Electronic Effect-Guided Rational Design of Candida antarctica Lipase B for Kinetic Resolution Towards Diarylmethanols

Article abstract of DOI:10.1002/adsc.202001367

Herein, we developed an electronic effect-guided rational design strategy to enhance the enantioselectivity of Candida antarctica lipase B (CALB) mutants towards bulky pyridyl(phenyl)methanols. Compared to W104A mutant previously reported with reversed S-stereoselectivity toward sec-alcohols, three mutants (W104C, W104S and W104T) displayed significant improvement of S-enantioselectivity in the kinetic resolution (KR) of various phenyl pyridyl methyl acetates due to the increased electronic effects between pyridyl and polar residues. The electronic effects were also observed when mutating other residues surrounding the stereospecificity pocket of CALB, such as T42A, S47A, A281S or A281C, and can be used to manipulate the stereoselectivity. A series of bulky pyridyl(phenyl) methanols, including S-(4-chlorophenyl)(pyridin-2-yl) methanol (S-CPMA), the intermediate of bepotastine, were obtained in good yields and ee values. (Figure presented.).

Full text of DOI:10.1002/adsc.202001367

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DOI: 10.1002/adsc.202001367
Electronic Effect-Guided Rational Design of Candida antarctica
Lipase B for Kinetic Resolution Towards Diarylmethanols
Dan-Yang Li,a Yu-Jiao Lou,a Jian Xu,a Xiao-Yang Chen,b,* Xian-Fu Lin,a and
Qi Wua,*
a
Department of Chemistry
Zhejiang University
Hangzhou 310027, People’s Republic of China
Fax (+86)-571-8795-1895
E-mail: wuqi1000@163.com
College of Biological, Chemical Science and Engineering
b
Jiaxing University
118 Jiahang Road, Jiaxing 314001, People’s Republic of China
E-mail: chenxychem@163.com
Manuscript received: November 3, 2020; Revised manuscript received: January 24, 2021;
Version of record online: Februar 5, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001367
ure 1a). Consequently, the efficient synthesis of struc-
turally diverse diarylmethanols, especially in an
enantioselective manner is highly coveted. Their
Abstract: Herein, we developed an electronic ef-
fect-guided rational design strategy to enhance the
enantioselectivity of Candida antarctica lipase B
(CALB) mutants towards bulky pyridyl(phenyl)
preparation typically involves asymmetric addition of
aryl nucleophiles to benzaldehyde,[2] or reduction of
methanols. Compared to W104A mutant previously
diaryl ketones via asymmetric transfer hydrogenation
reported with reversed S-stereoselectivity toward
(ATH)[3] or via other biocatalytic transformation
sec-alcohols, three mutants (W104C, W104S and
W104T) displayed significant improvement of S-
enantioselectivity in the kinetic resolution (KR) of
processes.[4]
In comparison with traditional chemical catalysts,
biocatalysts have inherent advantages such as environ-
various phenyl pyridyl methyl acetates due to the
mental compatibility, high enantioselectivity, and mild
increased electronic effects between pyridyl and
reaction conditions.[5] Ketoreductases or carbonyl
polar residues. The electronic effects were also
reductases were widely used in asymmetric reductions
observed when mutating other residues surrounding
of carbonyl compounds,[6] including diaryl ketones.[7]
the stereospecificity pocket of CALB, such as
Recently, Ni and co-workers developed an alcohol
T42A, S47A, A281S or A281C, and can be used to
dehydrogenase from Kluyveromyces polyspora
manipulate the stereoselectivity. A series of bulky
pyridyl(phenyl) methanols, including S-(4-chloro-
phenyl)(pyridin-2-yl) methanol (S-CPMA), the in-
termediate of bepotastine, were obtained in good
(KpADH)-catalysed reduction for the synthesis of
diarylmethanols, and both configurations of them were
obtained via iterative combinatorial mutagenesis.[7a]
Sun and Nie engineered ADH from Thermoanaero-
bacter brockii (TbSADH) under the guidance of
yields and ee values.
conformational dynamics for the enantioselective
transformation of diaryl ketones.[7c]
Keywords: Rational design; Electronic effect; Li-
Kinetic resolution (KR) catalysed by lipase offers
pase; Diarylmethanols; Kinetic resolution
an alternative process to achieve enantioselective
diarylmethanols. For example, Bäckvall and co-work-
ers utilized the engineered Candida antarctica lipase B
Enantiomerically enriched diarylmethanols continue to (CALB), the most extensively used lipase, to establish
emerge with high frequency in disclosures of structural the resolution of racemic diarylmethanols without any
motifs of pharmaceuticals,[1] such as antihistaminic, expensive cofactors.[8] According to the study from
analgesic, antiarrhythmic, antidepressive, diuretic, lax- Hult and coworkers, the hot spot W104, which located
ative, local-anaesthetic and anticholinergic drugs (Fig- in the bottom of the stereospecificity pocket, limited
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heterocyclic or halogenated moiety might lead to
improved enantioselectivity.
The hydrolytic KR of racemic phenyl(pyridin-4-yl)
methyl acetate (rac-1a) was chosen as the model
reaction (Scheme 1). This substrate is difficult to be
resolved by WT CALB owing to the well-known steric
effect of the position W104.[9] When using W104A
mutant with the increased significantly volume of
binding pocket, a successful KR of 1a was achieved
with good yield and enantioselectivity (50% yield,
91% ee, E=67).
W104A mutant was S-selective for 1a, meaning
that it can distinguish the two groups with similar size
and prefer to bind the more polar pyridyl in the
reshaped stereospecificity pocket, probably due to
electronic effects between pyridyl and polar residues.
In order to further enhance the enantioselectivity of
enzymatic KR toward 1a, we chose three polar amino
acids (cysteine (C), serine (S) and threonine (T))[13]
with similar size as alanine for the exchange of W104
respectively, to reconstruct a more polar environment
of stereospecificity pocket than W104A mutant.
W104C mutant displayed a remarkable improvement
of S-selectivity in comparison with W104A as ex-
Figure 1. a) Several pharmaceuticals with diarylmethanol scaf-
fold; b) CALB W104A-catalyzed KR of diarylmethanols; c)
Electronic effect-guided rational design reported herein for
engineered CALB-catalyzed KR of diarylmethanols.
the size of this pocket to fit larger groups than ethyl, pected (ee and E values increased from 91% to 99%
and W104A mutant showed wider substrate scopes and and from 67 to >500, respectively, entries 1–2 in
reversed enantioselectivity for sec-alcohol compared to Table S4). A similar phenomenon was also observed
wide-type (WT).[9] In this significant wok, the authors for W104T. Interestingly, W104S mutant only showed
found that W104A could also catalyze enantioselective moderate S-selectivity for 1a, perhaps due to the
transesterification of diarylmethanols. The results opposite orientation of hydroxyl to pyridyl group.
showed that the enantioselectivity was mainly depend-
To probe the molecular mechanisms between target
ent on the size difference between two substituents. A mutants and substrate, S-1a was docked into W104A
larger size-difference led to a higher enantioselectivity. and W104C, respectively, then 10 ns molecular dynam-
However, the efficient enzymatic KR of diarylmetha- ics (MD) simulation were performed (Figure 2). As
nols is still challenging because of their high steric anticipated, the enzyme-S-1a complex in both mutants
hindrance and similarity in size of two aromatic matched suitably with the enlarged binding pocked of
substituents, especially the diarylmethanols substituted CALB, which displayed the chief difference from the
by pyridyl and phenyl. Indeed, only 27–74% ee values WT, resulting in high reactivity. In order to further
and 2–10 E values were observed using 2-, 3- and 4-
pyridyl(phenyl)methanols as substrates under the catal-
ysis of W104A (Figure 1b).[8]
Previous results with CALB and other enzymes
suggest that apart from steric effects, electronic and
solvation effects can also affect the binding of the
substrates in enzymes and correspondingly their
enantioselectivity.[10] Accordingly, we considered the
electronic effects between enzyme and substrates may
be more crucial to selectivity than steric attributes in
these cases of diarylmethanols with one phenyl and
one pyridyl group. Herein, the substrate binding pocket
of CALB is rationally engineered to modify the
polarity of residues and the cavity volume (Figure 1c),
on the basis of the structural cognition of CALB from
previous works of our group,[11] thus avoiding the
Scheme 1. CALB mutants-catalyzed KR of phenyl(pyridin-4-
yl)methyl acetate. Reactions were performed with substrate 1a
(0.01 mmol), acetonitrile (50 μL) and enzymes (~50 μg) in PBS
laborious high-throughput screening procedures.[12] We
hypothesize the electrostatic attraction and/or hydrogen
bonding that involves polar amino acids and substrate’s
°
(950 μL, 50 mM, pH=7.5) at 37 C.
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Figure 2. MD optimized structure of W104A (a) and W104C
(b) in complex with S-1a (yellow). Diagram of interactions
between substrate S-1a and mutants W104A and W104C (c).
gain insight of the improved selectivity of W104C in
comparison with W104A, we focused on the distribu-
tion of interactions between S-1a and amino acids
surrounding the surface of binding pockets (Figure 2c).
In W104C, the stereospecificity pocket (C104, S42,
T47) focused on maintaining a relatively polar envi-
ronment with the pyridine group of S-1a. In mutant
W104A, the polar interaction was weakened, resulting
in a reduced enantioselectivity. Nevertheless, compared
with W104C, more interactions could be formed in
W104A (Figure 2c), which favored a stronger affinity
and a lower Km toward the substrate (Table S2).
Although the kcat/Km of 104C displayed relative
Figure 3. CALB mutants-catalyzed KR of various phenyl
pyridyl methyl acetates. Reactions were performed with
substrates 1b or 1c (0.01 mmol), acetonitrile (50 μL) and
°
enzymes (~50 μg) in PBS (950 μL, 50 mM, pH=7.5) at 37 C.
decrease compared with 104A, the absolute value was the X-ray structure of CALB, the 104 site located in
still at a high level revealing high hydrolytic activity. the bottom of the stereospecificity pocket, resulting in
Inspired by the positive results, phenyl(pyridin-3- a shorter distance and stronger intermolecular force
yl)methyl acetate (rac-1b) and phenyl(pyridin-2-yl) between the 104 polar residues and N atom of pyridin-
methyl acetate (rac-1c) were also tested (Figure 3). All 4-yl (1a) than those of pyridin-3-yl (1b) and pyridin-
the mutants showed S-selectivity toward these two 2-yl (1c). Therefore, the best KR enantioselectivity of
substrates, indicating that the pyridyl groups of rac-1b 1a (E>200, entries 2 and 4 in Table S4) catalyzed by
and rac-1c bind in the stereospecificity pocket, CALB mutants was higher than 1b (E=5, entry 11 in
similarly as 1a. Interestingly, enhanced selectivity was Table S4) and 1c (E=44, entry 21 in Table S4).
obtained by reconstructing the stereospecificity pocket
Apart from N atom, halogens also have free
with polar residues in all cases. The best mutant for 1b electron pairs, which may interact with polar residues.
was W104S, which exhibited a decreased selectivity in To further evaluate electronic effects on the enantiose-
the KR of 1a. For 1c, W104C, W104S and W104T lectivity of CALB mutants, diarylmethanols substituted
gave similar enantioselectivities, indicating a synergis- with phenyl and halogenated phenyl were studied
tic effect of polar residues and pyridyl group. An (Scheme 2). For substrates 1d–1f, R-enantiomers were
acceptable selectivity with W104C was obtained (E= the major products under the catalysis of various
44, 39% yield, 92% ee, entry 21 in Table S4), CALB mutants of W104. The results indicated that the
compared with nonpolar W104A (E=14, 40% yield, phenyl was the preferential moiety binding into the
78% ee, entry 20 in Table S4).
stereospecificity pocket due to the different steric
For the electronic effect-guided mutants, the dis- effect between phenyl and halogenated phenyls. In-
tance between polar OH or SH groups and N atom of deed, the larger size difference between phenyl and
pyridyl made a major contribution to the stereo- halogenated phenyls led to a higher enantioselectivity
selectivity improvement theoretically.[14] According to (2d<2e<2f, Scheme 2). The steric effects were
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indicating a cumulative effect. In a preparative scale
KR reaction of rac-1h (261 mg) under the catalysis of
W104S mutant, S-2h was obtained in 40% isolated
yield (88 mg) with 94% ee, meanwhile R-1h was
recovered in 46% yield (120 mg) and 98% ee value
(see Supporting information).
To better understand the influence of electronic
factors on the enzymatic enantioselectivity, two other
polar residues lining the stereospecificity pocket, T42
and S47, were examined. As shown in Figure 4, when
introducing T42 A or S47A into the mutant W104A or
W104C respectively, the ee value decreased remark-
ably. For example, a double-point mutant 104A/47A
hydrolyzed rac-1b with negligible enantioselectivity.
The introduction of alanine decreased the polarity of
stereospecificity pocket, which was crucial for the
binding of pyridine ring.
In the KR of sec-alcohols containing phenyl and
alkyl groups, CALB mutant W104V/A281L/A282K
gave the best reversed selectivity compared to WT,
according to our previous study,[11c] showing the high
affinity between phenyl group and the reshaped stereo-
specificity pocket. We then further tested this mutant
for the KR of substrate rac-1b, and obtained a
reversed enantioselectivity (Figure 5, entries 17–19 in
Table S4), expectedly. Considering the importance of
site 281, an alanine located in the large binding
pocket,[17] we performed the hydrolysis of rac-1b
under the catalysis of mutants W104V/A281S and
W104V/A281C, respectively. The R-selectivity im-
proved significantly, and a good enantioselectivity was
observed with W104V/A281S mutant (Figure 5, E=
28, 49% yield, 84% ee).
Scheme 2. Enantioselectivity of CALB mutants in the KR
towards halogenated diarylmethanols. Reactions were per-
formed with different substrates (0.01 mmol), acetonitrile
(50 μL) and enzymes (~50 μg) in PBS (950 μL, 50 mM, pH=
To reveal the root of reversed enantiopreference,
molecular simulations of substrates R-1b and S-1b
°
7.5) at 37 C.
further validated by the enzymatic KR of 1g. When
the phenyl was replaced by 4-methylphenyl (1g), a
larger group than 4-fluorophenyl, 4-fluorophenyl was
accommodated into the alcohol-binding pocket and
thus reversed (S)-selectivity was observed in compar-
ison with 1d–1f. For 1g with 4-fluorophenyl binding
into the active site, electronic effects from 104C or
104S improved the enantioselectivity on different
degrees.
One interesting finding is that S-(4-chlorophenyl)-
(pyridin-2-yl) methanol (S-CPMA, S-2h), an important
precursor for synthesizing the antiallergy drugs
bepotastine[15] and carbinoxamine[16] (Figure 1a), was
obtained by efficient S-selective KR. The electronic
effect-guided mutagenesis provided improved variants
W104S and W104T for the KR of rac-1h. There could
be a combination of steric and electronic effects to
give an even higher enantioselectivity for 1h (E=75,
entry 46 in Table S4) than 1c (E=37, entry 22 in
Table S4) and 1e (E=3, entry 34 in Table S4),
Figure 4. The influence of T42 and S47 to the enzymatic
enantioselectivity. Reactions were performed with substrates
1a, 1b and 1c (0.01 mmol, respectively), acetonitrile (50 μL)
and enzymes (~50 μg) in PBS (950 μL, 50 mM, pH=7.5) at
°
37 C.
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to engineer various enzymes more conveniently and
efficiently to obtain the optically pure products bearing
a pyridyl or other heterocycle moieties in further
investigation.
Experimental Section
General Procedure of Site-Directed Mutagenesis
A 3-step PCR method was applied to construct all mutants as
°
°
follows: 94 C for 5 min, followed by denaturation at 94 C for
°
°
1 min, annealing at 64 C for 1 min, and elongation at 72 C for
°
14 min repeated 30 times, 72 C for 10 min ended the reaction.
The 50 μL PCR mix contained ddH2O (29 μL), Pfu 10X buffer
(5 μL), dNTP (4 μL, 2.5 mM each), forward primers (2 μL,
10 μM each), silent reverse primer (2 μL, 10 μM), WT-CALB
plasmid (pETM11-CALB) as DNA template (1 μL, 100 ng/μL)
and 1 μL of Pfu polymerase. To ensure elimination of the
circular methylated template plasmid, 25 μL of PCR reaction
mixture were mixed with 2 μL DpnI (10 U/μL) restriction
Figure 5. The reversed selectivity of CALB mutants-catalyzed
KR of rac-1b. Reactions were performed with substrate 1b
(0.01 mmol), acetonitrile (50 μL) and enzymes (~50 μg) in PBS
°
(950 μL, 50 mM, pH=7.5) at 37 C.
°
enzyme at 37 C for more than 3 h. After digestion, the genes
were purified using an Omega Biotek Cycle Pure kit. The PCR
product (15 μL) was transformed to 50 μL of E. coli Origami2
electrocompetent cells. Transformation mixture was incubated
were performed for mutant W104V/A281S, respec-
tively (Figure S3). In comparison with 104A, the
hydrophobic interaction of 104V was increased signifi-
cantly (Figure S3, W104V/A281S-R-1b), which stabi-
lized the phenyl group. Furthermore, the stronger
polarity induced by the S281 offered more stable
interactions of pyridine group. It’s worth noting that
the hydrogen-bond interaction is observed between
S281 and the N atom on pyridine group, to bind the
substrate in R-Pose, which was also considered as the
°
with 1 mL LB medium at 37 C with shaking at 200 rpm and
spread on LB-agar plates containing kanamycin (34 μg/mL) and
chloramphenicol (34 μg/mL). All CALB various primers in this
work were listed in Table S1 in Supporting Information.
Expression of CALB Mutants
°
Colonies appeared after cultivation for 12–16 h at 37 C and
core effect to convert the selectivity in organic phase were picked into 5.0 mL LB medium containing kanamycin
in the previous work.[17a] Thus, we considered the
(34 μg/mL) and chloramphenicol (34 μg/mL), and then incu-
°
bated at 37 C under shaking at 200 rpm overnight. A fresh
above mentioned factors may affect the enantioselec-
200 mL of TB media was added to 2 mL preculture containing
kanamycin (34 μg/mL), chloramphenicol (34 μg/mL) and
1.0 mg/mL L-arabinose as the inducer for expression of
chaperone pGro7. The cultures were shaken at 37 C until the
optical density at 600 nm reached 0.6, and then cooled to 4 C
for 1 h. Next, 1.0 mM isopropyl β-thiogalactopyranoside
(IPTG) was added into the cultures to induce CALB expression
tivity reversion, synthetically.
In conclusion, an efficient rational design strategy
under the guidance of electronic effect was proposed to
enhance the enantioselectivity of the CALB mutants
towards bulky pyridyl(phenyl)methanols. The recon-
struction of the polar environment at W104 site was
performed, and three mutants (W104C/S/T) displayed
significant improvement of enantioselectivity for vari-
ous phenyl pyridyl methyl acetates. In addition,
mutating residues T42 or S47 into nonpolar alanine
caused a decline of enantioselectivity of these mutants
(W104A and W104C). Moreover, the mutants W104V/
A281S and W104V/A281C displayed reversed stereo-
selectivity for the substrate rac-1b in comparison with
W104C/S/T mutants, because of the reversed binding
orientation of pyridyl groups induced by the changed
polar environment. These results implied the impor-
tance of electronic effects, and even the ability to
manipulate the stereoselectivity of enzymes. A series
of bulky pyridyl(phenyl) methanols, including S-(4-
chlorophenyl)-(pyridin-2-yl) methanol (S-CPMA), the
intermediate of bepotastine, were obtained in good
yields and ee values. The electronic effect-guided
rational design strategy demonstrated herein enables us
°
°
°
for 48 h at 18 C. The tubes were centrifuged at 8000 rpm and
°
4 C for 5 min, and then the supernatants were discarded. The
cell pellet of each tube was resuspended in 50 mM PBS buffer
(pH 7.5) and lysed by sonification (15×10 sec with 10 sec
intervals, at 40% pulse, in a water-ice bath). The cell debris was
°
removed by centrifugation for 25 min at 4 C. The supernatant
was stored at À 78 C.
°
Hydrolytic Reactions Screening using Substrate
1a–1h
50 μL solution of substrate rac-1 (0.25 M in acetonitrile) was
added into 5.0 mL EP tubes containing 950 μL crude enzyme.
The hydrolytic reaction was performed at 37 C for the
appropriate time. Then the reaction mixture was diluted with
MTBE for three times and determined by chiral HPLC. To
obtain the isolated yields conveniently, the reaction scale was
increased 40 times.
°
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Z. X. Wang, Y. H. Wang, X. F. Wu, H. Lu, Z. D. Huang,
Acknowledgements
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This research was funded by National Natural Science
Foundation of China (No. 91956128), Zhejiang Provincial
Natural Science Foundation (No. LY19B020014), Ph.D. Scien-
tific Research Starting Foundation of Jiaxing University (No.
CD70519086) and Scientific Research Starting Foundation of
Zhejiang University of Technology (No. 2020105009029).
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