CN109504690A - Participate in stress, signal and the transcriptional modulatory gene of regulation streptomycete ACT yield - Google Patents
Participate in stress, signal and the transcriptional modulatory gene of regulation streptomycete ACT yield Download PDFInfo
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
The application belongs to microbial fermentation engineering technical field, and in particular to gene relevant to polyketides actinorhodin (ACT) yield in streptomycete.The application is more particularly to stress, the application of signal and transcriptional modulatory gene in terms of streptomycete ACT yield regulation, the stress, signal and transcriptional modulatory gene totally 14；After such gene mutation, there is regulation to influence streptomycete ACT yield.Inventor has carried out mutagenesis to Streptomyces coelicolor M145, is screened to the bacterial strain of actinorhodin change of production.Digestion is passed through to the positive clone molecule filtered out, connects certainly and is sequenced and orient the position of transposons in the genome, and spontaneous mutation gene, the final determining gene for influencing actinorhodin yield are excluded with the principle of multiple screening positioning same gene.
Description
Technical field
The application belongs to microbial fermentation engineering technical field, and in particular to purple with polyketides unwrapping wire in streptomycete
The relevant gene of red pigment (ACT) yield.
Background technique
Existing research is it is believed that microbial secondary is metabolized generated small molecule compound to human health with important
Meaning.Statistics shows that the anti-infective and anti-tumor drug of current 60% or more FDA approval is produced from microbial secondary metabolism
Object.And with the progress of more and more microbial genome examining orders, genomic sequence analysis shows that microorganism has and generates
The great potential of various secondary metabolites, but part is studies have shown that many microbial secondary metabolism under the conditions of laboratory cultures
Product is beyond expression, and most environmental microorganisms can not be cultivated effectively in laboratory conditions, therefore serious resistance
The exploitation of microbial secondary metabolites is hindered.
In existing research, streptomycete is important antibiotics generated bacterium, and the generation of antibiotic is by environmental signal and itself
The control of controlling gene.Wherein streptomyces coelicolor is the type strain for studying Streptomyces differentiation and cometabolism, it can be generated
Two kinds of coloured antibiotic actinorhodins (ACT blue) and undecylprodigiosin (Red is red), and ACT and RED
Synzyme is belonging respectively to I type polyketide synthase (I-PKS) and II type polyketide synthase (II-PKS).This 2 kinds in streptomyces coelicolor
Secondary metabolite is by the model as research secondary metabolism of Streptomyces synthesis regulation, for this 2 kinds of secondary metabolite regulations
The screening of gene, can swashing for antibiotics generated bacterium genetic modification, the output increased of antibiotic industrial strain or cryptiogene cluster
Good basis is established in expression living.
In the prior art, functional genome of inventor's early utilization transposon mutagenesis technology to streptomyces coelicolor A3(2)
It is studied, and Primary Construction streptomyces coelicolor A (3) 2 mutant library (for details, reference can be made to: Xu Zhong utilizes transposon mutagenesis
Study streptomyces coelicolor A3(2) functional genome, Hua Zhong Agriculture University's Master's thesis in 2011), but due to dependency basis
Because of the complexity and uncertainty of regulatory function, therefore which specific gene is related to secondary metabolite adjusting that then it is still necessary into one
Step further investigation and discussion.
Summary of the invention
The application is designed to provide the resulting part of screening gene relevant to ACT metabolic regulation in microorganism, thus
It lays the foundation for secondary metabolism of Streptomyces Study on product and newtype drug exploitation.
The technical solution that the application is taken, which is discussed in detail, to be described as follows.
The gene of ACT yield is influenced in streptomycete, the gene has in the synthesis of streptomycete polyketides ACT
Regulating and controlling effect；The microorganism specifically for example streptomyces coelicolor (Streptomyces coelicolor)；The gene foundation
Its existing gene annotation, is divided into four major class, specifically:
Cell is synthesized regulation class:
Totally 7, including geneSCO1525、SCO2097、SCO2132、SCO3150、SCO4440、SCO4878、SCO5174；According to
According to existing gene annotation, specifically:
It is glycosylation modified that SCO1525 and SCO2132 participates in cell wall phosphatidylinositol manno；
SCO2097 participates in Cell wall synthesis；
SCO3150 participates in cell cracking；
SCO4440 participates in cell membrane phospholipid acyl inositol signals-modulating；
It is glycosylation modified that SCO4878 and SCO5174 participates in cell wall；
In the application, after such gene mutation after (gene delection or inactivation), ACT expression quantity (yield) decline, in other words, such
Gene has positive regulation effect for ACT expression quantity (yield)；That is, the genoid (gene delection or inactivation) after mutation
Afterwards, regulation ACT expression quantity (yield) decline, and after such gene copy number is increased or overexpressed, there is regulation ACT expression
Measure (yield) increased potential；
Amino acid metabolism class:
Totally 7；Including relevant to amino acid metabolismSCO2241、SCO2528、SCO3345、SCO5281、SCO5512、SCO2999、SCO3962；According to existing gene annotation, specifically:
SCO2241 participates in glutamic acid synthesis；
SCO2528 participates in leucine synthesis；
The synthesis of SCO3345 participation valine and isoleucine；
SCO5281 α-ketoglutaric acid decarboxylase；
SCO5512 participates in branched chain amino acid metabolism；
SCO2999 participates in glutamic acid metabolism,
SCO3962 participates in prephenic acid metabolism；
In the application, after such gene mutation after (gene delection or inactivation), there is uncertain adjust to ACT expression quantity (yield)
Control influences, furthermore:
SCO2241、SCO2528、SCO3345、SCO5281WithSCO5512(gene delection after the mutation of any of this 5 genes
Or inactivation) after, ACT expression quantity (yield) decline, in other words, this 5 genes have positive regulation effect；That is, this 5 bases
After mutation after (gene delection or inactivation), regulation ACT expression quantity (yield) declines any of cause, and copies by the genoid
After shellfish number increases or overexpresses, there is regulation ACT expression quantity (yield) increased potential；
SCO2999WithSCO3962After the mutation of any of this 2 genes after (gene delection or inactivation), ACT expression quantity (yield)
Rise, in other words, this 2 genes have negative regulation effect；That is, any of this 2 genes (gene delection after mutation
Or inactivation) after, regulation ACT expression quantity (yield) rises, and after such gene copy number is increased or even overexpressed, have and adjusts
A possibility that controlling ACT expression quantity (yield) decline；
Stress, signal and transcriptional control class:
Totally 14, including gene:SCO0871、SCO1663、SCO2832、SCO2987、SCO3571、SCO4204、SCO4215、SCO4358、SCO6994、SCO1728、SCO2686、SCO3008、SCO5220、SCO6636；
According to existing gene annotation, specifically:
SCO0871 participates in signals-modulating,
SCO1663, SCO4204 and SCO2987 participate in environment-stress regulation,
SCO2832、SCO3571、SCO4215、 SCO4358、 SCO6994、SCO1728、SCO2686、SCO3008、SCO5220
It is transcriptional regulation protein with SCO6636；
In the application, after such gene mutation after (gene delection or inactivation), there is uncertain adjust to ACT expression quantity (yield)
Control influences, furthermore:
SCO0871、SCO1663、SCO2832、SCO2987、SCO3571、SCO4204、SCO4215、SCO4358WithSCO6994
After the mutation of any of this 9 genes after (gene delection or inactivation), ACT expression quantity (yield) decline, in other words, this 9 bases
Because having positive regulation effect；That is, any of this 9 genes after (gene delection or inactivation), regulate and control ACT table after mutation
Decline up to amount (yield), and after such gene copy number is increased or overexpressed, there is regulation ACT expression quantity (yield) to increase
Potential；
SCO1728、SCO2686、SCO3008、SCO5220WithSCO6636(gene delection after the mutation of any of this 5 genes
Or inactivation) after, ACT expression quantity (yield) rises, and in other words, this 5 genes have negative regulation effect；That is, this 5 genes
Any of after mutation after (gene delection or inactivation), regulation ACT expression quantity (yield) rises, and returns by the genoid
It mends, after copy number increase or overexpression, there is a possibility that regulation ACT expression quantity (yield) decline；
Transport proteins:
Totally 6；Include:SCO2254、SCO2534、SCO3765、SCO6160、SCO2519、SCO3185；It is infused according to existing gene
It releases, specifically:
SCO2254 is transmembrane channel albumen；
SCO2534, SCO3765 and SCO3185 participate in ion transport；
SCO2519 participates in lipid transfer and antibiotic outlet；
SCO6160 participates in Protein transport；
In the application, after such gene mutation after (gene delection or inactivation), there is uncertain adjust to ACT expression quantity (yield)
Control influences, furthermore:
SCO2254、SCO2534、SCO3765WithSCO6160After the mutation of any of this 4 genes (gene delection or inactivation)
Afterwards, ACT expression quantity (yield) declines, and in other words, this 4 genes have positive regulation effect；That is, any in this 4 genes
It is a after (gene delection or inactivation), to regulate and control ACT expression quantity (yield) decline after mutation, and increase by such gene copy number
Or after overexpression, there is regulation ACT expression quantity (yield) increased potential；
SCO2519WithSCO3185After the mutation of any of this 2 genes after (gene delection or inactivation), ACT expression quantity (yield)
Rise, in other words, this 2 genes have negative regulation effect；That is, any of this 2 genes (gene delection after mutation
Or inactivation) after, regulation ACT expression quantity (yield) rises, and after by genoid covering, copy number increase or overexpression, tool
There is a possibility that regulation ACT expression quantity (yield) decline.
It is that regulation unwrapping wire purple is influenced in the excavation antibiotics generated bacterium type strain streptomyces coelicolor of system in the application
The serial genes of red pigment (ACT, Actinorhodin) yield, inventor use an internal transposon system based on mini-Tn5
Mutagenesis has been carried out to Streptomyces coelicolor M145, further the bacterial strain of actinorhodin change of production has been screened.Experiment
The result shows that: the carrier (pHL734) that the mutagenesis system uses does not contain streptomycete replicon and integration site, is turned by engagement
After moving up into streptomyces cell, a transposition event can only occur, so on each positive colony subgenom filtered out only
Mini-Tn5 copy containing a radom insertion.Digestion further is passed through to the positive clone molecule filtered out, connects certainly and is sequenced
The position of transposons in the genome is oriented, and spontaneous mutation gene is excluded with the principle of multiple screening positioning same gene,
It is final to determine the gene for influencing actinorhodin yield.It is final true by fermented and cultured further using wild-type strain as reference
Determine related gene and influence is caused on actinorhodin yield.And these the selection results are based on, further pass through genetic engineering skill
Art means can lay the foundation for the synthesis of associated metabolites Production adjustment or new secondary metabolite.
Specific embodiment
Explanation is further explained to the application below with reference to embodiment.Before introducing specific embodiment, with regard to following realities
It applies Experimental Background situation in part in example and briefly introduces and be described as follows.
Biomaterial:
Streptomyces coelicolor M145 (Streptomyces coelicolor M145) (former breeding wild type strains A 3 (2)), as
Transposon mutagenesis starting strain；
Escherichia coli ET12567/pUZ8002(Escherichia coliET12567/pUZ8002 it) is used for plasmid pHL734
Import Streptomyces coelicolor M145；
Plasmid pHL734 carries swivel base original part Mini-Tn5 and transposase, the transposon mutagenesis for Streptomyces coelicolor M145；
Experiment reagent:
LB culture medium is used for 37 DEG C of culture Escherichia coli；
YEME culture medium and TSBY culture medium are used for streptomycete Liquid Culture,
MgSO is added in SFM culture medium4The engagement of (20 mM) for streptomycete is shifted；
YBP culture medium is used for streptomycete solid culture and fermentation, and streptomycete cultivation temperature is 30 DEG C；
Apramycin (Apramycin, Apr), resistant geneAcc(3)IV, use 50 μ g/mL of concentration；
Metopycide (Trimethoprim, TMP) uses 50 μ g/mL of concentration.
Embodiment 1
The present embodiment mainly just briefly introduces such as the mutagenic processes of Streptomyces coelicolor M145 using mini-Tn5 transposon system
Under.It should be noted that non-procedure detailed, which can be found in, " utilizes the functional gene of transposon mutagenesis research streptomyces coelicolor A3(2)
Group " (Xu Zhong, Hua Zhong Agriculture University's Master's thesis in 2011).
(1) transposons carries out transposon mutagenesis to streptomyces coelicolor
Firstly, with reference to the prior art, by Transposon plasmid pHL734 by coli strain ET12567/pUZ8002 with it is sky blue
The engagement transfer of color streptomycete imports in streptomycete, and the ratio of recipient bacterium and donor bacterium is 1:1；
Theoretically, start to express into transposase Tnp (5) after streptomycete, mini-Tn5 segment cut, radom insertion to streptomycete
Genome on, since the plasmid can not replicate and integration site in streptomycete, plasmid disappears after swivel base generation；
12 ~ 14 hours or so after engagement transfer, (pass through the apramycin resistance base inside Mini-Tn5 with TMP and Apr covering
Because the muton of swivel base insertion occurs for screening), it cultivates 4 ~ 5 days or so；Obtained engagement transfer clone is transferred to YBP culture
On base (each muton contains a swivel base insertion), the mutant strain of secondary metabolites change of production is screened.
(2) swivel base of mutant strain is inserted into positioning
Respectively in extraction step (one) secondary metabolites change of production mutant strain total DNA, and with ApaI restriction enzyme
Digestion is carried out to total DNA；
DNA sample after digestion, which is passed through, to be connected, certainly in chemical conversion importing bacillus coli DH 5 alpha；
With clone of the apramycin screening containing mini-Tn5 segment, sequencing, mini-Tn5 and its swivel base insertion point are obtained
The genome sequence at both ends orients the position of swivel base insertion on chromosome by sequence alignment.
(3) mutant strain covers
Choose wherein 5 genes relevant to transcriptional controlSCO2832、SCO4215、SCO4358、SCO2686WithSCO3008Into
Row covering verifying,
The 250 bp promoter region sequence of CDS and its upstream of these genes of PCR amplification, is connected to streptomycete integration vector pMT3
On, after sequence verification is correct, Escherichia coli ET12567/pUZ8002 is converted, is shifted by the engagement of Escherichia coli and streptomycete
Into in streptomycete mutant strain；
After being directed respectively into corresponding normal gene copy in the mutant strain genome of this 5 genes, actinorhodin is produced
Amount is all restored to the level of wild type, illustrates the gene that these multiplicatings filter out, the regulation to actinorhodin yield
100% is correct.
(4) the ACT yield of mutant strain is measured
Transpositional mutation and starting strain respectively in solid YBP 30 DEG C cultivate 84 hours, each cultured products take 0.5 g to be used for
ACT determination of yield；ACT determination of yield:
The 1 M NaOH of 0.5 mL is added in 0.5 g cultured products, smashes (5,000 rpm, 15 s with homogenizer；Twice),
Centrifugation (12000 × g, 5 min) takes supernatant, and 633 nm ultraviolet lights measure the absorbance of supernatant, obtained according to absorbance ratio prominent
Become the fractional yield (Mutant633/WT633) of strains A CT.
Embodiment 2
The present embodiment is briefly introduced with regard to the related the selection result of embodiment 1 and is described as follows.
On the basis of the screening technique of embodiment 1,988 actinorhodins are as a result filtered out from 50000 mutons
The bacterial strain of change of production, these mutant strains of the swivel base insertion point locating and displaying of these bacterial strains are related to 551 genes；Its middle part
The gene specific explanations that there is regulation to influence actinorhodin yield are divided to be described as follows.
Cell is synthesized regulation class:
Totally 7, including geneSCO1525、SCO2097、SCO2132、SCO3150、SCO4440、SCO4878、SCO5174；
Note (following table data meaning is identical, no longer illustrates): ACT fractional yield indicates mutant strain and wild-type strain in table
ACT yield ratio illustrates the reduction of mutant strain ACT yield less than 1, and 0 indicates not detecting that ACT is generated, multiple values use ", " every
It opens, indicates multiple mutant strains of same gene, insertion point of the mini-Tn5 of these mutant strains on the gene is different.
It should be noted that in above table data, notes content according to StrepDB data (http: //
) and document report comprehensive income strepdb.streptomyces.org.uk；ACT fractional yield is average according to each mutant strain
Value calculates gained (following table data meaning is identical, no longer illustrates).
To the analysis of upper table data as can be seen that after 7 cells are synthesized relevant gene inactivation, actinorhodin yield
It reduces, illustrates that the integrality of cell quilt is the mutation (inactivation) of this genoid and actinorhodin necessary to the synthesis of ACT
Yield has positive correlation effect.
Amino acid metabolism class:
Totally 7；Including relevant to amino acid metabolismSCO2241、SCO2528、SCO3345、SCO5281、SCO5512、SCO2999、SCO3962；
。
Analysis it can be seen that
SCO2241、SCO2528、SCO3345、SCO5281WithSCO5512All mutant strain ACT yield of gene reduce,
Illustrate that these gene encoding productions are conducive to ACT synthesis,
AndSCO2999WithSCO3962All mutant strain ACT yield of gene all increase, and illustrate the coded product of these genes
It is unfavorable for ACT synthesis.
Stress, signal and transcriptional control class:
Totally 14, including geneSCO0871、SCO1663、SCO2832、SCO2987、SCO3571、SCO4204、 SCO4215、SCO4358、SCO6994、SCO1728、SCO2686、SCO3008、SCO5220、SCO6636；
。
Analysis it can be seen that
SCO0871、SCO1663、SCO2832、SCO2987、SCO3571、SCO4204、SCO4215、SCO4358WithSCO6994
All mutant strain ACT yield of gene reduce, and illustrate that the coded product of these genes is conducive to ACT synthesis；
SCO1728、SCO2686、SCO3008、SCO5220WithSCO6636All mutant strain ACT yield of gene increase,
Illustrate that the coded product of these genes is unfavorable for ACT synthesis.
Transport proteins:
Totally 6, including geneSCO2254、SCO2534、SCO3765、SCO6160、SCO2519、SCO3185；
。
Analysis it can be seen that
SCO2254、SCO2534、SCO3765WithSCO6160All mutant strain ACT yield of gene reduce, and illustrate these
The coded product of gene is conducive to ACT synthesis；
SCO2519WithSCO3185All mutant strain ACT yield of gene increase, and illustrate the coded product of these genes not
Conducive to ACT synthesis.
To sum up, ACT yield effect can respectively carry out one of them or several genes single based on above-mentioned different genes
Solely mutation or joint mutation make its inactivation, or are overexpressed using transgenic engineering, produce to targetedly adjust ACT
Amount, and then further improve the production performance of antibiotic.
Claims (3)
1. stress, the application of signal and transcriptional modulatory gene in terms of streptomycete ACT yield regulation, which is characterized in that the side of body
Compel, signal and transcriptional modulatory gene totally 14；Include: SCO0871, SCO1663, SCO2832, SCO2987, SCO3571,
SCO4204,SCO4215,SCO4358,SCO6994,SCO1728,SCO2686,SCO3008,SCO5220,SCO6636；
After such gene mutation, there is regulation to influence streptomycete ACT yield.
2. stress, the application of signal and transcriptional modulatory gene in terms of streptomycete ACT yield regulation as described in claim 1,
It being characterized in that, the regulation influences, specifically:
SCO0871, SCO1663, SCO2832, SCO2987, SCO3571, SCO4204, SCO4215, SCO4358 and SCO6994
After the mutation of any of this 9 genes, the decline of ACT yield, in other words, this 9 genes have positive regulation effect；And should
After genoid copy number increases or overexpresses, there is the regulation increased potential of ACT yield；
After after the mutation of any of this 5 genes of SCO1728, SCO2686, SCO3008, SCO5220 and SCO6636, ACT yield
Rise, in other words, this 5 genes have negative regulation effect；And this 5 gene covering, copy number are being increased or overexpressed
Afterwards, has the function of the decline of ACT yield.
3. stress, the application of signal and transcriptional modulatory gene in terms of streptomycete ACT yield regulation as described in claim 1,
It is characterized in that, the streptomycete is streptomyces coelicolor.
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Citations (4)
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|---|---|---|---|---|
| US20090221038A1 (en) * | 2005-12-20 | 2009-09-03 | Tracy Palmer | Twin-Arginine Translocation (TAT) Streptomyces Signal Sequences |
| US20110143394A1 (en) * | 2006-02-14 | 2011-06-16 | Universiteit Leiden | Methods and Means for Metabolic Engineering and Improved Product Formation by Micro-Organisms |
| CN102212533A (en) * | 2011-04-18 | 2011-10-12 | 河北农业大学 | Negative regulator gene of streptomyces roseofulvus as well as preparation method and application thereof |
| CN103881951A (en) * | 2014-03-26 | 2014-06-25 | 中国科学院微生物研究所 | SCO6974 gene deleted streptomyces coelicolor and application thereof to yield increment of antibiotics |
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2019
- 2019-01-16 CN CN201910040557.0A patent/CN109504690B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090221038A1 (en) * | 2005-12-20 | 2009-09-03 | Tracy Palmer | Twin-Arginine Translocation (TAT) Streptomyces Signal Sequences |
| US20110143394A1 (en) * | 2006-02-14 | 2011-06-16 | Universiteit Leiden | Methods and Means for Metabolic Engineering and Improved Product Formation by Micro-Organisms |
| CN102212533A (en) * | 2011-04-18 | 2011-10-12 | 河北农业大学 | Negative regulator gene of streptomyces roseofulvus as well as preparation method and application thereof |
| CN103881951A (en) * | 2014-03-26 | 2014-06-25 | 中国科学院微生物研究所 | SCO6974 gene deleted streptomyces coelicolor and application thereof to yield increment of antibiotics |
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| Title |
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| ZHONG XU ETAL.: "Genome-Wide Mutagenesis Links Multiple Metabolic Pathways with Actinorhodin Production in Streptomyces coelicolor", 《APPLIED AND ENVIRONMENTAL MICROBIOLOGY》 * |
| 芦银华 等: "链霉菌次级代谢调控相关的双组分系统研究进展", 《微生物学报》 * |
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