CN108330154B - Application of esterase EstP00714 in catalytic resolution of racemic linalyl acetate to obtain (S) -linalool - Google Patents
Application of esterase EstP00714 in catalytic resolution of racemic linalyl acetate to obtain (S) -linalool Download PDFInfo
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- CN108330154B CN108330154B CN201810078725.0A CN201810078725A CN108330154B CN 108330154 B CN108330154 B CN 108330154B CN 201810078725 A CN201810078725 A CN 201810078725A CN 108330154 B CN108330154 B CN 108330154B
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- China
- Prior art keywords
- esterase
- estp00714
- racemic
- linalyl acetate
- linalool
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Abstract
The invention discloses application of esterase EstP00714 in catalytic resolution of racemic linalyl acetate to obtain (S) -linalool. The invention uses esterase EstP00714 as a catalyst, obtains (S) -linalool with an enantiomeric excess value of more than 96 percent by optimizing a reaction system and reaction conditions, and the conversion rate reaches 55 percent. Compared with the traditional chemical resolution, the method has the advantages of mild reaction conditions, no pollution and high enantiomeric excess value. Can be used in the fields of biological medicine, cosmetics, fine chemical engineering and the like, and has great application value.
Description
The technical field is as follows:
the invention belongs to the fields of biochemical engineering and biotechnology, and particularly relates to application of esterase EstP00714 in catalytic resolution of racemic linalyl acetate to obtain (S) -linalool.
Background art:
esterases (EC 3.1.1.1) are widely found in animals, plants and microorganisms and are a class of enzymes that catalyze hydrolysis or the formation of ester bonds, the substrates for which are usually esters with less than ten carbon atoms in the aliphatic chain. The esterase belongs to an alpha/beta sheet hydrolase superfamily, a catalytic center consists of serine, aspartic acid/glutamic acid and histidine, and a conserved sequence is a pentapeptide (GXSXG) sequence near the serine. Esterase can catalyze various chemical reactions such as hydrolysis, esterification, transesterification and the like, is an important industrial biocatalyst, and is widely applied to the fields of fine chemical engineering, washing, medicines, food, papermaking, leather processing, textile, wastewater treatment, feed industry and the like. From the catalytic property, the esterase has high chemoselectivity and stereoselectivity, and the reaction does not need coenzyme, has mild reaction condition and less byproducts. Another significant feature of esterases in production applications is their ability to function in heterogeneous systems (i.e., oil-water interfaces) or in the organic phase. In the aqueous phase, esterases generally catalyze hydrolysis reactions, while in the organic phase, esterases catalyze esterification and transesterification reactions. The method for preparing the novel drug intermediate or removing the non-effective components of the drug racemate by the biotransformation of microbial esterase is an important chiral technology, has very wide application prospect, can provide a new platform for synthesizing chiral drugs, and provides a new method for preparing optical pure compounds in large quantities. The enzymatic method for selectively resolving the racemate compound has the advantages of high stereospecificity, less side reaction, high yield, good optical purity of the product and mild reaction conditions, so the method is a widely accepted resolving method.
The invention content is as follows:
the invention aims to provide application of esterase EstP00714 in catalytic resolution of racemic linalyl acetate to obtain (S) -linalool.
The esterase EstP00714 (the amino acid sequence of the esterase is shown in SEQ ID NO. 2) and the coding gene EstP00714 (the nucleotide sequence of the esterase is shown in SEQ ID NO. 1) are developed from a strain of pseudomonas pseudomonad antipruralis HUP007, a recombinant expression vector containing the esterase gene EstP00714 and a genetic engineering bacterium are constructed, and the esterase EstP00714 is obtained after the genetic engineering bacterium is cultured and can be applied to catalyzing ester hydrolysis reaction.
The esterase EstP00714 disclosed by the invention is applied to catalytic resolution of racemic linalyl acetate to obtain (S) -linalool, and the amino acid sequence of the esterase EstP00714 is shown as SEQ ID No. 2.
Preferably, the catalytic resolution of racemic linalyl acetate to (S) -linalool is carried out in the presence of an organic solvent and/or a surfactant.
The organic solvent is preferably ethanol.
The surfactant is preferably sodium tripolyphosphate.
The reaction system for obtaining (S) -linalool by catalytically resolving racemic linalyl acetate is preferably as follows: comprises 20mg/mL esterase EstP00714, 50mM substrate racemic linalyl acetate, 10% volume fraction ethanol and 5g/L sodium tripolyphosphate, and the balance pH6PBS buffer.
The reaction temperature for obtaining (S) -linalool by catalytically resolving racemic linalyl acetate is 30 ℃, and the reaction time is 2 hours.
The esterase gene Estp00714 of the invention is derived from Pseudomonas aeruginosa antitumoralisHUP007 (stored in the south China sea research institute of academy of sciences). The amino acid sequence of the esterase EstP00714 is shown as SEQ ID NO.2, the nucleotide sequence of the coding gene EstP00714 is shown as SEQ ID NO.1, and the esterase EstP00714 is disclosed in the patent application number: 201610605466.3, title of the invention: in a patent application of esterase EstP00714 and a coding gene and application thereof, a preparation method of the esterase EstP00714 is disclosed in the patent, so that esterase EstP00714 enzyme powder (namely purified esterase EstP00714) can be obtained.
The invention uses esterase EstP00714 as a catalyst, obtains (S) -linalool with an enantiomeric excess value of more than 96 percent by optimizing a reaction system and reaction conditions, and the conversion rate reaches 55 percent. Compared with the traditional chemical resolution, the method has the advantages of mild reaction conditions, no pollution and high enantiomeric excess value. Can be used in the fields of biological medicine, cosmetics, fine chemical engineering and the like, and has great application value.
Description of the drawings:
FIG. 1 shows the effect of substrate concentration on the resolution of racemic linalyl acetate by esterase EstP 00714.
FIG. 2 shows the effect of enzyme concentration on the resolution of racemic linalyl acetate by esterase EstP 00714.
FIG. 3 shows the effect of reaction time on the resolution of racemic linalyl acetate by esterase EstP 00714.
FIG. 4 is a gas chromatogram of racemic linalyl acetate before reaction; wherein, 1 represents racemic linalyl acetate.
FIG. 5 is a gas chromatogram of (. + -.) -linalool; wherein R represents (R) -linalool and S represents (S) -linalool.
FIG. 6 is a gas chromatogram of racemic linalyl acetate and the product linalool after the reaction; wherein R represents (R) -linalool, S represents (S) -linalool, and 1 represents linalyl acetate.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
The esterase gene Estp00714 is derived from Pseudomonas atrophaeus HUP007, which is stored in the south China sea research institute laboratory. The amino acid sequence of the esterase EstP00714 is shown as SEQ ID NO.2, the nucleotide sequence of the coding gene EstP00714 is shown as SEQ ID NO.1, and the esterase EstP00714 is disclosed in the patent application number: 201610605466.3, title of the invention: in a patent application of esterase EstP00714 and a coding gene and application thereof, a preparation method of the esterase EstP00714 is disclosed in the patent, so that purified esterase EstP00714 (namely esterase EstP00714 enzyme powder) can be obtained.
Example 1: esterase EstP00714 resolution of racemic linalyl acetate
1.1 Effect of reaction pH and temperature on the resolution of racemic linalyl acetate by esterase EstP00714
The reaction system with different pH values is 0.5mL, and comprises 10mg esterase EstP00714 enzyme powder, 50mM substrate racemic linalyl acetate, and the balance of reaction buffer solutions with different pH values; the reaction was carried out for 2h at different temperatures. GC measures the stereoselectivity of esterase EstP00714 for resolving racemic linalyl acetate, and the enantiomeric excess value (e.e.) and the conversion rate (C) of the product are calculated according to the peak area, and the results are shown in Table 1.
in the formula: a. theSAnd ARRespectively represent the peak areas of (S) -linalool and (R) -linalool, A0And A represents the peak areas of linalyl acetate before and after the reaction.
The conversion (C) increases with increasing pH between pH6.0 and 10.0, but the e.e. decreases with increasing pH. The highest e.e.92% was obtained at pH 6.0. Thus, the esterase EstP00714 has the optimum pH value of 6.0 for resolving racemic linalyl acetate.
C increases and then decreases with increasing temperature, and the e.e. decrease is not significant between 25-35 ℃. The C decreases significantly when the temperature is higher than 35 ℃, which is associated with the high temperature affecting the activity of the enzyme. The maximum conversion of 55% was achieved at 30 ℃ and the e.e. reached 94%. Thus, the esterase EstP00714 has an optimum temperature of 30 ℃ for resolving racemic linalyl acetate.
TABLE 1 Effect of reaction pH and temperature on the resolution of racemic linalyl acetate by esterase EstP00714
aThe expression PBS buffer is used herein to indicate,brepresents a Tris/HCl buffer
1.2 Effect of organic solvent on resolution of racemic linalyl acetate by esterase EstP00714
The reaction system is 0.5mL, and comprises 10mg esterase EstP00714 enzyme powder, 50mM substrate racemic linalyl acetate, 10% volume fraction, 30% organic solvent and the balance of PBS buffer solution with the pH value of 6.0; using no organic solvent as a reference; the reaction is carried out for 2h at 30 ℃, and the results are shown in Table 2 by detecting with a gas chromatography chiral column.
TABLE 2 Effect of organic solvents on the resolution of racemic linalyl acetate by esterase EstP00714
It can be seen from Table 2 that the stereoselectivity of esterase EstP00714 was slightly improved in the presence of most of the organic solvent, but the conversion was reduced to a different extent in the alkanes. Although the e.e. reaches 98% in the presence of 10% by volume of isooctane, n-hexane and toluene, the relative decrease of C is more obvious. In ethanol with a volume fraction of 10%, both e.e. and C were increased to 97% and 52%, respectively. Ethanol was therefore used as a co-solvent in subsequent experiments.
1.3 Effect of surfactants on the resolution of racemic linalyl acetate by esterase EstP00714
Under optimized conditions (30 ℃, pH6.0PBS buffer solution), the reaction system is 0.5mL, and comprises 10mg esterase EstP00714 enzyme powder, 50mM substrate racemic linalyl acetate, ethanol with the final concentration of 10% by volume fraction, 1g/L, 5g/L and 10g/L of surfactants (sodium tripolyphosphate, Tween-20, Tween-80 and TritonX-100), and the balance pH6.0PBS buffer solution; after 2h reaction at 30 ℃ with no surfactant added as a control, samples were used for GC detection, and the results are shown in Table 3. As can be seen from Table 3, compared with the control, 4 surfactants had no significant effect on the e.e. resolution of racemic linalyl acetate by esterase EstP00714, and 5g/L sodium tripolyphosphate could increase the conversion rate to 54%, so 5g/L sodium tripolyphosphate was added in the subsequent experiments.
TABLE 3 Effect of surfactants on the resolution of racemic linalyl acetate by esterase EstP00714
1.4 Effect of substrate concentration on the resolution of racemic linalyl acetate by esterase EstP00714
Under optimized conditions (30 ℃, pH6.0PBS buffer solution), the reaction system is 0.5mL, and comprises 10mg esterase EstP00714 enzyme powder, 10-100mM substrate racemic linalyl acetate, 10% volume fraction ethanol, 5g/L sodium tripolyphosphate and the balance of pH6.0PBS buffer solution; after 2h reaction at 30 ℃ the samples were used for GC detection and the results are shown in FIG. 1. As can be seen from fig. 1, the conversion C gradually decreases as the substrate concentration increases, the e.e. slowly increases. Indicating that higher concentrations of substrate inhibit the enzymatic reaction and decrease the conversion. At substrate concentrations >50mM, e.e. is essentially unchanged, so that the optimum substrate concentration for the resolution of racemic linalyl acetate by esterase EstP00714 is 50mM, with 96% and 50% for e.e. and C, respectively.
1.5 Effect of enzyme concentration on the resolution of racemic linalyl acetate by esterase EstP00714
Under optimized conditions (30 ℃, pH6.0PBS buffer solution), the reaction system is 0.5mL, and comprises 5-35mg esterase EstP00714 enzyme powder, 50mM substrate racemic linalyl acetate, ethanol with the volume fraction of 10%, 5g/L sodium tripolyphosphate and the balance of pH6.0PBS buffer solution; GC detection after 2h reaction at 30 ℃ gave the results shown in FIG. 2. As can be seen from fig. 2, the e.e. and conversion do not vary much with increasing enzyme concentration. At an enzyme concentration of 20mg/mL, the e.e. and conversion were 96% and 53%, respectively.
1.6 Effect of reaction time on resolution of racemic linalyl acetate by esterase EstP00714
Under optimized conditions (30 ℃, pH6.0PBS buffer solution), the reaction system is 0.5mL, and comprises 10mg esterase EstP00714 enzyme powder, 50mM substrate racemic linalyl acetate, 10% volume fraction of ethanol, 5g/L sodium tripolyphosphate and the balance of pH6.0PBS buffer solution; reacting at 30 ℃, taking out 500 mu L of the mixture every 1h, extracting the mixture by using ethyl acetate, removing water by using anhydrous sodium sulfate, adding L-methyl lactate as an internal standard, and detecting the mixture by using a gas chromatography chiral column. The results of the resolution of racemic linalyl acetate by esterase EstP00714 at different reaction times are shown in FIG. 3.
As can be seen from fig. 3, C gradually increased with time, and over the 2h reaction, the e.e. and conversion reached substantially the highest, 96% and 55%, respectively. After 2h, neither the conversion nor the e.e. change was significant. FIGS. 4, 5 and 6 are gas chromatograms of racemic linalyl acetate, (±) -linalool before reaction and linalyl acetate and linalool after reaction, respectively.
Sequence listing
<110> Nanhai ocean institute of Chinese academy of sciences
Application of <120> esterase EstP00714 in catalytic resolution of racemic linalyl acetate to obtain (S) -linalool
<160>2
<170>SIPOSequenceListing 1.0
<210>1
<211>1146
<212>DNA
<213> Pseudomonas HUP007 (Pseudonocardia antipruralis HUP007)
<400>1
gtgcagatcc agggtcacta tgagctgaag ttcgaggcgg tgcgcgatgc cttcgccgcg 60
ttgttcgagg atccccagga acgtggtgcc gcattgtgca tccaggttgg cggcgagacc 120
gtggtcgacc tgtgggccgg cagcgccgac aaggacggcc gcgaggcctg gcacagcgat 180
accatcgcca acctgttctc ctgcaccaag accttcaccg ccgtcaccgc cctgcaactg 240
gtgggcgagg gcaagctggc cctcgatgcg ccggtggcgc gctactggcc ggagttcgcc 300
caggccggca aggagcaggt caccctgcgc cagttgctca gccaccgcgc cggcctgccg 360
gccatccgcg agctgctgcc ggccgaggcg ctgtacgact ggcaagccat ggttgatgcc 420
ctggccgccg aagcgccctg gtggacaccc ggaagcgaac acggttacgc ggcgatcacc 480
tatggctggc tgatcggtga gctgatccgc cgcgccgacg gtcgcggccc gggcgactcg 540
atcgtggctc gcaccgcccg gccattgggg ttggatttcc atgtcggcct ggccgacgac 600
gagttccacc gcgtggcgca tatcgcccgc ggcaagggca accccggcga tgccgcggcc 660
cagcgcctgc tgcaggtcac catgcgcgag cccgaggccc tgtcgacccg ggccttcacc 720
aacccgccgg cgatcctcac cagcaccaac aagcccgaat ggcggcgcat gcagcagcca 780
gcggccaatg gccacggcaa cgcccgcagc ctggcgggct tctatgccgg cctgctcgac 840
ggcagcctgc tggagtccga gctgctcgac gaactgaccc gcgagcacag cctcggccag 900
gaccgcaccc tgttgaccca gacccgcttc ggcctgggct gcatgctcga ccagccagaa 960
gtggccaacg ccactttcgg ccttggcgcg cgggcgttcg gccatcccgg cgcgggcggc 1020
tcggtcggct ttgccgaccc cgaacacgac gtggcctttg gcttcgtcac caataccctg 1080
ggcccctatg tgctgatgga cccgcgcgct caacgcctgg tgcgtgtcct tggcagttgc 1140
ctttga 1146
<210>2
<211>381
<212>PRT
<213> Pseudomonas HUP007 (Pseudonocardia antipruralis HUP007)
<400>2
Val Gln Ile Gln Gly His Tyr Glu Leu Lys Phe Glu Ala Val Arg Asp
1 5 10 15
Ala Phe Ala Ala Leu Phe Glu Asp Pro Gln Glu Arg Gly Ala Ala Leu
20 25 30
Cys Ile Gln Val Gly Gly Glu Thr Val Val Asp Leu Trp Ala Gly Ser
35 40 45
Ala Asp Lys Asp Gly Arg Glu Ala Trp His Ser Asp Thr Ile Ala Asn
50 55 60
Leu Phe Ser Cys Thr Lys Thr Phe Thr Ala Val Thr Ala Leu Gln Leu
65 70 75 80
Val Gly Glu Gly Lys Leu Ala Leu Asp Ala Pro Val Ala Arg Tyr Trp
85 90 95
Pro Glu Phe Ala Gln Ala Gly Lys Glu Gln Val Thr Leu Arg Gln Leu
100 105 110
Leu Ser His Arg Ala Gly Leu Pro Ala Ile Arg Glu Leu Leu Pro Ala
115 120 125
Glu Ala Leu Tyr Asp Trp Gln Ala Met Val Asp Ala Leu Ala Ala Glu
130 135 140
Ala Pro Trp Trp Thr Pro Gly Ser Glu His Gly Tyr Ala Ala Ile Thr
145 150155 160
Tyr Gly Trp Leu Ile Gly Glu Leu Ile Arg Arg Ala Asp Gly Arg Gly
165 170 175
Pro Gly Asp Ser Ile Val Ala Arg Thr Ala Arg Pro Leu Gly Leu Asp
180 185 190
Phe His Val Gly Leu Ala Asp Asp Glu Phe His Arg Val Ala His Ile
195 200 205
Ala Arg Gly Lys Gly Asn Pro Gly Asp Ala Ala Ala Gln Arg Leu Leu
210 215 220
Gln Val Thr Met Arg Glu Pro Glu Ala Leu Ser Thr Arg Ala Phe Thr
225 230 235 240
Asn Pro Pro Ala Ile Leu Thr Ser Thr Asn Lys Pro Glu Trp Arg Arg
245 250 255
Met Gln Gln Pro Ala Ala Asn Gly His Gly Asn Ala Arg Ser Leu Ala
260 265 270
Gly Phe Tyr Ala Gly Leu Leu Asp Gly Ser Leu Leu Glu Ser Glu Leu
275 280 285
Leu Asp Glu Leu Thr Arg Glu His Ser Leu Gly Gln Asp Arg Thr Leu
290 295 300
Leu Thr Gln Thr Arg Phe Gly Leu Gly Cys Met Leu Asp Gln Pro Glu
305 310 315320
Val Ala Asn Ala Thr Phe Gly Leu Gly Ala Arg Ala Phe Gly His Pro
325 330 335
Gly Ala Gly Gly Ser Val Gly Phe Ala Asp Pro Glu His Asp Val Ala
340 345 350
Phe Gly Phe Val Thr Asn Thr Leu Gly Pro Tyr Val Leu Met Asp Pro
355 360 365
Arg Ala Gln Arg Leu Val Arg Val Leu Gly Ser Cys Leu
370 375 380
Claims (6)
1. The esterase EstP00714 is applied to catalytic resolution of racemic linalyl acetate to obtain (S) -linalool, and the amino acid sequence of the esterase EstP00714 is shown as SEQ ID No. 2.
2. The use according to claim 1, wherein said catalytic resolution of racemic linalyl acetate to (S) -linalool is carried out in the presence of an organic solvent and/or a surfactant.
3. The use according to claim 2, wherein the organic solvent is ethanol.
4. Use according to claim 2 or 3, wherein the surfactant is sodium tripolyphosphate.
5. The use according to claim 4, wherein the reaction system for catalytically resolving racemic linalyl acetate to obtain (S) -linalool is: comprises 20mg/mL esterase EstP00714, 50mM substrate racemic linalyl acetate, 10% volume fraction ethanol and 5g/L sodium tripolyphosphate, and the balance of PBS buffer with the pH of 6.
6. The use according to claim 5, wherein the catalytic resolution of racemic linalyl acetate to give (S) -linalool is carried out at 30 ℃ and for 2 h.
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WO2003031609A1 (en) * | 2001-10-09 | 2003-04-17 | Degussa Ag | Esterase esta of rhodococcus sp. |
CN106119224A (en) * | 2016-07-27 | 2016-11-16 | 中国科学院南海海洋研究所 | A kind of esterase EstP00714 and encoding gene thereof and application |
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WO2003031609A1 (en) * | 2001-10-09 | 2003-04-17 | Degussa Ag | Esterase esta of rhodococcus sp. |
CN106119224A (en) * | 2016-07-27 | 2016-11-16 | 中国科学院南海海洋研究所 | A kind of esterase EstP00714 and encoding gene thereof and application |
Non-Patent Citations (1)
Title |
---|
一个新颖南极微生物酯酶EST112-2的功能鉴定和在手性叔醇(S)-芳樟醇制备中的应用(英文);邓盾等;《有机化学》;20180118;第38卷(第5期);第1187-1192页 * |
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