Facile Enzymatic Synthesis of Phosphorylated Ketopentoses

Article abstract of DOI:10.1021/acscatal.5b02234

An efficient and convenient platform for the facile synthesis of phosphorylated ketoses is described. All eight phosphorylated ketopentoses were produced using this platform starting from two common and inexpensive aldoses (d-xylose and l-arabinose) in more than 84% isolated yield (gram scale). In this method, reversible conversions (isomerization or epimerization) were accurately controlled toward the formation of desired ketose phosphates by targeted phosphorylation reactions catalyzed by substrate-specific kinases. The byproducts were selectively removed by silver nitrate precipitation avoiding the tedious and time-consuming separation of sugar phosphate from adenosine phosphates (ATP and ADP). Moreover, the described strategy can be expanded for the synthesis of other sugar phosphates.

Full text of DOI:10.1021/acscatal.5b02234

Letter
pubs.acs.org/acscatalysis
Facile Enzymatic Synthesis of Phosphorylated Ketopentoses
Liuqing Wen,† Kenneth Huang,† Yunpeng Liu,*,†,‡ and Peng George Wang*,†,‡
†Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States
‡National Glycoengineering Research Center, Shandong University, Jinan 250100, China
S
* Supporting Information
ABSTRACT: An efficient and convenient platform for the
facile synthesis of phosphorylated ketoses is described. All
eight phosphorylated ketopentoses were produced using this
platform starting from two common and inexpensive aldoses
(D-xylose and L-arabinose) in more than 84% isolated yield
(gram scale). In this method, reversible conversions (isomer-
ization or epimerization) were accurately controlled toward
the formation of desired ketose phosphates by targeted
phosphorylation reactions catalyzed by substrate-specific
kinases. The byproducts were selectively removed by silver
nitrate precipitation avoiding the tedious and time-consuming separation of sugar phosphate from adenosine phosphates (ATP
and ADP). Moreover, the described strategy can be expanded for the synthesis of other sugar phosphates.
KEYWORDS: biocatalysis, enzymatic synthesis, phosphorylated ketopentoses, one-pot reactions, silver nitrate precipitation
phosphate acts as a glucose signaling compound, recruiting and
activating a specific protein serine/threonine phosphatase
(PPase), which is responsible for the activation of transcription
of the L-type pyruvate kinase gene and lipogenic enzyme
genes.8−10 Enzymes involved in phosphorylated ketopentoses
metabolism are exciting potential targets for therapeutic
treatment.11−14 Additionally, phosphorylated ketopentoses are
important intermediates in sugar metabolism pathway. All
pentoses including aldopentose and ketopentose that could be
utilized by bacteria or other organisms must first be converted
to their phosphorylated ketopentose forms to enable metabolic
function.15−18 In these metabolism pathways, ketopentose 1-
phosphates are split into glycolaldehyde and dihydroxyacetone
phosphate, which is an intermediate in the glycolytic pathway,
by aldolases.19−21 Ketose 5-phosphates will be epimerized to D-
xylulose 5-phospahte or D-ribulose 5-phosphate, which are key
participants in the pentose phosphate pathway (PPP), by
epimerases.22−24 PPP is a universal metabolic process present
in bacteria, plants, and animals,25 and its main function is to
produce reducing power and building blocks for cell growth.26
Because of their critical position in the sugar metabolism
pathway, phosphorylated ketopentoses are also the starting
materials in synthetic chemistry.27 For example, D-xylulose 5-
phosphate can act as the starting material for the synthesis of
heptose in bacteria.28 Likewise, D-ribulose 5-phosphate can be
used for the synthesis of 3-deoxy-D-manno-octulosonic acid
(KDO).29 Therefore, phosphorylated ketopentoses have great
potential for applications in investigating the mechanistic and
f all possible structures, only 12 pentoses naturally occur,
Ocomprising eight aldopentoses (D-xylose,
D-lyxose, D-
ribose, D-arabinose, L-xylose, L-lyxose, L-ribose, and L-arabinose)
and four corresponding ketopentoses (D-xylulose, D-ribulose, L-
xylulose, and L-ribulose).1 The ketopentoses can be phosphory-
lated at the C-1 or C-5 position, resulting in eight
phosphorylated ketopentoses (Figure 1). It is now well-
established that abnormal levels of phosphorylated ketopen-
toses in mammals are directly correlated to a wide range of
diseases such as diabetes, cancer, atherosclerosis, and cystic
fibrosis.2−7 Uyeda and co-workers found that xylulose 5-
Received: October 5, 2015
Revised: January 31, 2016
Figure 1. Eight phosphorylated ketopentoses.
© XXXX American Chemical Society
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Letter
Scheme 1. Total Synthesis of Phosphorylated Ketopentoses from D-Xylose and L-Arabinose
regulatory aspects of sugar metabolism, identification and
characterization of new enzymes in nature, and being raw
materials in synthetic chemistry.30−32 A platform for the highly
efficient and convenient synthesis of phosphorylated ketopen-
toses is therefore of considerable interest.
strategies are mainly based on “isomerization → phosphor-
ylation” and “isomerization → epimerization → phosphor-
ylation” cascade reactions. We combined the thermodynami-
cally unfavorable bioconversions of D-xylose to D-series of
ketopentose (D-xylulose and D-ribulose), or L-arabinose to L-
series of ketopentose (L-ribulose and L-xylulose) with
phosphorylation reactions by substrate-specific kinases to
prepare the desired phosphorylated ketopentoses (1 to 3, and
5 to 7). D-ribulose 5-phosphate (4) and L-xylulose 5-phosphate
(8) were synthesized by a two-step strategy.
D-Xylose and L-arabinose are the two common pentoses
found in substantial quantities in nature.52 Although the
reactions are reversible, aldose-ketose isomerization and
ketose−ketose epimerization has been the main method for
ketose preparation.52 Nevertheless, separation of the desired
ketose from its isomeric mixture is difficult. To avoid such
separation, we combined these reversible reactions with
targeted phosphorylation reactions catalyzed by kinases in a
one-pot fashion to prepare phosphorylated ketopentoses
instead of directly phosphorylating the ketoses. These reactions
are known as one-pot multienzyme reaction (OPME).53 The
phosphorylation reaction coupled with the reversible con-
versions (isomerization or epimerization) drives the reactions
(isomerization or epimerization) toward the formation of
ketoses in their phosphorylated forms until a high conversion
ratio was reached.
In order to establish the basis of OPME reactions for the
preparation of D-xylulose 5-phosphate from D-xylose, and L-
ribulose 5-phosphate from L-arabinose, the substrate specificity
of D-xylulose kinase (XylB) and L-ribulose kinase (AraB) from
E. coli,39,41 were tested (see Supporting Information). No
detectable activity of XylB toward D-xylose, or AraB toward L-
arabinose was found (Table 1), indicating their potential for
OPME reactions. To test the practicability of the designed
OPME reactions, analytical reactions were first carried in 50 ul
system containing conversion-related enzymes (Table 2),
starting materials and ATP. Reactions without isomerase were
performed as negative controls. The reactions were tested by
Regarding the biological and synthetic applications of
phosphorylated ketopentoses, multiple methods have been
developed. The chemical phosphorylation of ketoses involves
protection/deprotection steps.33−35 Alternatively, enzymatic
catalysis (kinase) with mild reaction conditions and high
reaction efficiency is able to proceed regio- and stereoselectively
without requiring protection.36−41 However, ketopentoses are
cost prohibitive for preparative-scale synthesis. The strategy
includes enzymatic isomerization in a one-pot fashion to enable
the use of cheaper aldose as starting materials to prepare
phosphorylated ketoses,34,42−44 but the availability of substrate-
specific kinases is a prerequisite. Moreover, enzymatic
phosphorylation requires the separation of sugar phosphate
from adenosine phosphates (ATP and ADP) to obtain a sugar
phosphate in pure form. The two most common methods used
for sugar phosphate purification are ion-exchange chromatog-
raphy and barium precipitation,34,45,46 but both methods are
labor-intensive and time-consuming. Additionally, enzymatic
synthesis of phosphorylated ketopentoses employing trans-
ketolase,47−49 aldolase,42,45,50 or oxidase51 has also been
suggested. However, these methods suffer from both expensive
starting materials and extensive purification steps. Therefore,
while some phosphorylated ketopentoses are commercially
available, they are extremely expensive (D-ribulose 5-phosphate,
$1245/25 mg, Sigma-Aldrich; D-xylulose 5-phosphate, $1150/
10 mg, Carbosynth). Studies of this fundamental class of
carbohydrates have been hindered by a lack of efficient
preparation methods to readily provide substantial amounts
of the desired products.
In this work, an efficient and convenient platform for
phosphorylated ketose syntheses is described. All eight
phosphorylated ketopentoses were produced from D-xylose
and L-arabinose utilizing this platform (Scheme 1). Our
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isomerase (XylA) from E. coli54 and XylB in the presence of
ATP (1.25 molar equiv) as phosphate donor to prepare D-
xylulose 5-phosphate (OPME 1, Scheme 1). L-Arabinose was
incubated with ATP (1.25 molar equiv), L-arabinose isomerase
(AraA) from Bacillus subtilis,55 and AraB to prepare L-ribulose
5-phosphate (OPME 5, Scheme 1). No buffer was used in
consideration to purification. The reaction pH was held near
7.5, where all enzymes are quite active, using sodium hydroxide
as the reaction occurred. Both reactions were allowed to
proceed until a conversion ratio exceeding 99% was reached (as
confirmed by HPLC). Afterward, the silver nitrate precipitation
method56 was used to purify D-xylulose 5-phosphate and L-
ribulose 5-phosphate. In detail, silver nitrate was added to the
solution to precipitate ATP and ADP selectively until no new
precipitation was observed. Precipitates were removed by
centrifugation. Sodium chloride was added to precipitate
residual silver ions, and silver chloride precipitate was removed
by centrifugation. The entire separation process can be finished
in less than 15 min. After desalting by a P-2 column, D-xylulose
5-phosphate and L-ribulose 5-phosphate were isolated in more
a
Table 1. Substrate Specificity of Kinases
b
b
XylB
activity
(%)
AraB
activity
(%)
LyxK
activity
(%)
RhaB
HK
activity
(%)
activity
(%)
substrate
L-arabinose
D-xylose
ND
ND
7.3
ND
ND
1.3
ND
ND
100
2.5
ND
0.1
ND
ND
NA
NA
100
349
L-xylulose
D-ribulose
L-ribulose
D-xylulose
100
111
ND
0.3
4.9
139
100
3.4
16.9
100
2.5
1.6
a
Substrate specificity was studied by the reactions that were performed
at 37 °C for 10 min in 50 ul reaction mixture containing a Tris-HCl
buffer (100 mM, pH 7.5), 20 mM of sugar standards, 20 mM of ATP,
b
5 mM of Mg2+, and 10 μg of enzymes. Data from ref 56. NA: not
assayed. ND: no detectable activity was observed.
TLC (EtOAc/MeOH/H2O/HOAc = 5:2:1.4:0.4). After
observing sugar phosphates formation by TLC and no reactions
in control samples, preparative scale syntheses were performed.
Preparative-scale syntheses were routinely performed in gram
scale (Table 2). D-Xylose was incubated with D-xylose
Table 2. Total Synthesis of Phosphorylated Ketopentoses from D-Xylose and L-Arabinose Using the Strategy Shown in Scheme 1
a
Defined as the percentage of desired phosphorylated ketose out of the sum of all possible isomers (as confirmed by HPLC).
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than 90% yield (Table 2) comparable to the yield for ion-
exchange purification methods. Compared to the barium
precipitation method, by which sugar phosphate was isolated
as a barium salt in the presence of barium and ethanol,34,46 no
additional steps to remove toxic ions and no accurate pH
control are necessary. Moreover, silver is safer than barium. The
isolated products were confirmed by NMR and MS analysis
(see Supporting Information). Compared to the previous
synthesis,34,44,49 we not only obtained a higher isolated yield
but also avoided the tedious purification step.
To assess product purity, the phosphate groups on both
phosphorylated sugars were hydrolyzed by acid phosphatase.
The resultant monosaccharides were analyzed by HPLC (see
Supporting Information). A product distribution of D-xylulose
to D-xylose (98.4:1.6) was observed indicating the isolated
product of D-xylulose 5-phosphate contains 1.6% of D-xylose 5-
phosphate (as also observed by NMR). Similarly, a product
distribution of L-ribulose to L-arabinose (99.5:0.5) was observed
indicating the isolated product of L-ribulose 5-phosphate
contains 0.5% of L-arabinose 5-phosphate (as also observed
by NMR). The existence of aldoses may because XylA and
AraA can incorrectly isomerize D-xylulose 5-phosphate and L-
ribulose 5-phosphate to a certain extent.
which is different from D-xylose and L-arabinose. To prepare D-
ribulose 1-phosphate from D-xylose, and L-xylulose 1-phosphate
from L-arabinose, isomerization catalyzed by isomerase (XylA
or AraA) and a C-3 epimerization catalyzed by D-tagatose 3-
epimerase (DTE) from Pseudomonas Sp, ST-2459 were
combined in one-pot. These two reversible conversions were
coupled with L-rhamnulose kinase (RhaB) from Thermotoga
maritima MSB8, a novel enzyme that requires ketoses with
(3R)-configuration,56 resulting in the formation of (3R)-ketose
1-phosphates. Once the starting aldoses were no longer
detected, D-ribulose 1-phosphate and L-xylulose 1-phosphate
were purified by silver nitrate precipitation in more than 90%
yield (Table 2) and confirmed by NMR and MS analysis (see
Supporting Information). A product distribution of D-ribulose,
D-xylulose and D-xylose (98.2:1.2:0.6) was observed indicating
the purity of D-ribulose 1-phosphate is 98.2%. For L-xylulose 1-
phosphate analysis, no detectable L-arabinose or L-ribulose was
found indicating L-xylulose 1-phosphate has a purity exceeding
99%. Such conversions are important because most of sugars
that naturally occur in large amounts are (3S)-aldoses.52
Therefore, the reactions described herein (OPME 3 and OPME
7) represent a novel strategy for the preparation of (3R)-
ketoses from (3S)-aldoses directly.
To prepare D-xylulose 1-phosphate and L-ribulose 1-
phosphate from D-xylose and L-arabinose using OPME
reactions, an enzyme that could phosphorylate D-xylulose and
L-ribulose at the C-1 position but not D-xylose and L-arabinose
is required. Human fructosekinase (HK) catalyzes the
phosphorylation of ketoses to ketose 1-phosphates.57 Recently,
we found HK could specifically recognize D-xylulose and L-
ribulose but not D-xylose and L-arabinose.56 Analytical reactions
containing conversion-related enzymes (Table 2) were
performed and tested as described above. Once the formation
of sugar phosphates were observed by TLC and no further
reactions in control samples seen, preparative scale syntheses
were performed. D-Xylose was incubated with ATP (1.25 molar
equiv), XylA, and HK to prepare D-xylulose 1-phosphate
(OPME 2, Scheme 1). L-Arabinose was incubated with ATP
(1.25 molar equiv), AraA, and HK to prepare L-ribulose 1-
phosphate (OPME 6, Scheme 1). Both reactions were
monitored by TLC and HPLC. Once no detectable amounts
of the starting aldoses were observed (conversion ratio
exceeding 99%), silver nitrate precipitation was used to purify
the sugar phosphates. After desalting by a P-2 column, D-
xylulose 1-phosphate and L-ribulose 1-phosphate were isolated
in more than 90% yield (Table 2). The products were
confirmed by NMR and MS analysis (see Supporting
Information). The purity was analyzed in the same manner
mentioned above (see Supporting Information). Because the C-
1 position was blocked by the phosphate group, the side
reactions were avoided to result in a product purity exceeding
99% (Table 2).
D-Ribulose 5-phosphate and L-xylulose 5-phosphate also have
been difficult to prepare in quantity. The methods known in the
literature for the synthesis of D-ribulose 5-phosphate are the
phosphorylation of D-ribulose,34 the isomerization of D-ribose
5-phosphate, and the oxidization of D-gluconate 6-phosphate.51
L-Xylulose 5-phosphate could be prepared by phosphorylating
L-xylulose.38 Nevertheless, these methods also suffer from
expensive starting materials or a tedious purification step. In
this work, D-ribulose 5-phosphate and L-xylulose 5-phosphate
were prepared from D-xylose and L-arabinose by a two-step
strategy (conversion 4 and conversion 8, Scheme 1) due to an
inability to identify kinases that could specifically phosphorylate
D-ribulose and L-xylulose at the C-5 position. In the first
conversion step, D-ribulose and L-xylulose were obtained by
hydrolyzing the phosphate groups of D-ribulose 1-phosphate
and L-xylulose 1-phosphate, both of which were prepared from
D-xylose and L-arabinose using OPME 3 and OPME 7, by acid
phosphatase (AphA) from E. coli,.60 AraB is welL-known as L-
ribulose kinase,41 but it also displays high activity toward D-
ribulose (Table 1). Thus, in the second conversion step, D-
ribulose was incubated with AraB to prepare D-ribulose 5-
phosphate. L-xylulose was incubated with L-xylulose kinase
(LyxK) from E. coli38 to prepare L-xylulose 5-phosphate. The
products were purified by using silver nitrate precipitation.
After desalting by using a P-2 column, the products were
isolated in more than 84% yield with regard to D-xylose and L-
arabinose (Table 2), respectively. Purity analysis indicated both
D-ribulose 5-phosphate and L-xylulose 5-phosphate have a
purity of 99%.
D-Ribulose 1-phosphate and L-xylulose 1-phosphate were
prepared from D-xylose and L-arabinose using OPME 3 and
OPME 7 (Scheme 1). Although D-ribulose 1-phosphate and L-
xylulose 1-phosphate have great potential applications, they
have been difficult to prepare in substantial quantities. For
example, it has been reported that D-ribulose 1-phosphate can
be isomerized from D-ribose 1-phopshate, which results from
the phosphorylation of D-ribose, by MTR 1-P isomerase.58
However, this process is impractical, requiring not only a sugar
phosphate purification step but also a protracted isomer
separation. D-ribulose and L-xylulose have a (3R)-configuration
In summary, a novel method for the efficient and convenient
synthesis of phosphorylated ketoses was established. This
method relies on substrate-specific kinases and a convenient
sugar phosphates purification method (silver nitrate precip-
itation). Starting from two common and inexpensive aldoses
(D-xylose and L-arabinose), all phosphorylated ketopentoses
were produced utilizing this strategy with high yield and purity
without a tedious sugar phosphate separation step. ATP is also
commercially affordable due to the increased industrial
production over the past decades,61,62 making the trans-
formation reaction described herein of particular interest for
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* Supporting Information
The Supporting Information is available free of charge on the
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AUTHOR INFORMATION
■
(27) Stincone, A.; Prigione, A.; Cramer, T.; Wamelink, M. M.;
Campbell, K.; Cheung, E.; Olin-Sandoval, V.; Gruning, N.; Kruger, A.;
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Corresponding Authors
*E-mail: yliu65@gsu.edu.
*E-mail: pwang11@gsu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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■
This work was supported NIH (GM085267), National Basic
Research (973) Program of China (2012CB822102), and the
Key Grant Project of Chinese Ministry of Education (313033).
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