Light-Driven Kinetic Resolution of α-Functionalized Carboxylic Acids Enabled by an Engineered Fatty Acid Photodecarboxylase

Article abstract of DOI:10.1002/anie.201903165

Chiral α-functionalized carboxylic acids are valuable precursors for a variety of medicines and natural products. Herein, we described an engineered fatty acid photodecarboxylase (CvFAP)-catalyzed kinetic resolution of α-amino acids and α-hydroxy acids, which provides the unreacted R-configured substrates with high yields and excellent stereoselectivity (ee up to 99 %). This efficient light-driven process requires neither NADPH recycling nor prior preparation of esters, which were required in previous biocatalytic approaches. The structure-guided engineering strategy is based on the scanning of large amino acids at hotspots to narrow the substrate binding tunnel. To the best of our knowledge, this is the first example of asymmetric catalysis by an engineered CvFAP.

Full text of DOI:10.1002/anie.201903165

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Accepted Article
Title: Light-Driven Kinetic Resolution of α-Functionalized Carboxylic
Acids Enabled by Engineered Fatty Acid Photodecarboxylase
Authors: Qi Wu, Jian Xu, Yujing Hu, Jiajie Fan, Mamatjan Arkin,
Danyang Li, Yongzhen Peng, Weihua Xu, and Xianfu Lin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903165
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10.1002/anie.201903165
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Light-Driven Kinetic Resolution of α-Functionalized Carboxylic
Acids Enabled by Engineered Fatty Acid Photodecarboxylase
Jian Xu, Yujing Hu, Jiajie Fan, Mamatjan arkin, Danyang Li, Yongzhen Peng, Weihua Xu, Xianfu Lin &
Qi Wu*
Abstract: Chiral α-functionalized carboxylic acids are valuable
precursors for a variety of medicines and natural products. Herein,
we described an engineered fatty acid photodecarboxylase
(CvFAP)-catalyzed kinetic resolution of α-amino acids and α-
hydroxy acids providing the unreacted (R)-configured substrates
with high yields and excellent stereoselectivity (ee up to 99%).
This efficient light-driven process requires neither NADPH
recycling nor prerequisite preparation of esters, which are
required in previous biocatalytic approaches. The structure-
guided engineering strategy is based on large-sized amino acid
scanning at hotspots to narrow the substrate binding tunnel. To
the best of our knowledge, this is the first example of asymmetric
catalysis by an engineered CvFAP.
research topic, particularly in combination with biocatalysis for
cascade reactions.[7] Although light-dependent enzymes that
directly utilize visible light as an energy source are highly
sought after, photoenzymes have seldom been found in
nature. The activities of these type of enzymes depend on the
irradiation of the cofactor in the active site with light, such as
DNA-repair
enzymes[8]
and
protochlorophyllide
oxidoreductases[9]. Very recently, Beisson and co-workers
discovered a fatty acid photodecarboxylase from Chlorella
variabilis NC64A (CvFAP) which they used to convert long-
chain fatty acids into hydrocarbons.[9] In another key study,
Hollmann’s group reported the synthesis of alkanes from
triglycerides through
a designed lipase/CvFAP-catalyzed
cascade reaction.[11a] The different activity of cis- and trans-
oleic acid mentioned in these reports strongly aroused our
interest. We envisioned that CvFAP could recognize not only
cis/trans isomers, but stereoisomers as well. To the best of
our knowledge, no examples of enantioselective reactions
catalyzed by CvFAP have been reported to date.[10-11] Herein,
we demonstrate a new KR method catalyzed by engineered
CvFAP variants for the synthesis of chiral α-hydroxy/amino
carboxylic acids. This photo-activated biotransformation
proceeds without NADPH circulation or any other reaction
pretreatment, thus providing a more efficient route to chiral
compounds with high activity and stereoselectivity.
Multifunctional chiral molecules, such as unnatural α-amino
acids and α-hydroxy carboxylic acids, are important building
blocks in pharmaceutical chemistry and chemical biology.[1]
Over the past years, the development of new methods for the
synthesis of chiral α-functionalized carboxylic acids has
received considerable attention. The common chemical
synthesis routes heavily depend on transition metal catalysts
and complex chiral ligands, which suffer from high costs and
environmental problems.[2] Therefore, the development of
new methods to synthesize chiral α-functionalized carboxylic
acids through an eco-friendly approach is still a topic of
continuous scientific interest.
In contrast to traditional chemical methods, biocatalysis
provides in many cases a greener and more sustainable
process to obtain these classes of compounds. For example,
keto reductases (KRED) and imine reductases (IRED) have
been successfully used to convert α-keto acids into α-
hydroxy/amino acids.[3] These reduction processes require a
stoichiometric amount of an expensive cofactor (e.g. NADPH)
as a hydrogen donor. One way to overcome this limitation is
to introduce another oxidoreductase, such as glucose
dehydrogenase (GDH), to recycle the cofactors.[4] However, a
series of reaction conditions, such as temperature and pH,
have to be optimized to ensure that each enzyme works with
acceptable activity in the multi-enzyme system. Another
widely used method is kinetic resolution (KR) using lipases.[5-
6]
However, there are still some limitations that need to be
addressed, such as the requirement of prerequisite ester or
amide preparation. Accordingly, exploring other highly
efficient and versatile biocatalytic methods to access chiral α-
functionalized carboxylic acids is certainly desirable.
Due to the advantages of low consumption of energy and
being a clean process, photocatalysis is becoming a popular
Scheme 1. Enzymatic asymmetric synthesis of α-hydroxy/amino acids
Initially, we studied the catalytic ability of wild-type (WT)
CvFAP to promote the KR of 2-hydroxyoctanoic acid (1a).
After irradiation with a 450 nm light for 12 hours, only 20% of
the substrate was converted into decarboxylation products by
WT CvFAP with low substrate stereoselectivity (ees=22%)
having (R)-configuration. The yield and stereoselectivity failed
to increase upon prolonging the reaction time (Figure 1). In
[*]
Jian Xu, Yujing Hu, Jiajie Fan, Mamatjan arkin, Danyang Li,
Yongzhen Peng, Weihua Xu, Xianfu Lin and Qi Wu*
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
E-mail: llc123@zju.edu.cn, wuqi1000@163.com
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10.1002/anie.201903165
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an effort to tackle this problem, CvFAP was engineered by
directed evolution which had been identified as a versatile
strategy to improve the targeted feature of an enzyme, such
as catalytic activity or selectivity.[12] We assumed that the
improvement of the activity might also influence substrate
stereoselectivity.[13] As shown in Figure 2, the geometry of the
active site of WT CvFAP reveals a narrow substrate-binding
channel for long-chain fatty acids such as palmitic acid (PLM)
(PDB:5NCC[10]), and the substrate positioning is mainly
stabilized by the hydrophobic interaction of Y466 with the 9th
and 10th carbon atom of PLM.[10] However, when 1a (chain
length of C8) was docked into WT CvFAP, we found that
Y466 does not effectively influence the substrate. Thus, to
improve the activity and stereoselectivity of CvFAP for
medium-chain fatty acids, we targeted other residues
between Y466 and the flavin adenine dinucleotide (FAD)
binding region for genetic modification. We aimed to modify
the substrate binding tunnel so that it becomes narrower, thus
better stabilizing the substrate via hydrophobic interactions.
Residues A384, L386 and G462 were considered to be the
largest potential contributors in influencing the space of the
binding tunnel due to their short side chains. Therefore, site-
specific mutagenesis of large size amino acids including Q, K,
F and Y was used to scan these hot positions. As indicated
by the screening results in Table 1, the effect of residue L386
on the activity was evident, while stereoselectivity of L386
variants remained sub-optimal (ee=55%-67%). As anticipated,
mutagenesis at the other two positions led to a moderate
enhancement of the activity, but to a remarkable influence on
enantiopreference for the (S)-substrate. The best hit in the
present study proved to be variant G462Y, showing the
highest ee-value of the unreacted (R)-1a (up to 99%) under
an ideal conversion (51%). The kinetic parameters were then
measured for WT CvFAP and G462Y to compare their
catalytic activity (see supporting information). Variant G462Y
displayed a catalytic efficiency (kcat/Km = 6.99 s-1mM-1) which
is 30-fold higher than that of WT (kcat/Km = 0.23 s-1mM-1)
(Table S1). Moreover, the enantiopreference of variant
G462Y for the (S)-substrate is much better than that of WT
CvFAP ((kcat/Km)s/(kcat/Km)R=205 vs. (kcat/Km)s/(kcat/Km)R=5.7)
(Table S1). Noteworthy, a little heptaldehyde was observed
as by-product when screening the model reaction. We
speculated that the hydroxy ions in water can also attack the
reaction intermediate, and then spontaneously dehydrate to
produce such aldehyde by-product.
binding tunnel, also reacted to give the (R)-isomer with
excellent enantioselectivity (ee=99%).
We next turned our attention to the KR of α-amino acids.
As an extension of the substrate scope, α-amino acids
underwent smooth decarboxylation with the best mutant
G462Y, and produced the expected (R)-stereoisomers of
unnatural
amino
acids
(R)-1l
with
satisfactory
stereoselectivity. Unexpectedly, the enantioselectivity of 1m
was reversed to (S)-configuration with a moderate ee value.
Surprisingly, no reactions of 1n and 1o were observed under
the catalysis of WT CvFAP or G462Y mutant, probably due to
Figure 1. The progress curve of the KR of 1a with WT and variant G462Y.
Dotted gray lines are for WT-CvFAP, and black straight lines for G462Y.
(●) conversion; (■) ee.
Figure 2. Active site of CvFAP with palmitic acid (PLM), showing the
minimum distance between PLM and hot positions (A384, L386, G462,
Y466).
Table 1: Assessing the introduction of large-sized amino acids (K, Q, F, Y)
at the chosen hot spots [a]
As our goal was to develop an efficient KR method of α-
functionalized carboxylic acids, the substrate scope was next
investigated. To our delight, although biocatalysts can hardly
be expected to be universal, mutant G462Y displayed a
satisfactory substrate scope. As shown in Figure 3, a series
of α-hydroxy acids with different chain length from C6 to C12
were all accepted by this mutant with excellent
stereoselectivity (E up to 211). Besides compounds with
different alkyl chain length, α-hydroxy acids bearing functional
groups (1g, 1h, 1j) also proved to be good substrates for
G462Y, and afforded (R)-isomers in good yields and high
stereoselectivity (ee up to 99%). Particularly noteworthy is the
observation that α-hydroxy acids with thioether-groups, which
can easily be oxidized to sulfoxide or sulfone by FAD, were
also suitable for this reaction. In the case of substrate 1i,
however, the carbon chain is too short to be accepted by
G462Y, leading to low activity. Interestingly, the bulky tertiary
carboxylic acid (1k), which we thought could hardly enter the
Entry
1
2
3
4
5
6
7
8
Mutant
WT
Conv. (%)
20
ees(%) [b]
22
91
93
36
33
55
67
57
60
87
36
56
A384K
A384Q
A384F
A384Y
L386K
L386Q
L386F
L386Y
G462K
G462Q
G462F
G462Y
53
50
29
38
48
60
65
63
70
45
35
51
9
10
11
12
13
99
[a] Reaction conditions: rac-1a was dissolved in 20 μL DMSO, then
added to 2 mL crude enzyme solution (final concentration: 10 mM,
see supporting information), under the irradiation of blue LEDs for
12 h at 20 oC; [b] the ee values of (R)-1a were determined by chiral
GC after methyl ester derivatization.
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O
O
O
O
O
O
OH
7
OH
OH
OH
OH
OH
OH
2
4
5
OH
(R)-1b
OH
OH
OH
OH
(R)-1f
(R)-1a
(R)-1d
(R)-1e
(R)-1c
O
O
O
O
O
O
O
S
S
OH
H2N
OH
Cl
OH
Cl
OH
OH
OH
OH
NH2
OH
OH
OH
OH
(R)-1k
(R)-1i
(R)-1l
(R)-1j
(R)-1g
(R)-1h
O
O
O
S
OH
OH
OH
NH2
(R)-1n
(S)-1m
(R)-1o
Figure 3. Substrate scope of light-driven kinetic resolution enabled by WT CvFAP and variant G462Y.
the weak electron withdrawing ability of the methyl substituent.
To assess the scalability of these light-driven KR processes,
large scale reactions were carried out with rac-1a and rac-1b
(100 mg) in 50 mL enzyme solutions, separately. After
o
irradiation at 450 nm at 20 C for 12 hours, simple extraction
and purification steps were performed, and the desired (R)-
isomers were obtained in good isolated yields (45% for (R)-1a,
40% for (R)-1b) and high stereoselectivity (99% ee for (R)-1a,
98% ee for (R)-1b).
The enantioenriched products can be transformed into a
variety of complex biologically active molecules. For example,
(R)-1b is the chiral precursor of the antimicrobial natural
product Lipoxazolidinone A[14] or the essential building block
of a series of novel neutral thrombin inhibitors[15] (Scheme 2).
To gain insight into the source of high stereoselectivity, we
performed docking and molecular dynamics (MD) simulation
with (R)- and (S)-isomers of 2-hydroxyoctanoic acid (1a),
respectively, using the best mutant G462Y. Two
representative structures from the cluster analysis are shown
in Figure 4. The hydrogen bonded network of the residues
near the active site such as 451R, 572H, 575N, enable the
Figure 4. Models of variant G462Y with (S)-1a (A), and (R)-1a (B) docked
into the active site. The overall structure (PDB: 5NCC) is shown as a gray
cartoon and the FAD, and (S)-1a (tan) and (R)-1a (blue) are depicted by a
stick representation.
stabilization of the (R)-isomer and prevents it from
approaching FAD (Figure 4B). In contrast, this effect was
greatly reduced in the case of the favored quick-reacting (S)-
isomer, resulting in a shorter distance between 1a and FAD
(Figure 4A). Furthermore, the average distance between the
two oxygen atoms in the carboxyl moiety of 1a and the N5
atom in FAD is clearly shorter for the (S)-isomer than for the
disfavored (R)-isomer (5.08 Å and 5.60 Å for (S)-isomer vs
Scheme 2. Derivatization of enantioenriched products.
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Acknowledgements
The financial support from National Natural Science
Foundation of China (21574113) and Zhejiang Provincial
Natural Science Foundation (LY19B020014) is gratefully
acknowledged.
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COMMUNICATION
Jian Xu, Yujing Hu, Jiajie Fan, Mamatjan
arkin, Danyang Li, Yongzhen Peng,
Weihua Xu, Xianfu Lin & Qi Wu*
Page No. – Page No.
Light-Driven Kinetic Resolution of α-
Functionalized Carboxylic Acids
Enabled by Engineered Fatty Acid
Photodecarboxylase
Photoenzyme-catalyzed Kinetic Resolution of α-amino acids and α-hydroxy
acids was developed for the first time by using engineered CvFAP variants, which
were generated with a site-specific mutagenesis based on large-sized amino acid
scanning. A series of (R)-configured α-functionalized carboxylic acids were
obtained with ee up to 99% and E >200.
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