includes the steps that being extracted to the bacterium solution using organic solvent.It is described organic
Solvent concretely ethyl acetate and dichloromethane.
Further, being extracted to the bacterium solution using ethyl acetate and dichloromethane can be according to including the following steps
Method carry out：The bacterium solution is extracted using ethyl acetate；Gained ethyl acetate phase is evaporated under reduced pressure, medicinal extract is obtained；
Gained medicinal extract is extracted with dichloromethane, is evaporated under reduced pressure, obtains dichloromethane phase medicinal extract.
Wherein, described " ethyl acetate is used to extract the bacterium solution " can for using ethyl acetate to the bacterium solution into
The row repeatedly extraction (as three times)；The extract of single extraction is the water phase obtained by preceding single extraction afterwards.
More specifically, being extracted to the bacterium solution using ethyl acetate and dichloromethane can be according to including the following steps
Method carry out：
(1) bacterium solution is taken, is extracted with isometric ethyl acetate and (selects the separatory funnel of appropriate volume, successively
Isometric bacterium solution and ethyl acetate is added, fully vibrates), it is then stored at room temperature to ethyl acetate phase and aqueous phase separation, respectively
Collect water phase and ethyl acetate phase；
(2) water phase for taking step (1) to obtain is added isometric ethyl acetate and is extracted (fully oscillation), then room
Temperature is stood to ethyl acetate phase and aqueous phase separation, collects water phase and ethyl acetate phase respectively；
(3) water phase for taking step (2) to obtain is added isometric ethyl acetate and is extracted (fully oscillation), then room
Temperature is stood to ethyl acetate phase and aqueous phase separation, collects water phase and ethyl acetate phase respectively；
(4) by the ethyl acetate phase that ethyl acetate phase that step (1) obtains, step (2) obtain and the second that step (3) obtains
Acetoacetic ester mutually merges, and vacuum distillation obtains medicinal extract；
(5) extracting step (4) obtained medicinal extract with dichloromethane (can specifically wait for that dichloromethane fully penetrated is soaked
After cream, it is stored at room temperature 1 hour), vacuum distillation obtains the dichloromethane phase medicinal extract (also known as crude extract).
Further, the method further includes that the step of phenazocine is obtained from the dichloromethane phase medicinal extract (crude extract)
Suddenly.
Further, phenazocine is obtained from the dichloromethane phase medicinal extract can be according to the method included the following steps
It realizes：The dichloromethane phase medicinal extract (crude extract) is dissolved with dichloromethane, then with 0.45 μm of filtering with microporous membrane and is received
Collect filtrate, carry out gas chromatography-mass spectrography detection, collects the peak that retention time is 25.222min, that is, obtain phenazocine.
Wherein, carrying out the GC conditions used when gas chromatography-mass spectrography detection can be for：Bruker 320
Triple quadrupole bar gas chromatograph-mass spectrometer, the special capillary chromatographic columns of DB-5MS (the μ m 30m of 0.25mm × 0.25), carrier gas is high-pure helium
Gas (99.999%), volume flow are 1.0mL min-1；250 DEG C of injection port；1 μ L of sample size, Splitless injecting samples；Originate column temperature 50
DEG C, 5min is stopped, is warming up to 290 DEG C later with the rate of 10 DEG C/min, and stop 11min.
Carrying out the Mass Spectrometry Conditions used when gas chromatography-mass spectrography detection can be for：200 DEG C of EI source temperatures；Transmission
250 DEG C of line；Electron energy 70eV；Scanning of the mass spectrum range 45-800Da.
The Pseudogymnoascus pannorum BJZ13 are also claimed in the third aspect, the present invention.
The invention discloses a kind of new applications of Pseudogymnoascus pannorum BJZ13, i.e.,
It can obtain phenazocine after Pseudogymnoascus pannorum BJZ13 fermented and cultureds, easy to operate, of low cost,
It is with short production cycle, the application potential with industrial-scale production.The present invention provides for the development of resources of phenazocine class drug
New way.
Preservation explanation
It is recommended that Classification And Nomenclature：Pseudogymnoascus pannorum
Join the biomaterial (strain) of Ju：BJZ13
Preservation mechanism：China Committee for Culture Collection of Microorganisms's common micro-organisms center
Preservation mechanism is referred to as：CGMCC
Address：Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3
Preservation date：On March 8th, 2018
Collection is registered on the books number：CGMCC No.15389
Description of the drawings
Fig. 1 is GC-MS total ion current figures.
It Fig. 2 is retention time mass spectrogram when being 25.222min and is compared with NIST databases.
Specific implementation mode
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Quantitative test in following embodiment, is respectively provided with three repeated experiments, and results are averaged.
Filter paper：Hangzhou Special Paper Industry Co., Ltd., qualitative filter paper (102) middling speed, diameter 9-15cm are reduced as needed.
The acquisition and identification of embodiment 1, Pseudogymnoascus pannorum BJZ13
1, it pre-processes：The Sanyo moss plant that will be collected with sterile water【It is acquired within 8th in August in 2015.Place is located at north
The archipelago polar region Svalbard (Svalbard) Ny-Alesund area (78 ° 54 ' 01.242 " N, 12 ° 09 '
33.816″E)】In the impurity such as silt clean.
2, plant surface sterilizes：Aseptically clean Sanyo moss plant is shredded, 75% ethanol disinfection 1min, nothing
Bacterium water rinses 1min, rinses 5 times.
3, fungal component is cultivated：Aseptically, the bryophyte Jing Guo surface sterilization is uniformly layered on culture medium.15
It is cultivated 5-15 days under the conditions of DEG C.Medium component：Soluble starch 20g/L, FeCl30.00065g/L, MgSO40.5g/L,
KH2PO40.5g/L, (NH4)2SO40.65g/L, pH are to 7.2-7.4, agar 2%, and ammonia is added after 121 DEG C of 20min high pressure sterilizations
Benzyl antibiotic, 1 μ l/ml of final concentration.
4, the purifying of fungal component：In constant incubator after cultivating a couple of days, aseptically, the bacterium that gradually will newly grow
Body is chosen on new tablet, and bacterium colony is formed after a couple of days, and growing the time according to the difference and bacterium colony that fall form, color tentatively judges bacterium
Type is picked out different strain and is inoculated in respectively on new tablet, repeats above operation until isolating pure bacterium colony.
5, strain idenfication：Purified strain is inoculated on tablet, the limited public affairs of Beijing six directions Hua Da Gene science are sent to
Department carries out sequencing identification.18S sequencings are carried out to purified fungi, ITS sequence length is 570bp, sequence such as SEQ ID
Shown in No.1.The fungal strain and Pseudogymnoascus pannorum (Geomyces are obtained by sequence alignment
Pannorus) homology is 99%, therefore is Pseudogymnoascus pannorum BJZ13 to the strain number.
I.e. identified, BJZ13 bacterial strains are Pseudogymnoascus pannorum.Pseudogymnoascus
Pannorum BJZ13 are preserved on March 8th, 2018 in China Committee for Culture Collection of Microorganisms's common micro-organisms
(abbreviation CGMCC, address are the heart：Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3, Institute of Microorganism, Academia Sinica), preservation
Registration number is CGMCC No.15389.
Embodiment 2 prepares phenazocine using Pseudogymnoascus pannorum BJZ13
One, culture Pseudogymnoascus pannorum BJZ13
The group of fermentation medium becomes：Soluble starch 20g, FeCl30.00065g, MgSO40.5g, KH2PO4
0.5g, (NH4)2SO40.65g adds distilled water to be settled to 1000mL.The preparation method of the culture medium is concretely：It weighs solvable
Property starch 20g, be put into beaker be heated to solution clarification, be cooled to room temperature be added FeCl3、MgSO4、KH2PO4、(NH4)2SO4,
It adds water to and is slightly less than 1000ml, with 2mol/L NaOH tune pH to 7.2-7.4, moisturizing to 1000ml.By the 200ml Liquid Cultures
Base is loaded in 500ml triangular flasks, 121 DEG C, 20min, and it is standby to its final concentration of 1 μ l/ml that ammonia benzyl antibiotic is added after high pressure sterilization
With.
The single bacterium colony of Pseudogymnoascus pannorum BJZ13 is seeded to the above-mentioned fermentation mediums of 200ml, 28
DEG C, 120r/min shaken cultivations 34 days.
Two, crude extract is prepared
1, the fermentation system for taking step 1 to obtain, is detached using filter paper and collects bacterium solution.
2, the bacterium solution (about 200ml) that step 1 obtains is taken, is extracted with 200ml ethyl acetate, volume is selected to be leaked for the liquid separation of 1L
Bucket, sequentially adds bacterium solution and ethyl acetate, fully vibrates, is then stored at room temperature to ethyl acetate phase and aqueous phase separation, receives respectively
Collect water phase and ethyl acetate phase；
3, the water phase (about 200ml) that step 2 obtains is taken, 200ml ethyl acetate is added, fully vibrates, is then stored at room temperature
To ethyl acetate phase and aqueous phase separation, water phase and ethyl acetate phase are collected respectively；
4, the water phase (about 200ml) that step 3 obtains is taken, 200ml ethyl acetate is added, fully vibrates, is then stored at room temperature
To ethyl acetate phase and aqueous phase separation, water phase and ethyl acetate phase are collected respectively；
5, by the ethyl acetate phase that ethyl acetate phase that step 2 obtains, step 3 obtain and the ethyl acetate that step 4 obtains
Mutually merge, vacuum distillation obtains medicinal extract.
6, the obtained medicinal extract of step 5 is extracted with dichloromethane, after dichloromethane fully penetrated enters medicinal extract, room temperature
1 hour is stood, vacuum distillation obtains dichloromethane phase medicinal extract (also known as crude extract).
Three, GC-MS is analyzed
The 6 of step 2 obtained crude extract is taken, is dissolved with dichloromethane, then with 0.45 μm of filtering with microporous membrane and is collected
Filtrate, using the progress online identifications of GC-MS.
GC conditions：320 triple quadrupole bar gas chromatograph-mass spectrometers of Bruker, the special capillary chromatographic columns of DB-5MS
(0.25mm × 0.25um × 30m), carrier gas are high-purity helium (99.999%), and volume flow is 1.0mL min-1；Injection port 250
℃；1 μ L of sample size, Splitless injecting samples；50 DEG C of column temperature is originated, 5min is stopped, is warming up to 290 later with the rate of 10 DEG C/min
DEG C, and stop 11min.
Mass Spectrometry Conditions：200 DEG C of EI source temperatures；250 DEG C of transmission line；Electron energy 70eV；Scanning of the mass spectrum range 45-800Da.
GC-MS total ion current figures are shown in Fig. 1.
Mass spectrogram when retention time is 25.222min is compared with NIST databases sees Fig. 2.
The crude extract that the 6 of step 2 obtain isolates 20 peaks.The identification of the corresponding mass spectrogram of chromatographic peak passes through NIST numbers
It is qualitative according to the forward and reverse descriptor index method progress of library mass spectral database, it is accredited as phenazocine at the peak that retention time is 25.222min.
The structural formula of phenazocine is as follows：
<110>Beijing Normal University
<120>A kind of method and its bacterial strain preparing phenazocine by microbial fermentation
<130> GNCLN180735
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 570
<212> DNA
<213> Pseudogymnoascus pannorum
<400> 1
tttccgtagg gtgacctgcg gaaggatcat tacagtagtc gcccgggttg ccgcaaggcc 60
tcccgggtaa cctaccaccc tttgtttatt acactttgtt gctttggcaa gcctgccctc 120
gggctgctgg ctccggccgg cgagcgcttg ccagaggacc taaactctgt ttgtctatac 180
tgtctgagta ctatataata gttaaaactt tcaacaacgg atctcttggt tctggcatcg 240
atgaagaacg cagcgaaatg cgataagtaa tgtgaattgc agaattcagt gaatcatcga 300
atctttgaac gcacattgcg ccccctggta ttccgggggg catgcctgtc cgagcgtcat 360
tacaaccctc aagctcagct tggtgttggg ccccgccgcc ccggcgggcc ctaaagtcag 420
tggcggtgcc gtccggctcc gagcgtagta attcttctcg ctctggaggt ccggtcgtgt 480
gctcgccagc aacccccaat ttttttcagg ttgacctcgg atcaggtagg gatacccgct 540
gaacttaagc atatcaataa agcggaggaa 570
Claims (10)
- Applications of the 1.Pseudogymnoascus pannorum BJZ13 in preparing phenazocine；The Pseudogymnoascus pannorum BJZ13 are in China Committee for Culture Collection of Microorganisms's commonly micro- life The preservation registration number at object center is CGMCC No.15389.
- 2. a kind of method preparing phenazocine, includes the following steps：Fermented and cultured Pseudogymnoascus pannorum BJZ13 obtains phenazocine；The Pseudogymnoascus pannorum BJZ13 are in China Committee for Culture Collection of Microorganisms's commonly micro- life The preservation registration number at object center is CGMCC No.15389.
- 3. according to the method described in claim 2, it is characterized in that：The method further includes the hair obtained from the fermented and cultured The step of bacterium solution is detached in ferment system.
- 4. according to the method described in claim 3, it is characterized in that：The method further includes using organic solvent to the bacterium solution The step of extracting.
- 5. according to the method described in claim 4, it is characterized in that：The organic solvent is ethyl acetate and dichloromethane.
- 6. according to the method described in claim 5, it is characterized in that：The bacterium solution is carried out using ethyl acetate and dichloromethane Extraction is carried out according to the method included the following steps：The bacterium solution is extracted using ethyl acetate；By gained acetic acid Ethyl ester is mutually evaporated under reduced pressure, and obtains medicinal extract；Gained medicinal extract is extracted with dichloromethane, is evaporated under reduced pressure, obtains dichloromethane phase Medicinal extract.
- 7. according to the method described in claim 6, it is characterized in that：The bacterium solution is carried out using ethyl acetate and dichloromethane Extraction is carried out according to the method included the following steps：(1) bacterium solution is taken, is extracted with isometric ethyl acetate, collects water phase and ethyl acetate phase respectively；(2) water phase for taking step (1) to obtain is added isometric ethyl acetate and is extracted, and collects water phase and acetic acid second respectively Ester phase；(3) water phase for taking step (2) to obtain is added isometric ethyl acetate and is extracted, and collects water phase and acetic acid second respectively Ester phase；(4) by the ethyl acetate phase that ethyl acetate phase that step (1) obtains, step (2) obtain and the acetic acid second that step (3) obtains Ester mutually merges, and vacuum distillation obtains medicinal extract；(5) step (4) obtained medicinal extract is extracted with dichloromethane, is evaporated under reduced pressure, obtains the dichloromethane and mutually soak Cream.
- 8. the method described according to claim 6 or 7, it is characterised in that：The method further includes mutually being soaked from the dichloromethane The step of phenazocine is obtained in cream.
- 9. according to the method described in claim 8, it is characterized in that：Obtaining phenazocine from the dichloromethane phase medicinal extract is It is realized according to the method included the following steps：The dichloromethane phase medicinal extract is subjected to gas chromatography-mass spectrography detection, is received Integrate retention time as the peak of 25.222min, that is, obtains phenazocine.
- 10.Pseudogymnoascus pannorum BJZ13, it is commonly micro- in China Committee for Culture Collection of Microorganisms The preservation registration number of Bio-Centers is CGMCC No.15389.
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| CN110218744A (en) * | 2019-05-10 | 2019-09-10 | 北京师范大学 | A method of bent ground acid is prepared by microbial fermentation |
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| CN110218744B (en) * | 2019-05-10 | 2020-11-27 | 北京师范大学 | Method for preparing kojic acid by microbial fermentation |
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