CN116059228A - Application of astilbin in preparation of jerusalem artichoke urease inhibitor - Google Patents
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- CN116059228A CN116059228A CN202310113619.2A CN202310113619A CN116059228A CN 116059228 A CN116059228 A CN 116059228A CN 202310113619 A CN202310113619 A CN 202310113619A CN 116059228 A CN116059228 A CN 116059228A
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- astilbin
- jerusalem artichoke
- urease
- urease inhibitor
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- ZROGCCBNZBKLEL-FHXNIQKESA-N Astilbin Natural products O([C@H]1[C@@H](c2cc(O)c(O)cc2)Oc2c(c(O)cc(O)c2)C1=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O1 ZROGCCBNZBKLEL-FHXNIQKESA-N 0.000 title claims abstract description 52
- ZROGCCBNZBKLEL-MPRHSVQHSA-N astilbin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1C(=O)C2=C(O)C=C(O)C=C2O[C@@H]1C1=CC=C(O)C(O)=C1 ZROGCCBNZBKLEL-MPRHSVQHSA-N 0.000 title claims abstract description 52
- 240000008892 Helianthus tuberosus Species 0.000 title claims abstract description 51
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- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
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- FPJQGFLUORYYPE-UHFFFAOYSA-N epiberberine Chemical compound C1=C2C=C(C3=C(C=C(C(=C3)OC)OC)CC3)[N+]3=CC2=C2OCOC2=C1 FPJQGFLUORYYPE-UHFFFAOYSA-N 0.000 description 1
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- C05—FERTILISERS; MANUFACTURE THEREOF
- C05G—MIXTURES OF FERTILISERS COVERED INDIVIDUALLY BY DIFFERENT SUBCLASSES OF CLASS C05; MIXTURES OF ONE OR MORE FERTILISERS WITH MATERIALS NOT HAVING A SPECIFIC FERTILISING ACTIVITY, e.g. PESTICIDES, SOIL-CONDITIONERS, WETTING AGENTS; FERTILISERS CHARACTERISED BY THEIR FORM
- C05G3/00—Mixtures of one or more fertilisers with additives not having a specially fertilising activity
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K10/00—Animal feeding-stuffs
- A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
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Abstract
The invention belongs to the technical field of application of natural compounds, and discloses application of astilbin in preparation of a jerusalem artichoke urease inhibitor. The astilbin has good effect of inhibiting the urease of the jerusalem artichoke, has the characteristics of simple structure, good safety and the like, and has good application value and development prospect in the field of plant fertilizers or animal feed additives.
Description
Technical Field
The invention belongs to the technical field of application of natural compounds, and particularly relates to application of astilbin in preparation of a jerusalem artichoke urease inhibitor.
Background
Urease, also known as urease or urease amide hydrolase, has a molecular weight of about 120000 ～ 130000, and the urease, is a metalloenzyme which is found to contain nickel ions for the first time, has a milestone significance in the history of biochemical development, is widely existing in various bacteria, fungi, actinomycetes and plants, and can decompose urea into carbon dioxide compounds and ammonia. Urease helps plants and microorganisms to utilize endogenous and exogenous urea as a nitrogen source and to synthesize body proteins from ammonia produced by decomposition. But the presence of urease accelerates the process of decomposing urea to release ammonia, greatly reduces the utilization rate of nitrogen by animals and plants, causes the pH value of soil to be increased, increases the agricultural production cost and pollutes agricultural products. Meanwhile, volatile ammonia in the animal body is easy to cause ammonia poisoning and even death of the animal blood; the volatile ammonia gas can cause serious soil pollution and water eutrophication after entering the environmental water body through leaching; the urease in human body can re-decompose the metabolite urea of human body and then be absorbed again, so as to change the acid-base balance in human body, raise the pH value of body fluid and urine, and cause kidney and urinary calculus, gastrointestinal ulcer, urinary system infection, and even cerebral paralysis, liver disease and other diseases. Based on the above, development of urease inhibitors is increasingly receiving attention.
At present, aiming at the serious harm of urease to human production and life, students at home and abroad research and use urease inhibitors for prevention and treatment. Heretofore, urease inhibitors have been widely used in the fields of medicine, agriculture, animal husbandry, etc., and the types thereof mainly include urea analogues, hydroxamic acids, heavy metal ions, phosphoramidates, quinones, polyphenols, etc. However, most of the existing urease inhibitors have problems of poor stability, short acting time, obvious toxic and side effects and the like, and have certain limitations in practical application. Because of long development cycle, low development success rate and high probability of ending clinical research stage, research and excavation of active ingredients in natural plant medicines are widely paid more attention to.
At present, the prior art CN115154444A, CN115211491A, CN115176878A, CN113666790A, CN106333947A respectively discloses the application of components such as syringaldehyde, sanguinarine, extract, piceatannol, epiberberine and the like in a jerusalem artichoke urease inhibitor, but the application of astilbin in the jerusalem artichoke urease inhibitor is not reported temporarily.
Disclosure of Invention
Aiming at the defects of the prior art, the invention researches the application of astilbin in the jerusalem artichoke urease inhibitor.
One of the purposes of the present invention is to provide the use of astilbin or a pharmaceutically acceptable salt thereof in the preparation of a jerusalem artichoke urease inhibitor.
Wherein, the structural formula of astilbin is shown as formula (I):
astilbin (Astilbin) is a dihydroflavonol glycoside compound, its chemical name is (2R, 3R) -taxifolin-3-O-alpha-L-rhamnopyranoside, its molecular formula is C 21 H 22 O 11 The molecular weight is 450.408, and is mainly derived from astilbe chinensis of astilbe of Saxifragaceae, smilax of Liliaceae, engelhardtia chrysolepis of Engelhardtia of Juglandaceae, vitis of Vitaceae, etc. Astilbin is a known safe, low-toxic compound. In recent years, pharmacological and pharmacodynamic researches are widely and deeply carried out at home and abroad, and astilbin has various pharmacological activities, including inhibition of coenzyme A reductase, inhibition of aldose reductase, anti-inflammation, immunosuppression, antibiosis, liver protection, pain relief, edema resistance and the like, and potential pharmacological effect researches thereof relate to cardiovascular pharmacology and immunopharmacology.
The invention discovers that astilbin has the effect of inhibiting the activity of the urease of the jerusalem artichoke, so that the astilbin can be applied to the preparation of the urease inhibitor of the jerusalem artichoke.
Another object of the present invention is to provide a jerusalem artichoke urease inhibitor comprising astilbin or a pharmaceutically acceptable salt thereof.
Further, the jerusalem artichoke urease inhibitor also comprises pharmaceutically acceptable auxiliary materials.
The invention also provides an application of the jerusalem artichoke urease inhibitor in preparing an animal feed additive.
Further, the animal is a ruminant or a monogastric animal.
The astilbin or the pharmaceutically acceptable salt thereof is added into the feed as an animal feed additive, so that the decomposition speed of urea in ruminants such as dairy cows, beef cattle, mutton sheep, broilers and the like or monogastric animals can be slowed down, the utilization rate of urea is improved, and the ammonia content in air in poultry houses and livestock houses is reduced.
The invention also provides application of the jerusalem artichoke urease inhibitor in preparing plant fertilizers.
The jerusalem artichoke urease inhibitor is added into the nitrogenous fertilizer, so that the urea utilization rate is improved, the crop yield is increased, and the production performance is improved.
The invention exploits the new application of astilbin as a jerusalem artichoke urease inhibitor in plant fertilizers or animal feed additives, enriches the selectable varieties of the existing urease inhibitors, and is beneficial to reducing the drug resistance of drugs. Meanwhile, as astilbin is a natural medicinal component and has the characteristics of high efficiency and low toxicity, the astilbin has good development prospect in inhibiting the activity of the urease of jerusalem artichoke.
Drawings
FIG. 1 is a schematic representation of the inhibitory activity of astilbin on jerusalem artichoke urease;
FIG. 2 is a schematic diagram of a study of the type of inhibition of jerusalem artichoke by astilbin;
FIG. 3 is a schematic representation of the molecular docking of astilbin to jerusalem artichoke urease.
Detailed Description
The following is a further detailed description of the embodiments:
in order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited to the following embodiments, and any modifications, substitutions, and combinations made without departing from the spirit and principles of the present invention are included in the scope of the present invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
Experimental materials
Test agent
Astilbin is purchased from Dou Desai special biotechnology Co., ltd, and the purity is more than 98%; canavalia sonchifolia urease (Type III, 40.3U/mg) available from sigma aldrich, U.S.A.; urea, dithiothreitol, and cysteine are all purchased from soribao; glutathione is purchased from melphalan organisms; sodium fluoride, boric acid were purchased from microphone. HEPES, sodium salicylate, sodium nitroprusside, sodium hydroxide, sodium hypochlorite, glycerol, all purchased from Guangzhou chemical reagent plants, all analytically pure.
Preparation of medicine
Weighing proper amount of astilbin respectively, preparing into corresponding concentration with 20mM HEPES buffer (pH 7.5), and storing at 4deg.C in dark place for use.
Preparation of urease of jerusalem artichoke
Weighing a proper amount of jerusalem artichoke urease, dissolving in 20mM HEPES buffer (pH 7.5) to prepare 10U/mL jerusalem artichoke urease solution, and freeze-preserving in a refrigerator at 4 ℃ for later use.
Preparation of urea
Weighing a proper amount of urea, dissolving in 20mM HEPES buffer (pH 7.5) to prepare 150mM urea solution, and storing in a refrigerator at 4 ℃ for later use.
Preparation of Berthelot color development liquid
And (3) solution A: respectively weighing appropriate amount of sodium nitroprusside and sodium salicylate powder, dissolving in 20mM HEPES buffer (pH 7.5) to prepare color development A solution containing 9.73mM sodium nitroferricyanide and 700mM sodium salicylate, and storing at 4deg.C in dark place for use.
And (2) liquid B: 9g of sodium hydroxide is weighed, dissolved in 20mM HEPES buffer solution (pH 7.5), cooled, added with 12mL of sodium hypochlorite, uniformly mixed, fixed to 50mL, and stored at 4 ℃ in a dark place for later use.
Example 1: study on inhibition effect of astilbin on jerusalem artichoke urease
Uniformly mixing a jerusalem artichoke urease solution and a series of test drug solutions, and incubating at 37 ℃ for 20 minutes; adding urea solution, and carrying out light-shielding reaction for 20 minutes at room temperature; adding Berthelot color development liquid, developing for 10 min in dark, absorbing 200 μl of the incubation liquid onto 96-well plate, and measuring OD at 595nm on enzyme-labeled instrument Absolute value (Absolute) Values. Each concentration was done 3 times in parallel. The blank was replaced with the solvent of each dilution and the rest was the same as above to determine OD Blank space . Obtaining corresponding OD according to formula 1 Relative to each other Values. Residual enzyme activity was determined according to equation 2 and the corresponding median inhibitory concentration IC was determined by GraphPad 50 Expressed as mean ± standard deviation.
OD Relative to each other ＝OD Absolute value (Absolute) –OD Blank space (equation 1)
Residual enzyme activity (%) =od Relative to each other Test article /OD Relative to each other Blank space X 100% (formula 2)
As shown in fig. 1, the half Inhibitory Concentration (IC) of astilbin for inhibiting the urease activity of jerusalem artichoke 50 ) 2.22+/-0.05 mM, which shows that astilbin has obvious effect of inhibiting the activity of the jerusalem artichoke urease.
Example 2: type of inhibition study of astilbin on urease
A series of astilbin solutions (0, 0.75, 1.5, 2.0 mM) were mixed with a concentration of urease, and incubated at 37℃for 20 minutes. Then a series of urea solutions (0.469-15 mM) were added at room temperature and reacted for 20 minutes in the dark, and then developed and OD was measured according to the method of 2.1 Absolute value (Absolute) Value and find the corresponding OD Relative to each other Values. The solvent with the added substance was used as a blank and assayed in parallel for 3 times. The experiment was carried out by the inverse of the reaction rate (1/V, i.e.1/OD Relative to each other ) Inverse of substrate concentration (1/[ urea)]) Making a Lineweaver-Burk graph, and finally obtaining a kinetic parameter K through the L-B curve and the formula 3 M 、v max And obtaining the inhibition constant K by performing secondary plotting through the L-B curve i 、K is 。
The results are shown in FIG. 2, wherein A represents a Lineweaver-Burk double-reciprocal graph of astilbin inhibition of jerusalem artichoke, B represents a graph of slope versus inhibitor concentration of a curve in the Lineweaver-Burk double-reciprocal graph of astilbin inhibition of jerusalem artichoke, and C represents a graph of intercept versus inhibitor concentration of a curve in the Lineweaver-Burk double-reciprocal graph of astilbin inhibition of jerusalem artichoke; from the Lineweaver-Burk double reciprocal graph, it can be seen that as the astilbin concentration increases, astilbin inhibits the kinetic parameter K of jerusalem artichoke urease M Gradually increase, v max Gradually decreasing, from which it can be preliminarily deduced that the type of action of astilbin to inhibit jerusalem artichoke is a mixed type of inhibition. In addition, the inhibition constant K of the astilbin for inhibiting the urease of the jerusalem artichoke can be obtained by combining the astilbin for inhibiting the type of the urease of the jerusalem artichoke and performing secondary plotting on a Lineweaver-Burk double reciprocal graph i 0.201+ -0.014 mM, K is 1.172.+ -. 0.167mM.
Example 3: molecular docking research of astilbin and jerusalem artichoke urease active site
The 3D structure of astilbin was first saved and energy minimized in the mol2 format using ChemOffice 19.1 software. Downloading a 3D structure PDB format of the jerusalem artichoke urease (PDB ID:3LA 4) from a PDB database (https:// www.Rcsb.org /), carrying out operations such as dehydration, hydrogenation and the like on proteins by using PyMOL software, converting a compound and target protein format into a pddqt format by using AutoDuckTools1.5.6 software, and finally carrying out small molecule and protein butt joint by using Autodock Vina 1.1.2, and analyzing and mapping by taking the most scored conformation.
Through the operation calculation of a molecular docking program, the docking score of astilbin and jerusalem artichoke urease is-7.6 kcal/mol. In FIG. 3, A shows a schematic diagram of the enzyme surface pattern of binding of astilbin to jerusalem artichoke, B shows a cartoon pattern of binding of astilbin to jerusalem artichoke, and FIG. 3 shows a schematic diagram of molecular docking showing binding of astilbin to jerusalem artichoke active site and formation of O-H.O, N-H.O, O-H.N hydrogen bond mainly with jerusalem artichoke active site Ni 2+ G in the upper Flap regionFour amino acid residues LY 638, MET 637, MET 588 and GLN 635 form strong hydrogen bond interactions. In addition, astilbin may interact with jerusalem artichoke amino acid residue HIS 593,ALA 440,ARG609,ARG 639, etc. by hydrophobic force, etc., thereby affecting jerusalem artichoke urease activity conformation, maintaining the flap conformation in an open state, and thus changing enzyme activity.
The experiment shows that astilbin can obviously inhibit the activity of the jerusalem artichoke urease. In addition, the study on the action mechanism of astilbin for inhibiting urease proves that astilbin is a mixed type urease inhibitor, the action of inhibiting the urease is concentration-dependent, and the urease activity conformation can be influenced by the essential group acting on the urease flap region, so that the urease activity can be inhibited. In conclusion, astilbin has the function of resisting the jerusalem artichoke urease and has obvious action and effect. And the astilbin has good application value and development prospect in inhibiting the activity of the urease of the jerusalem artichoke and is a potential urease inhibitor.
The foregoing is merely exemplary embodiments of the present invention, and specific structures and features that are well known in the art are not described in detail herein. It should be noted that modifications and improvements can be made by those skilled in the art without departing from the structure of the present invention, and these should also be considered as the scope of the present invention, which does not affect the effect of the implementation of the present invention and the utility of the patent. The protection scope of the present application shall be subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.
Claims (6)
1. Use of astilbin or a pharmaceutically acceptable salt thereof in the preparation of a jerusalem artichoke urease inhibitor.
2. A jack bean urease inhibitor, characterized in that: comprises astilbin or pharmaceutically acceptable salt thereof.
3. The jerusalem artichoke urease inhibitor according to claim 2, characterized in that: pharmaceutically acceptable auxiliary materials are also included.
4. Use of a jerusalem artichoke urease inhibitor according to claim 2 or 3 for the preparation of an animal feed additive.
5. The use according to claim 4, characterized in that: the animal is a ruminant or a monogastric animal.
6. Use of a jerusalem artichoke urease inhibitor according to claim 2 or 3 in the preparation of a plant fertilizer.
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