CN105254751B - A kind of biologically active polypeptide WNIPMGLIV and its preparation and application - Google Patents
A kind of biologically active polypeptide WNIPMGLIV and its preparation and application Download PDFInfo
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- CN105254751B CN105254751B CN201510673343.9A CN201510673343A CN105254751B CN 105254751 B CN105254751 B CN 105254751B CN 201510673343 A CN201510673343 A CN 201510673343A CN 105254751 B CN105254751 B CN 105254751B
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- biologically active
- active polypeptide
- leu
- wnipmgliv
- ala
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- AOILQMZPNLUXCM-AVGNSLFASA-N Val-Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN AOILQMZPNLUXCM-AVGNSLFASA-N 0.000 description 1
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- WHNSHJJNWNSTSU-BZSNNMDCSA-N Val-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 WHNSHJJNWNSTSU-BZSNNMDCSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
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- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- 108010060802 alpha-casein (90-95) Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
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- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
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- 230000007423 decrease Effects 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
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- 238000005886 esterification reaction Methods 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010075431 glycyl-alanyl-phenylalanine Proteins 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 108010025306 histidylleucine Proteins 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 235000015141 kefir Nutrition 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010051673 leucyl-glycyl-phenylalanine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 108010044348 lysyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 235000020124 milk-based beverage Nutrition 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003399 opiate peptide Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000003024 peritoneal macrophage Anatomy 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
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- 108010079317 prolyl-tyrosine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000033458 reproduction Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 108010028629 tryptophyl-glutaminyl-tryptophyl-arginyl-methionyl-lysyl-lysyl-leucyl-glycine Proteins 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
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- 108010030651 valyl-glutamyl-prolyl-isoleucyl-prolyl-tyrosine Proteins 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
The present invention relates to albumen fields, and in particular to a kind of milk-derived biologically active polypeptide WNIPMGLIV from lactoferrin.The present invention is after extensive and in-depth study, it was found that biologically active polypeptide of the invention has antioxidation biology activity and promotes the activity of cellular immunity；Result of study shows that this milk-derived biologically active peptide of the invention has the function of potentially delaying senescence as small molecule substance.In addition, simulation digestion experiment is the result shows that this biologically active polypeptide of discovery still exists and stablizes under the conditions of common animal body is digested, it will not further be degraded, it can be directly absorbed and utilized by animal body and play its bioactive functions having, there is dairy products, health care product and the drug of anti-oxidation function, enhancing immune function and anti-aging to have a very important significance exploitation.
Description
Technical field
The present invention relates to albumen fields, and in particular to a kind of biologically active polypeptide WNIPMGLIV and its preparation and application.
Background technique
Since biologically active peptide is as sanatory bioactive ingredients, there is transmitting physiologic information, adjust physiology function
The effect of energy, for the dimension of the normal physiological activity of the systems such as the nerve of human body, digestion, reproduction, growth, movement, metabolism, circulation
It holds extremely important.They not only have the effects that antiviral, bacterium, anti-hypertension, norcholesterol, but also as immunomodulator
Have the function of to adjust immune response, antitumor etc.；Free radical, which can be removed, to be had effects that delay senescence, and is current international food
The function factor of boundary most popular research topic and great development prospect.Various active peptides are used frequently as functional food adding ingredient
It is produced in the practice of food, especially has been achieved with good result in the application aspect of milk beverage, food additives.Milk-derived is raw
The function of object active peptide and to consumer health influence just having attracted much attention.
In recent years, more and more scientific investigations showed that much living with various biological from the small peptides of bioprotein
Property, such as hormonal action, immunological regulation, antithrombotic, anti-hypertension, norcholesterol, antibacterial, antiviral, antitumaous effect.Meanwhile
Research finds that small peptide preferably can be absorbed and be utilized by human body, and amino acid can only be degraded to just by changing traditional protein
The viewpoint that can be absorbed and used.In numerous bioproteins various cow's milk proteins be very important biologically active polypeptide source it
One, they are decomposed by lactic acid bacteria and utilize, and a series of biochemical reactions have occurred, and protein is made to become polypeptide or free
Amino acid is finally digested or is directly entered by the absorption and transport of intestinal epithelial cell the blood circulation of human body,
Play its biological action.
Therefore, these bioactive micro peptides not only become the natural resources treasure-house and functional food work of screening drug
The primary raw material ingredient of industry.Currently, the preparation and its application and development of biologically active peptide have become the heat studied in world wide
Point.
Immune-active peptides are to obtain and prove that one kind biology of its physiological activity is living from cream for the first time after opioid peptides discovery
Property peptide.1981, Jolles et al. had found for the first time, using trypsin hydrolysis people lactoprotein, obtains one kind from hydrolysate and exempts from
Epidemic disease active peptide segment, amino acid sequence Val-Glu-Pro-Ile-Pro-Tyr, the small peptide are proved in vitro experiment can
Enhance phagocytosis of the Turnover of Mouse Peritoneal Macrophages to sheep erythrocyte, intravenous injection can then enhance mouse to pneumonia kirschner
The resistivity of bar infection.Elitsur et al. obtains Arg-Tyr-Leu-Gly-Tyr-Leu- through pepsin casein
Glu and Arg-Tyr-Leu-Gly-Tyr-Leu, research have shown that two small peptide not only has opioid activity, it may have immune to adjust
Section activity, can enhance lymphopoiesis, improve natural killer cells (NK) ability, promote the movement for biting neutrocyte.?
Few brightness et al. obtains biologically active polypeptide QEPVL and its catabolite QEPV using Lactobacillus helveticus fermentation skimmed milk, passes through
Antioxidation in vitro experiment, ion vitro immunization function promote experiment, and demonstrating polypeptide QEPV has preferable antioxidation biology activity
With the activity for promoting cellular immunity, on the one hand can the intracorporal free radical of removing machine, reduce injury of the free radical to human body；It is another
Aspect, biologically active polypeptide QEPVL and QEPV can also enhance immunity of organisms, the proliferation of enhancing lymphocyte, macrophage
Ability increases the macrophage nitric oxide amount of inducing, and promotees Factor of Macrophage.
Although being implied in cow's milk protein there are many biologically active peptide sequence, these bio-active peptide sequences only have
Competence exertion effect is released by certain means.There are two types of the main means for obtaining lactoprotein active peptide: hair
Ferment is obtained using microorganism (lactic acid bacteria) fermentation milk protein；Enzymatic hydrolysis, including the digestive enzyme from animal and from plant and
The protease of microorganism.
Result of study shows milk-derived biologically active peptide as small molecule substance, with its molecular weight it is low, active it is strong, use
Few unique advantage is measured, is more and more attracted people's attention.So they are used not only as functional food ingredient
In the manufacture of various functional foods, and have the function of to adjust immune response, antitumor etc. as immunomodulator；It can be clear
Except free radical has effects that delay senescence.In addition, most milk-derived biologically active peptides can resist the digestion of gastrointestinal tract, small
Enteral is absorbed by organisms in the form of complete, without being broken down into single amino acids, has absorption easy to digest, edible safety
It is high.Therefore the body that can be improved of milk-derived biologically active peptide resists the stimulation of extraneous undesirable element, reduces body disease incidence
Equal functional characteristics have attracted much attention, and are expected to become the non-medication object with removing free radical, reducing cancer probability and anti-aging
Matter raw material, has boundless application prospect in functional food and field of medicaments, will become from now on international food circle and
The most popular research topic of biopharmaceutical production industry, to improve level of human health, not falling ill and fall ill less in other words, delay to decline
Always, the extension service life plays an important role.
Summary of the invention
The purpose of the present invention is to provide a kind of isolated biologically active polypeptide WNIPMGLIV and its preparation and application.
To achieve the goals above and other related purposes, the present invention adopts the following technical scheme:
The first aspect of the present invention provides a kind of isolated biologically active polypeptide WNIPMGLIV comprising
(a) amino acid shown in Trp-Asn-Ile-Pro-Met-Gly-Leu-Ile-Val (SEQ ID NO:1) forms
Polypeptide；
(b) or in the amino acid sequence shown in SEQ ID NO:1 it is substituted, lacks or adds one or several amino acid
And there is the same active polypeptide as derived from (a).
Preferably, the source of the biologically active polypeptide is milk-derived.
Biologically active polypeptide WNIPMGLIV of the invention is milk-derived, is derive specifically from lactoferrin, and is newborn iron egg
The amino acid residue that white (SEQ ID NO:2) is the 467th~475.
The amino acid sequence of the lactoferrin is existing technology, and sequence is as shown in SEQ ID NO:2:
Ala Pro Arg Lys Asn Val Arg Trp Cys Thr Ile Ser Gln Pro Glu Trp Phe
Lys Cys Arg
Arg Trp Gln Trp Arg Met Lys Lys leu Gly Ala Pro Ser Ile Thr Cys Val
Arg Arg Ala
Phe Ala Leu Glu Cys Ile Arg Ala Ile Ala Glu Lys Lys Ala Asp Ala Val
Thr Leu Asp
Gly Gly Met Val Phe Glu Ala Gly Arg Asp Pro Tyr Lys Leu Arg Pro Val
Ala Ala
Glu Ile Tyr Gly Thr Lys Glu Ser Pro Gln Thr His Tyr Tyr Ala Val Ala
Val Val Lys
Lys Gly Ser Asn Phe Gln Leu Asp Gln Leu Gln Gly Arg Lys Ser Cys His
Thr Gly Leu
Gly Arg Ser Ala Gly Trp Ile Ile Pro Met Gly Ile Leu Arg Pro Tyr Leu
Ser Trp Thr
Glu Ser Leu Glu Pro Leu Gln Gly Ala Val Ala Lys Phe Phe Ser Ala Ser
Cys Val Pro
Cys Ile Asp Arg Gln Ala Tyr Pro Asn Leu Cys Gln Leu Cys Lys Gly Glu
Gly Glu Asn
Gln Cys Ala Cys Ser Ser Arg Glu Pro Tyr Phe Gly Tyr Ser Gly Ala Phe
Lys Cys Leu
Gln Asp Gly Ala Gly Asp Val Ala Phe Val Lys Glu Thr Thr Val Phe Glu
Asn Leu Pro
Glu Lys Ala Asp Arg Asp Gln Tyr Glu Leu Leu Cys Leu Asn Asn Ser Arg
Ala Pro Val
Asp Ala Phe Lys Glu Cys His Leu Ala Gln Val Pro Ser His Ala Val Val
Ala Arg Ser
Val Asp Gly Lys Glu Asp Leu Ile Trp Lys Leu Leu Ser Lys Ala Gln Glu
Lys Phe Gly
Lys Asn Lys Ser Arg Ser Phe Gln Leu Phe Gly Ser Pro Pro Gly Gln Arg
Asp Leu Leu
Phe Lys Asp Ser Ala Leu Gly Phe Leu Arg Ile Pro Ser Lys Val Asp Ser
Ala Leu Tyr
Leu Gly Ser Arg Tyr Leu Thr Thr Leu Lys Asn Leu Arg Glu Thr Ala Glu
Glu Val Lys
Ala Arg Tyr Thr Arg Val Val Trp Cys Ala Val Gly Pro Glu Glu Gln Lys
Lys Cys Gln
Gln Trp Ser Gln Gln Ser Gly Gln Asn Val Thr Cys Ala Thr Ala Ser Thr
Thr Asp Asp
Cys Ile Val Leu Val Leu Lys Gly Glu Ala Asp Ala Leu Asn Leu Asp Gly
Gly Tyr Ile
Tyr Thr Ala Gly Lys Cys Gly Leu Val pro Val Leu Ala Glu Asn Arg Lys
Ser Ser Lys
His Ser Ser Leu Asp Cys Val Leu Arg Pro Thr Glu Gly Tyr Leu Ala Val
Ala Val Val
Lys Lys Ala Asn Glu Gly Leu Thr Trp Asn Ser Leu Lys Asp Lys Lys Ser
Cys His Thr
Ala Val Asp Arg Thr Ala Gly Trp Asn Ile Pro Met Gly Leu Ile Val Asn
Gln Thr Gly
Ser Cys Ala Phe Asp Glu Phe Phe Ser Gln Ser Cys Ala Pro Gly Ala Asp
pro Lys Ser
Arg Leu Cys Ala Leu Cys Ala Gly Asp Asp Gln Gly Leu Asp Lys Cys Val
pro Asn Ser
Lys Glu Lys Tyr Tyr Gly Try Thr Gly Ala Phe Arg Cys Leu Ala Glu Asp
Val Gly Asp
Val Ala Phe Val Lys Asn Asp Thr Val Trp Glu Asn Thr Asn Gly Glu Ser
Thr Ala Asp
Trp Ala Lys Asn Leu Asn Arg Glu Asp Phe Arg Leu Leu Cys Leu Asp Gly
Thr Arg Lys
Pro Val Thr Glu Ala Gln Ser Cys His Leu Ala Val Ala Pro Asn His Ala
Val Val Ser
Arg Ser Asp Arg Ala Ala His Val Lys Gln Val Leu Leu His Gln Gln Ala
Leu Phe Gly
Lys Asn Gly Lys Asn Cys Pro Asp Lys Phe Cys Leu Phe Lys Ser Glu Thr
Lys Asn Leu
Leu Phe Asn Asp Asn Thr Glu Cys Leu Ala Lys Leu Gly Gly Arg Pro Thr
Tyr Glu Glu
Tyr Leu Gly Thr Glu Tyr Val Thr Ala Ile Ala Asn Leu Lys Lys Cys Ser
Thr Ser Pro
Leu Leu Glu Ala Cys Ala Phe Leu Thr Arg。
Preferably, the biologically active polypeptide WNIPMGLIV has antioxidation activity in vitro and enhances immunity of organisms
Function.
Biologically active polypeptide WNIPMGLIV of the invention can manually be closed by the method and chemical method of genetic engineering
At, can also from dairy products by isolate and purify, enzyme degradation method obtain.
The invention also discloses the nucleotide fragments of coding aforementioned biological active peptides WNIPMGLIV.
The amino acid sequence and nucleotides sequence of lactoferrin are classified as existing technology, coding lactoferrin (SEQ ID NO:
2) the biologically active polypeptide WNIPMGLIV of the nucleotide fragments energy encoding mature of the 467th~475 amino acid residue.
Second aspect of the present invention provides the preparation method of aforementioned biological active peptides, includes the following steps:
1) it ferments: Lactobacillus helveticus being added in skimmed milk and carries out anaerobic fermentation, obtain Lactobacillus helveticus acidified milk；
2) broken wall: ultrasound is carried out to the thallus obtained after acidified milk centrifugation, broken bacterium wall keeps peptide intracellular free, obtains bacterium peptide
Mixed liquor；
3) the thick of polypeptide mentions: the carry out low-temperature centrifugation separation to the bacterium peptide mixed liquor in step 2) takes supernatant；
4) purifying of polypeptide:
A. hyperfiltration treatment is carried out to the supernatant of step 3), collects filtrate；
B. Solid Phase Extraction post separation: the filtrate of collection uses Waters Sep-pak C18 Solid Phase Extraction column extracting, collects
Biologically active polypeptide mixture；
5) digestion and stability of polypeptide: use two step enzymatic isolation method enzymolysis steps 4) biologically active polypeptide mixture, obtain
Biologically active polypeptide mixture after must being digested；Enzyme used by the first step digests is pepsin, and second step enzymatic hydrolysis is adopted
Enzyme is pancreatin.
Skimmed milk of the present invention is the cow's milk by ungrease treatment, and fat content is less than 0.1% in usual skimmed milk.
Preferably, in step 1), Lactobacillus helveticus be Lactobacillus helveticus (Lactobacillus helveticus,
CICC6024)。
Preferably, in step 1), the condition of the anaerobic fermentation are as follows: 36~38 DEG C of fermentation temperature, 6~8h of fermented and cultured；
More preferable 37 DEG C of fermentation temperature, fermented and cultured 7h.
Preferably, the condition of the step 2) centrifugation is 20 DEG C, 4000~5000rpm, is centrifuged 15min..
Preferably, step 2) the broken wall condition is cell concentration 0.0238g/ml, is crushed power 300W, is crushed total time
26min。
Preferably, in step 3), the condition of the low-temperature centrifugation are as follows: 4 DEG C, 8000~10000rpm, centrifugation 15~
30min。
It preferably, is the super filter tube that molecular cut off is respectively 3kDa in step 4) a, used by the hyperfiltration treatment.
More preferably, in step 4) a, in the process of ultrafiltration treatment, revolving speed 4800r/min, time 30min, centrifugation
Temperature is 4 DEG C.
Preferably, in step 4) b, Solid Phase Extraction post separation, method particularly includes: activation and balance Waters Sep-pak
C18 solid-phase extraction column；The filtrate collected in step 4) a is diluted rear loading, using elution, is collected obtained
Eluent includes biologically active polypeptide mixture.
Preferably, in step 4) b, in solid-phase extraction column partition method, used eluent is methanol and ddH2The mixing of O
Liquid, the methanol and ddH2Methanol and ddH in the mixed liquor of O2The volume ratio of O is 80:20, the methanol and ddH2The mixing of O
Contain the formic acid of 0.1% (v/v) in liquid.
Preferably, solid using methanol activation Waters Sep-pak C18 in solid-phase extraction column partition method in step 4) b
Phase extraction column；It is preferred that 2ml methanol.
Preferably, in step 4) b, in solid-phase extraction column partition method, using ddH2It is solid that O balances Waters Sep-pak C18
Phase extraction column；It is preferred that 1mlddH2O。
Preferably, in step 4) b, in solid-phase extraction column partition method, the ultrafiltrate loading that will be collected in step 4) a is used
400ul elution.
Preferably, in step 4) b solid-phase extraction column partition method, Waters Sep-pak C18 is first activated using 2mL methanol
Solid-phase extraction column, using 1mLddH2O balances Waters Sep-pak C18 solid-phase extraction column；Loading sample is 2mL；By step
4) ultrafiltrate loading is collected in a, using 400 μ L elutions.
Preferably, the specific steps are the mixture containing polypeptide for obtaining step 4) is molten for step 5) the two steps enzymatic isolation method
In sterile deionized water, adjusting pH value is 2.0 ± 0.1, adds pepsin, reaction solution is obtained, in 37 ± 0.5 DEG C of perseverance
Insulation reaction 90min in tepidarium obtains first step enzymolysis liquid；The pH value of first step enzymolysis liquid is adjusted to 7.5 ± 0.1, and
Pancreatin is added, the insulation reaction 150min in 37 ± 0.5 DEG C of water bath with thermostatic control obtains second step enzymolysis liquid；Second step is digested
Liquid inactivates enzyme using Boiling bath method, time 5min, obtains enzymolysis product；Powdery enzymolysis product is obtained using freeze-drying.
It is furthermore preferred that the Boiling bath method is 95 DEG C of immersion methods.
Preferably, the additive amount of the step 5) pepsin is 10~30mg/g of pepsin substrate；The pancreatin
Additive amount is 30~50mg/g of pancreatin substrate.
More preferably, the additive amount of the step 5) pepsin is pepsin 20mg/g substrate；The addition of the pancreatin
Amount is pancreatin 40mg/g substrate.
Preferably, the eluting peak for the polypeptide that molecular weight is 1043.58Da, as biologically active polypeptide WNIPMGLIV are extracted.
In the present invention, it is known that the molecular weight of WNIPMGLIV extracts the eluting peak that molecular size is 1043.58Da, as
Biologically active polypeptide WNIPMGLIV of the invention.Specifically, WNIPMGLIV molecular size of the present invention is the elution of 1043.58Da
Its retention time of peak is 19.73min.
Third aspect present invention, provide aforementioned biological active peptides WNIPMGLIV or derivatives thereof prepare it is anti-oxidant
And/or the application in the enhancing food of immunity of organisms, health care product and drug.
Biologically active polypeptide WNIPMGLIV of the invention or derivatives thereof can be used for the dairy products such as Yoghourt and various foods
Product reduce free radical to the cosmetics of skin damage；And since biologically active polypeptide WNIPMGLIV of the invention can lead to
It crosses gastrointestinal tract and directly absorbs and be not degraded, therefore can be used for preparing the health care product for improving immunity, or be used to prepare and have
Anti-oxidant and/or enhancing immunity of organisms drug.
Fourth aspect present invention provides a kind of anti-oxidation medicine, includes aforementioned biological active peptides WNIPMGLIV or preceding
State the derivative of biologically active polypeptide.
Fifth aspect present invention provides a kind of enhancing immunity of organisms drug, includes aforementioned biological active peptides
The derivative of WNIPMGLIV or aforementioned biological active peptides.
The derivative of the polypeptide refers on the amino acid side groups of polypeptide, aminoterminal or c-terminus carry out hydroxyl
The modification such as change, carboxylated, carbonylation, methylation, acetylation, phosphorylation, esterification or glycosylation, obtained polypeptide derivative.
Compared with prior art, biologically active polypeptide of the present invention has the beneficial effect that
Milk-derived biologically active polypeptide WNIPMGLIV of the invention has good antioxidant activity and promotes immunity of organism
Power activity；On the one hand can the intracorporal free radical of removing machine, reduce injury of the free radical to human body；On the other hand, of the invention
Biologically active polypeptide can also enhance immunity of organisms, enhance the phagocytic function of macrophage, improve body and resist extraneous cause of disease
The ability of body-sensing dye reduces body disease incidence, and can directly absorb by pipe intestinal digesting simulated experiment and not be degraded, enters
It will not cause the immunological rejection of body in vivo.In addition, simulation digestion experiment is the result shows that this bioactivity of discovery is more
Peptide is stablized under the conditions of common animal body is digested, will not further be degraded, can be directly absorbed and utilized by animal body
Its bioactive functions having is played, there is anti-oxidation function, enhancing immune function, the food of anti-aging, guarantor to exploitation
Strong product and drug has a very important significance and application value.
Detailed description of the invention
Fig. 1: the elution map of thallus peptide digestion product intracellular in Lactobacillus helveticus acidified milk
Fig. 2: mass chromatography extracts figure (m/z=1043.58)
Fig. 3: the first mass spectrometric figure for the segment that mass-to-charge ratio is 1043.58
Fig. 4: the second order ms figure for the segment 1 that mass-to-charge ratio is 1043.58
Fig. 5: mass-to-charge ratio is the az for the sequence that 1043.58 predictions obtain, by crack conditions (WNIPMGLIV)
Fig. 6: Trolox standard curve
Specific embodiment
Before further describing the specific embodiments of the present invention, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, rather than limiting the scope of protection of the present invention.
When embodiment provides numberical range, it should be appreciated that except non-present invention is otherwise noted, two ends of each numberical range
Any one numerical value can be selected between point and two endpoints.Unless otherwise defined, the present invention used in all technologies and
Scientific term is identical as the normally understood meaning of those skilled in the art of the present technique.Except specific method, equipment used in embodiment,
Outside material, grasp and record of the invention according to those skilled in the art to the prior art can also be used and this
Any method, equipment and the material of the similar or equivalent prior art of method described in inventive embodiments, equipment, material come real
The existing present invention.
Unless otherwise stated, disclosed in this invention experimental method, detection method, preparation method be all made of this technology neck
Molecular biology, biochemistry, chromatin Structure and the analysis of domain routine, analytical chemistry, cell culture, recombinant DNA technology and
The routine techniques of related fields.These technologies have perfect explanation in the prior art, and for details, reference can be made to Sambrook etc.
MOLECULAR CLONING:A LABORATORY MANUAL, Second edition, Cold Spring Harbor
Laboratory Press, 1989and Third edition, 2001；Ausubel etc., CURRENT PROTOCOLS IN
MOLECULAR BIOLOGY, John Wiley&Sons, New York, 1987and periodic updates；the
Series METHODS IN ENZYMOLOGY, Academic Press, San Diego；Wolffe, CHROMATIN
STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998；METHODS IN
ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic
Press, San Diego, 1999；With METHODS IN MOLECULAR BIOLOGY, Vol.119, Chromatin
Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999 etc..
The discovery of 1 active peptide WNIPMGLIV of embodiment
One, the preparation of Lactobacillus helveticus acidified milk
Using the skimmed milk (degreasing of 12wt% of skimmed milk power (New Zealand NZMP board skimmed milk power) and water configuration 12wt%
Cream is prepared as 12g skimmed milk power being added in 88g water, similarly hereinafter).Then, by the strain (Lactobacillus of purchase
Helveticus, CICC6024) it activates and is cultivated in the sterilized non-fat cream for being inoculated into 12% (W/V) with 2% amount, temperature 37
DEG C, incubation time 7h completes the activation of Lactobacillus helveticus, continuous activation 2 times is made acidified milk, sends out as Lactobacillus helveticus
Kefir milk leavening is spare.
The Lactobacillus helveticus leavening for taking 10mL to prepare is inoculated into the sterilized 12wt% skimmed milk of 500mL (inoculation
Rate is 2v/v%), after 37 DEG C ferment 7 hours, after stirring out curdled milk, is saved under the conditions of 4 DEG C, obtain Lactobacillus helveticus acidified milk.
Two, the obtained and confirmation of biologically active polypeptide mixture
1. experimental method
1) sample treatment
Lactobacillus helveticus acidified milk prepared by previous step is fitted into centrifuge tube and carries out centrifugation collection thallus, centrifugal condition
For 4000rpm/min, 20 DEG C, 15min.Supernatant, taking precipitate, as required Lactobacillus helveticus thallus are abandoned after centrifugation.
By thallus obtained with 4000,4500,5000rpm/min, 20 DEG C, the centrifugal condition of 15min carries out terraced three times
Centrifuge washing is spent, supernatant, taking precipitate are abandoned after centrifugation.
Deionized water is added to be made into the phage solution that concentration is 0.0238g/ml the thallus after washing, the rear ultrasonic wave that carries out is broken
Wall, ultrasound condition are broken power 300W, are crushed total time 26min (ultrasonic 3s is spaced 5s).
Bacterium peptide mixed liquor after ultrasound is subjected to low-temperature centrifugation, centrifugal condition 9000rpm/min, 4 DEG C, 20min.Centrifugation
Precipitating is abandoned afterwards, takes supernatant.
Supernatant is poured into super filter tube respectively, the molecular cut off of filter membrane is 3kDa, and in ultra-filtration process, revolving speed is
4800r/min, time 30min, centrifuging temperature are 4 DEG C.The filtrate for collecting Lactobacillus helveticus acidified milk is protected in -4 DEG C of freezings
It deposits.
Ultrafiltrate is subjected to Solid Phase Extraction, with 1mL C18 pillar, 2mL methanol activates pillar, 1mLddH2O balances pillar,
Loading sample is the ultrafiltrate of 2mL, and last 400 μ L elution, wherein eluent is 80:20v/v methanol/water and 0.1%
The formic acid of v/v.
Be lyophilized into dry powder after obtained elution liquid nitrogen is blown, it is rear to simulate pipe intestinal digesting experiment: firstly, using sterilizing go from
Sub- water dissolves dry powder, is added in the solution pepsin (being purchased from Sigma company), and ratio is that pepsin is added in every gram of sample
20mg adjusts the pH value of reaction solution to 2.0, keeps the temperature 90min in 37 DEG C of waters bath with thermostatic control；Then by the pH value of reaction solution adjust to
7.5, pancreatin (Corolase PP is purchased from AB company of Germany) is added, ratio is that pancreatin 40mg is added in every gram of sample, in 37 DEG C of perseverances
150min is kept the temperature in tepidarium；Finally being placed in heating 5min in 95 DEG C of water-baths inactivates enzyme, reaction solution freeze concentration is dry, system
At dry powder, it is stored under the conditions of -20 DEG C, it is spare.
2) liquid matter is analyzed
Liquid phase chromatogram condition:
Instrument: Waters ACQUITY UPLC Ultra Performance Liquid Chromatography instrument
Chromatographic column specification: CSH C18 chromatographic column
Flow velocity: 0.4mL/min
Temperature: 45 DEG C
Ultraviolet detection wavelength: 220nm
Sample volume: 5 μ L
Mobile phase A liquid: ddH2O
Mobile phase B liquid: acetonitrile solution
Gradient condition: 0min-2.5min keeps 99%A liquid, 1%B liquid；2.5min-5minB liquid becomes 5%, A liquid from 1%
Become 95% from 99%；5min-10minB liquid, which becomes 10%, A liquid from 5%, becomes 90% from 95%；10min-17min%B liquid
Becoming 25%, A liquid from 10% becomes 75% from 90%；17min-22min, B liquid become 40%, A liquid from 25% to be become from 75%
60%；22min-27min, B liquid, which become 80%, A liquid from 40%, becomes 20% from 60%；27min-29min, B liquid become from 80%
It is 0% for 100%, A liquid, keeps 2min；31min-31.5min, B liquid, which become 5%, A liquid from 100%, becomes 95% from 0%；
31.5min-32min, B liquid, which become 1%, A liquid from 5%, becomes 99% from 95%；32min-34min keeps 99%A liquid, 1%B
Liquid.
Mass Spectrometry Conditions:
Ionic means: ES+
Mass range (m/z): 50-2000
Capillary voltage (Capillary) (kV): 3.0
Sampling spiroid (V): 35.0
Ion source temperature (DEG C)): 105
It goes solvent temperature (DEG C): 350
Taper hole throughput (L/Hr): 50.0
It goes solvent stream (L/hr): 600.0
Collision energy (eV): 6.0
Impinging air flows (ml/min): 0.6
Sweep time (sec): 0.26
Interior sweep time (sec): 0.02
According to above-mentioned experiment condition, is analyzed, obtained in Lactobacillus helveticus acidified milk digestion product using Masslynx software
Peptide material retention time and molecular weight extract figure, one with the mass chromatography that Masslynx software extracts polypeptide as shown in table 1
Grade mass spectrogram, is shown in Fig. 2 and Fig. 3.
Polypeptide nucleocytoplasmic ratio in 1 Lactobacillus helveticus acidified milk digestion product of table
Three, the amino acid sequence of biologically active polypeptide determines method
1. experimental method
(1) foundation in cow's milk source lactoferrin amino acid sequence library
Lactoferrin amino acid sequence is searched for obtain by BIOPEP, and the milk protein amino acid sequence that search obtains is built
At a database.
2) peptide masses is right
To the quality that UPLC-MS is analyzed, is scanned in milk seralbumin amino acid sequence library, obtain phase
The polypeptide sequence of pass.The step realizes that specific requirement is as follows: input is by UPLC-MS by JAVA program and MySQL database
Obtained quality, export polypeptide sequence of the quality error in ± 0.01, the quality of the sequence, the sequence specific albumen come
Source.
3) verifying of polypeptide sequence
By obtained amino acid sequence by the Biolynx verifying in Masslynx software, prediction is obtained into polypeptide sequence
The practical second order ms figure that theoretic second order ms figure and MS/MS are obtained compares, and software passes through main in second order ms figure
Whether peak provides score value to success, to confirm polypeptide that prediction obtains.The sequence that second order ms obtain figure and prediction
Az, by crack conditions figure are shown in Fig. 4 and Fig. 5.
2. experimental result
Obtaining biologically active polypeptide WNIPMGLIV by verifying is milk-derived, is derive specifically from cow's milk lactoferrin, for cream
The amino acid residue that ferritin is 467-475 is denoted as SEQ ID NO:1.
In addition, the biologically active polypeptide WNIPMGLIV is to simulate digestion degradation through gastrointestinal tract to obtain, it is not to deposit originally
It is in Lactobacillus helveticus acidified milk.It can exist after the effect of digestive ferment, illustrate that polypeptide has stability, through gastrointestinal tract mould
It is not easy to be degraded after quasi- digestion trial.
The antioxidant activity of 2 biologically active peptide of embodiment is tested
Using removing free radical method (DPPH method) and total antioxidant capacity method (ABTS method), the life that embodiment 1 is obtained
The antioxidant activity of object active peptides is tested.
1, the antioxidation activity in vitro of [DPPH] method measurement biologically active peptide
1) experiment reagent and instrument
Reagent: 1,1- diphenyl -2- trinitrophenyl-hydrazine (1,1-Diphenyl-2-picrylhydrazyl [DPPH]),
Japanese Wako company production；Methanol, Shanghai traditional Chinese medicines company provide；Milk-derived biologically active polypeptide obtained in synthetic example 1.
Key instrument: Pro200 microplate reader, Austrian Tecan Products；96 porocyte culture plates, the U.S.
The manufacture of Millipore company；Assay balance, Meitelei-tolido Products.
2) experimental method
(1) 0.1mmol/L [DPPH] methanol solution
It weighs 19.72mg [DPPH] with assay balance to be dissolved in 500mL methanol solution, the 0.1mmol/L prepared
[DPPH] methanol solution, tinfoil are kept in dark place, i.e., with i.e. use.
(2) antioxidant activity of [DPPH] method measurement biologically active peptide
500 μ L concentration are added in 1.5mL EP pipe to be separately added into for 0.1mmol/L [DPPH] methanol solution, by table 2
The sample to be tested and deionized water of 500 μ L various concentrations are as blank control.
After sample to be tested is loaded, it is uniformly mixed, takes 200 microlitres into 96 orifice plates after being stored at room temperature 30min, use enzyme
Mark instrument detects light absorption value at 517nm.Free radical scavenging activity is calculated according to the following formula, and experimental result is shown in Table 2.
Formula: [DPPH] free radical scavenging activity=(A0-As)/A0× 100%
Wherein A0Indicate the light absorption value of blank control group, AsIndicate the light absorption value of sample sets.
The total antioxidant capacity result of 2 DPPH method of table measurement biologically active polypeptide
The external total antioxidant activity of biologically active polypeptide WNIPMGLIV is determined by [DPPH] method, is found
It is with Scavenging ability, specific IC50(mg/mL)Value is shown in Table 2.Invention can be assert according to the standard of relative antioxidant ability
Biologically active polypeptide WNIPMGLIV has preferable oxidation resistance.
2, the antioxidation activity in vitro of ABTS method measurement biologically active peptide
1) experiment reagent and instrument
Reagent: antioxidative activities kit (ABTS method), green skies company production；Methanol, Shanghai traditional Chinese medicines company provide；It closes
At milk-derived biologically active polypeptide obtained in embodiment 1.
Key instrument: Pro200 microplate reader, Austrian Tecan Products；96 porocyte culture plates, the U.S.
The manufacture of Millipore company.
2) experimental method
(1) configuration of ABTS working solution
It takes 40 microlitres of ABTS solution and 40 microlitres of oxidizing agent solutions to be configured to ABTS working stocks, storage is protected from light after preparation
It is used after 12-16 hours, the ABTS working stocks prepared are protected from light storage at room temperature, stablize in 2-3 days.Before use, ABTS
Working stocks are diluted to ABTS working solution with PBS, and about 40 times, it is desirable that it is empty that the absorbance of ABTS working solution subtracts corresponding PBS
After white control, A734 is 0.7 ± 0.05.
(2) production of Trolox standard curve
With sample preparation solution dilution standard product, 10mM Trolox standard solution is diluted to 0.005,0.01,0.03,
0.05,0.1,0.25,0.5 and 1.0mM.200 microlitres of ABTS working solutions, standard curve are added in each detection hole of 96 orifice plates
The Trolox standard solution of 10 microlitres of various concentration is added in detection hole, mixes gently.After incubation at room temperature 4 minutes, microplate reader is used
Light absorption value is measured at 734nm.
Trolox concentration and light absorption value are in good proportional relation, and concentration is higher, and light absorption value is lower.Trolox mark of the present invention
Directrix curve result is shown in Fig. 6, and the linear relationship of standard curve is good, related coefficient 0.9995, the precision of Trolox standard curve
Degree and accuracy meet testing requirements, can be used for subsequent calculating.
(3) antioxidant activity of ABTS method measurement biologically active peptide
200 microlitres of ABTS working solutions are added in each detection hole of 96 orifice plates, 10 microlitres of PBS are added in blank control wells
10 microlitres of various samples are added in sample detection hole, mix gently for solution.After incubation at room temperature 4 minutes, with microplate reader in 734nm
Place's measurement light absorption value.Measurement calculates the total antioxidant capacity of sample according to standard curve.Total antioxidant capacity representation with
The concentration of Trolox standard solution indicates.Total antioxidant capacity is calculated according to the following formula, and experimental result is shown in Table 3:
The total antioxidant capacity result of 3 ABTS method of table measurement biologically active polypeptide
The external total antioxidant activity of biologically active polypeptide WNIPMGLIV is carried out by total antioxidant capacity method (ABTS method)
Measurement, discovery biologically active polypeptide WNIPMGLIV have oxidation resistance: when peptide concentration is 1mg/mL, institute
Corresponding Trolox concentration is 0.9100mmol/L.Therefore, it is preferable can to assert that the biologically active polypeptide WNIPMGLIV of invention has
Oxidation resistance.
The above, only presently preferred embodiments of the present invention, above-described embodiment be only illustrated the principle of the present invention and
Its effect, and not to the present invention in any form with substantial limitation, it is noted that for the common skill of the art
Art personnel can also make several improvement and supplement under the premise of not departing from the method for the present invention, these are improved and supplement
Also it should be regarded as protection scope of the present invention.All those skilled in the art are not departing from the spirit and scope of the present invention
In the case of, when the equivalent variations for a little variation, modification and evolution made using disclosed above technology contents, it is
Equivalent embodiment of the invention；Meanwhile all substantial technologicals according to the present invention are to any equivalent variations made by above-described embodiment
Variation, modification and evolution, in the range of still falling within technical solution of the present invention.
Claims (4)
1. a kind of isolated biologically active polypeptide WNIPMGLIV, the polypeptide that the amino acid shown in SEQ ID NO:1 forms.
2. encoding the nucleotide fragments of biologically active polypeptide WNIPMGLIV described in claim 1.
3. biologically active polypeptide WNIPMGLIV described in claim 1 is preparing answering in oxidation resistant food, health care product and drug
With.
4. a kind of anti-oxidation medicine includes biologically active polypeptide WNIPMGLIV as described in claim 1.
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| CN103232528A (en) * | 2012-12-12 | 2013-08-07 | 上海交通大学 | Bioactive polypeptide DELQ and preparation method and application thereof |
| CN104479002A (en) * | 2014-12-19 | 2015-04-01 | 上海交通大学 | Preparation and applications of biological active peptides derived from beta-casein of cow milk |
| CN104479001A (en) * | 2014-12-19 | 2015-04-01 | 上海交通大学 | Preparation and application of kappa-casein derived bioactive peptides |
| CN104710524A (en) * | 2014-12-19 | 2015-06-17 | 上海交通大学 | Bovine alpha s2-casein source bioactive peptides preparation and application thereof |
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| WO2010106437A1 (en) * | 2009-03-20 | 2010-09-23 | The Governors Of The University Of Alberta | Peptides that inhibit angiotensin converting enzyme and peptides with antioxidant activity purified from ovotransferrin and methods of producing and using the same |
| CN103232528A (en) * | 2012-12-12 | 2013-08-07 | 上海交通大学 | Bioactive polypeptide DELQ and preparation method and application thereof |
| CN104479002A (en) * | 2014-12-19 | 2015-04-01 | 上海交通大学 | Preparation and applications of biological active peptides derived from beta-casein of cow milk |
| CN104479001A (en) * | 2014-12-19 | 2015-04-01 | 上海交通大学 | Preparation and application of kappa-casein derived bioactive peptides |
| CN104710524A (en) * | 2014-12-19 | 2015-06-17 | 上海交通大学 | Bovine alpha s2-casein source bioactive peptides preparation and application thereof |
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