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Calculation of Maximum Theoretical Yield and Oxygen Consumption
for the Microbial Production of Selected Chemicals
Supplementary material for
From Biofuel to Bioproduct:
Is bioethanol a Suitable Fermentation Feedstock for Synthesis of Bulk
Chemicals?
Ruud A. Weusthuis
Chair for Valorisation of Plant Production Chains
Wageningen University and Research Centre
P.O. Box 17
6708 PD Wageningen
Corresponding author:
R. A. Weusthuis
P.O. Box 17, 6708 PD Wageningen
tel: +31 317 484002
ruud.weusthuis@wur.nl
Introduction
This supplementary material describes how the maximum theoretical yield and oxygen
consumption by microbial synthesis of selected chemicals (table 1) from glucose and ethanol were
calculated. The results are summarized in table 2.
Table 1. Selected chemicals
Number of C atoms in molecule
3
4
5
6
Chemical compound
Lactic acid
3-OH-propanoic acid
1,3-propanediol
Succinic acid
Fumaric acid
Malic acid
Aspartic acid
1,4-butanediamine
3-OH-butyrolactone
L-Glutamic acid
Itaconic acid
Citric acid
L-Lysine
Initial reactions with glucose
We assumed that glycolytic reactions were used for the conversion of glucose into pyruvate and that
pyruvate was converted into acetyl-CoA by pyruvate dehydrogenase. See figure 1 for an overview
of all biosynthetic reactions used.
Initial reactions with ethanol
We assumed that the conversion of ethanol into acetyl-CoA requires the input of one ATP, that the
alcohol dehydrogenase is specific for NAD+/NADH only and that the aldehyde dehydrogenase can
use both NADPH/NADP+ and NADH/NAD+ as cofactor.1 For biosynthetic purposes acetyl-CoA
enters the glyoxylic acid cycle, resulting in the net conversion of two acetyl-CoA molecules into
oxaloacetic acid, also generating reducing power in the form of NADH and FADH. Oxaloacetic
acid (or malic acid) is used as building block for further conversion. For some products the
gluconeogenic pathway was necessary.
Several routes are possible for the conversion of malate and oxaloacetate into the glycolysis
intermediates pyruvate or P-enolpyruvate. For sake of simplicity we assumed this occurs via NADH
or NADPH dependent malic enzyme only. The other required reactions of the gluconeogenesis
pathway were assumed to be the same as those of glycolysis, with the exception of the conversion
of pyruvate into PEP, which was assumed to occur by phosphoenolpyruvate synthase using two
ATP equivalents.
Cofactor regeneration
During biosynthesis the cofactors NAD+/NADH, NADP+/NADPH, FAD/FADH and ATP/ADP are
formed or consumed. The amount of these cofactors in the cell is limited and to allow product
formation to continue it is necessary to regenerate the cofactors.
Respiration was used to regenerate NAD+ and FAD, with a P/O ratio of two for both types of
cofactor, resulting in two ATP formed per molecule redox cofactor.
NADPH is used in many reductive reactions for the biosynthesis of cell components. To allow these
reactions to continue NADPH has to be regenerated from NADP+. Using glucose as a substrate this
½ Glucose
1,3-propanediol
ATP
NAD
NADH NAD
ADP
NADH
GAP
3-OH-propanal
Glycerol
NAD
ADP
NADH
ATP
Lactate
PEP
L-Lysine
Lactoyl-CoA
ATP
ADP
ADP
ATP
2 ADP
3 NADP
ADP
2 ADP
NAD
2 ATP
3 NADPH
ATP
2 ATP
NADH
3-OH-propanoate
NADP
Pyruvate
NADPH NADP
NADPH
NAD
L-Aspartate
NADP
NADPH
Malonyl-CoA
3-Oxopropanoate
NADH NAD
NADH
NAD(P)H
ATP
NAD(P)
Acetyl-CoA
ADP
Acetoacetyl-CoA
Acetate
3-OH-butyrolactone
Ethanol
Citrate
Oxaloacetate
NADH
ADP ATP
NAD(P)H NAD(P) NADH NAD
Itaconate
NAD
Malate
Isocitrate
Glyoxylate
NAD(P)
NADH
Fumarate
NAD
α-ketoglutarate
Succinate
FADH2
FAD
NAD(P)H
NADPH
NADP
1,4-butanediamine
L-Glutamate
2 ATP 2 ADP
2 NADPH 2 NADP
Figure 1. The metabolic pathways used to convert the substrates glucose and ethanol (in oval
boxes) into the products (in rectangular boxes) lactate, 3-hydroxypropanoic acid, 1,3-propanediol,
malic acid, fumaric acid, succinic acid, aspartic acid, 1,4-butanediamine, 3-oh-butyrolactone, Lglutamic acid, itaconic acid, citric acid and L-lysine. Dashed lines represent multiple reactions.
NH4, CO2 and water and proton co-reactants were omitted to simplify the picture. GAP =
glyceraldehyde-3-phosphate; PEP = phosphoenolpyruvate; ADP/ATP = adenosine
diphosphate/triphosphate; NAD(P)H/NAD(P)+ = nicotinamide adenine dinucleotide (phosphate),
reduced/oxidised form; FAD/FADH2 = flavin adenine dinucleotide, oxidised/reduced form.
is provided by the pentose phosphate route. The pentose-phosphate cycle is also active in bakers’
yeast with ethanol as a substrate, 2 but for the biosynthesis of chemical compounds this route is not
ideal. As many as four ethanol molecules are necessary to form one glucose-6-phosphate molecule
– the starting point of the pentose phosphate cycle – releasing 2 CO2 and generating a lot of
reducing power. This puts a burden on carbon yield and increases the oxygen requirement.
Alternatives for NADPH regeneration are NADP+-dependent isocitrate dehydrogenase which can
however only be used for glutamic acid and 1,4-butanediamine,3 and malic enzyme, which’ use in
our model is limited to L-lysine production. Another option is transhydrogenase activity in which
reducing power is transferred from NADH to NADPH, either via proton-motive force-driven,
membrane-bound transhydrogenase,4 or via energy-dependent “futile cycling” e.g. with the
combined action of malic enzyme, pyruvate carboxylase and malate dehydrogenase. It was assumed
that the conversion of NADH + NADP+ into NAD+ + NADPH required the input of 1 ATP. The
most elegant option for NADPH regeneration with ethanol as substrate however, is to make use of
NADP+ dependent acetaldehyde dehydrogenase1.
For the production of additional energy, if required, we assumed that acetyl-CoA is oxidized in the
citric acid cycle to two CO2 molecules, generating 1 ATP, 3 NAD(P)H and FADH, followed by
oxidation of the reduced cofactors by respiration.
Synthesis of C3 compounds
Lactic acid can be produced very efficiently from glucose, via glycolysis and reduction of pyruvate,
with a theoretical maximum carbon yield of 1, without oxygen consumption. 1,3-Propanediol can
be produced via 3-hydroxypropanal by glycerol hydratase followed by a reduction and 3hydroxypropionic acid via the same hydratase and then oxidized.5,6
Using ethanol to produce these C3 compounds is uneconomical since two ethanol molecules (4
carbons) will be converted into one C3 compound and CO2 via the glyoxylic acid cycle and
gluconeogenesis pathway. The 3-hydroxypropionate/4-hydroxybutyrate cycle of Sulfolobales seems
to be an interesting option however, in which acetyl-CoA, derived from ethanol, reacts with CO2 to
form malonyl-CoA. Key enzyme is acetyl-CoA carboxylase, an enzyme also involved in fatty acid
synthesis. Malonyl-CoA can be reduced in two steps into 3-OH-propanoic acid.7 3Hydroxypropanoic acid can be converted into lactic acid via acryloyl-CoA hydratase and lactoylCoA hydratase via a reversal of the pathway present in Clostridium propionicum.8 The obvious
advantage of this reaction sequence is that carbon dioxide can be build in, resulting in a more than
100% carbon yield based on ethanol input. Both pathways were used in the calculations for lactic
acid and 3-OH-propanoic acid. We assumed that the conversion of 3-OH-propanoic acid into 1,3proanediol via 3-OH-propanal is not thermodynamically feasible at physiological pH and used the
glyoxylate cycle and gluconeogenesis to calculate the maximum theoretical yield from ethanol via
glycerol.
Lactic acid
With glucose as substrate
Total:
Glucose + 2ADP → 2 lactate + 2 ATP
Yield = 1 Cmol/Cmol, oxygen consumption is not necessary
With ethanol as substrate, via gluconeogenesis
Biosynthesis:
2 ethanol + 2 ATP + 5 NAD + FAD = Lactate + CO2 + 2 ATP + 5 NADH + FADH
Respiration:
5 NADH + FADH + 3 O2 + 12 ADP = 5 NAD + FAD + 12 ATP
Total:
2 ethanol + 3 O2 + 10 ADP = Lactate + CO2 + 10 ATP
Yield = 0.75 Cmol/Cmol, oxygen consumption is 3 mol O 2/mol product
With ethanol as substrate, via malonyl-CoA
Biosynthesis:
Ethanol + CO2 + 2 ATP + NAD + NADPH = Lactate + 2 ADP + NADH + NADP
Transhydrogenase: NADH + NADP + ATP = NAD + NADPH + ADP
Respiration:
¼ Ethanol + 3 ADP + ¾ O2 = ½ CO2 + 3 ATP
Total:
1¼ Ethanol + ½ CO2 + ¾ O2 = Lactate
Yield = 1.2 Cmol/Cmol, oxygen consumption is 0.75 mol O 2/mol product
3-hydroxypropanoic acid
With glucose as substrate
Total:
Glucose = 2 3-hydroxypropionate
Yield = 1 Cmol/Cmol, oxygen consumption is not necessary
With ethanol as substrate via gluconeogenesis
Biosynthesis:
2 Ethanol + 3 ATP + 5 NAD + FAD = 3-hydroxypropionate + CO2 + 3 ADP + 5 NADH + FADH
Respiration:
5 NADH + FADH + 3 O2 + 12 ADP → 5 NAD + FAD + 12 ATP
Total:
2 ethanol + 3 O2 + 9 ADP → 3-hydroxypropionate + 9 ATP
Yield = 0.75 Cmol/Cmol, oxygen consumption is 3 mol O 2/mol product
With ethanol as substrate, via malonyl-CoA
Biosynthesis:
Ethanol + CO2 + ATP + NAD + NADPH = 3-hydroxypropionate + ADP + NADH + NADP
Transhydrogenase: NADH + NADP + ATP = NAD + NADPH + ADP
1
Respiration:
/6 Ethanol + 2 ADP + 1/2 O2 = 1/3 CO2 + 2 ATP
7
Total:
/6 Ethanol + 1/3 CO2 + ½ O2 = 3-hydroxypropionate
Yield = 1.29 Cmol/Cmol, oxygen consumption is 0.5 mol O2/mol product
1,3-Propanediol
With glucose as substrate
Biosynthesis:
Glucose + 2 ATP + 4 NADH = 2 1,3-propanediol + 2 ADP + 4 NAD
4
Oxidation:
/10 glucose + 4 NAD + 8/10 FAD + 16/10 ADP = 24/10 CO2 + 4 NADH + 8/10 FADH + 16/10 ATP
8
Respiration:
/10 FADH + 4/10 O2 + 16/10 ADP = 8/10 FAD + 16/10 ATP
14
Total:
/10 glucose + 4/10 O2 + 12/10 ADP = 2 1,3-propanediol + 12/10 ATP + 24/10 CO2
Yield = 0.71 Cmol/Cmol, oxygen consumption is 0.2 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
2 ethanol + 3 NAD + FAD + 5 ATP = 1,3-propanediol + CO2 + 3 NADH + FADH + 5 ADP
Respiration:
3 NADH + FADH + 2 O2 + 8 ADP = 3 NAD + FAD + 8 ATP
Total:
2 ethanol + 2 O2 + 3 ADP = 1,3-propanediol + CO2 + 3 ATP
Yield = 0.75 Cmol/Cmol, oxygen consumption is 2 mol O2/mol product
Synthesis of C4 compounds
Succinic acid, fumaric acid, malic acid and aspartic acid are synthesised by the conversion of one
glucose into two PEP molecules, which are subsequently carboxylated to oxaloacetate.
Oxaloacetate is then reduced in two steps to succinic acid via malic acid and fumaric acid.
Additional reducing power is necessary for the conversion of fumarate into succinate. We assumed
this was generated by the production of succinic acid via the glyoxylic acid cycle.
1,4-Butanediamine is synthesized via L-glutamic acid, as described by Qian et al.9 Aspartic acid is
produced from oxaloacetic acid by transamination. For aspartic acid, 1,4-butanediamine and 3hydroxybutyrolactone syntheses NADPH regeneration is required. We assumed this was generated
by the complete oxidation of glucose by the pentose-phosphate cycle, and by conversion of ethanol
via NADPH-dependent acetaldehyde dehydrogenase.
Succinic acid
With glucose as substrate
Red. biosynthesis: Glucose + 2 CO2 + 2 NADH → 2 Succinate + 2 NAD
2
Ox. biosynthesis:
/5 Glucose + 2 NAD + 4/5 ADP → 2/5 Succinate + 4/5 CO2 + 2 NADH + 4/5 ATP
7
Total:
/5 Glucose + 6/5 CO2 + 4/5 ADP → 12/5 Succinate + 4/5 ATP
Yield = 1.14 Cmol/Cmol, oxygen consumption is not necessary
With ethanol as substrate
Biosynthesis:
2 Ethanol + 5 NAD + 2 ATP → Succinate + 5 NADH + 2 ADP
Respiration:
5 NADH + 2.5 O2 + 10 ADP → 5 NAD + 10 ATP
Total:
2 Ethanol + 2.5 O2 + 8 ADP → Succinate + 8 ATP
Yield = 1 Cmol/Cmol, oxygen consumption is 2.5 mol O 2/mol product
Fumaric acid and malic acid
With glucose as substrate
Total:
Glucose + 2 CO2  2 fumarate/malate
Yield = 1.33 Cmol/Cmol, oxygen consumption is not necessary
With ethanol as substrate
Biosynthesis:
2 ethanol + 5 NAD + FAD + 2 ATP  Fumarate/malate + 5 NADH + FADH + 2 ADP
Respiration:
5 NADH + FADH + 3 O2 + 12 ADP  5 NAD + FAD + 12 ATP
Total:
2 ethanol + 3 O2 + 10 ADP  Fumarate/malate + 10 ATP
Yield = 1 Cmol/Cmol, oxygen consumption is 3 mol O 2/mol product
Aspartic acid
With glucose as substrate
Biosynthesis:
½ glucose + CO2 + NAD + NADPH  Aspartate + NADH + NADP
Respiration:
NADH + ½ O2 + 2 ADP  NAD + 2 ATP
1
NADPH regen.:
/12 glucose + 1/12 ATP + NADP  ½ CO2 + NADPH
7
Total:
/12 glucose + ½ CO2 + ½ O2 + 23/12 ADP  Aspartate + 23/12 ATP
Yield = 1.14 Cmol/Cmol, oxygen consumption is 0.5 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
2 ethanol + 4 NAD + FAD + 2 ATP = Aspartate + 4 NADH + FADH + 2 ADP
Respiration:
4 NADH + FADH + 2.5 O2 + 10 ADP = 4 NAD + FAD + 10 ATP
Total:
2 ethanol + 2.5 O2 + 8 ADP = Aspartate + 8 ATP
Yield = 1 Cmol/Cmol, oxygen consumption is 2.5 mol O 2/mol product
1,4-butanediamine
With glucose as substrate
Biosynthesis:
Glucose + 3 NAD + 2 NADPH + ATP = 1,4-butanediamine + 3 NADH + 2 NADP + ADP + 2 CO2
Respiration:
3 NADH + 1.5 O2 + 6 ADP = 3 NAD + 6 ATP
1
NADPH regen.:
/6 glucose + 1/6 ATP + 2 NADP → CO2 + 1/6 ADP + 2 NADPH
7
Total:
/6 Glucose + 1.5 O2 + 29/6 ADP → 1,4-butanediamine + 2 CO2 + 29/6 ATP
Yield = 0.57 Cmol/Cmol, oxygen consumption is 1.5 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
3 Ethanol + 6 NAD + FAD + 5 ATP = Glutamate + 6 NADH + 5 ADP + FADH + 2 CO2
Respiration:
6 NADH + FADH + 3.5 O2 + 14 ADP = 6 NAD + FAD + 14 ATP
Total:
3 Ethanol + 3.5 O2 + 9 ADP = 1,4-butanediamine + 2 CO2 + 9 ATP
Yield = 0.67 Cmol/Cmol, oxygen consumption is 3.5 mol O 2/mol product
3-hydroxybutyrolactone
With glucose as substrate
Biosynthesis:
Glucose + 4 NAD + NADPH + 2 ADP = 3-hydroxybutyrolactone + 4 NADH + NADP + 2 ATP
Respiration:
4 NADH + 2 O2 + 8 ADP = 4 NAD + 8 ATP
1
NADPH regen.:
/12 glucose + 1/12 ATP + NADP = ½ CO2 + 1/12 ADP + NADPH
13
Total:
/12 Glucose + 119/12 ADP + 2.5 O2 = 3-hydroxybutyrolactone + 119/12 ATP
Yield = 0.62 Cmol/Cmol, oxygen consumption is 2.5 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
2 ethanol + 3 NAD + 2 ATP = 3-hydroxybutyrolactone + 3 NADH + 2 ADP
Respiration:
3 NADH + 1.5 O2 + 6 ADP = 3 NAD + 6 ATP
Total:
2 ethanol + 4 ADP + 1.5 O2 = 3-hydroxybutyrolactone + 4 ATP
Yield = 1 Cmol/Cmol, oxygen consumption = 2 mol O 2/mol product
Synthesis of C5 compounds
Glutamic acid is synthesized from glucose by conversion into citric acid as discussed below. Citric
acid is then converted into glutamic acid using a NADP+-dependent isocitrate dehydrogenase and
NADPH-dependent glutamate dehydrogenase, allowing regeneration of NADPH. With ethanol as a
substrate, glutamic acid is synthesized by first converting the ethanol into citric acid. From that
point onwards, the same route is used as for glucose. Itaconic acid may also be synthesized from
ethanol through the same biosynthetic route, followed by decarboxylation of the citric acid
intermediate.
L-glutamic acid
With glucose as substrate
Biosynthesis:
Glucose + ADP + 3 NAD = Glutamate + ATP + 3 NADH + CO2
Respiration:
3 NADH +1.5 O2 + 6 ADP = 3 NAD + 6 ATP
Total:
Glucose + 1.5 O2 + 7 ADP = Glutamate + CO2 + 7 ATP
Yield = 0.83 Cmol/Cmol, oxygen consumption = 1.5 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
3 Ethanol + 8 NAD + FAD + 3 ATP = Glutamate + 8 NADH + 3 ADP + FADH + CO2
Respiration:
8 NADH + FADH + 4.5 O2 + 18 ADP = 8 NAD + FAD + 18 ATP
Total:
3 Ethanol + 4.5 O2 + 15 ADP = Glutamate + CO2 + 15 ATP
Yield = 0.83 Cmol/Cmol, oxygen consumption = 4.5 mol O 2/mol product
Itaconic acid
With glucose as substrate
Biosynthesis:
Glucose + ADP + 3 NAD = Itaconate + CO2 + ATP + 3 NADH
Respiration:
3 NADH + 1.5 O2 + 6 ADP = 3 NAD + 6 ATP
Total:
Glucose + 1.5 O2 + 7 ADP = Itaconate + CO2 + 7 ATP
Yield = 0.83 Cmol/Cmol, oxygen consumption = 1.5 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
3 Ethanol + 8 NAD + FAD + 3 ATP → Itaconate + CO2 + 8 NADH + FADH + 3 ADP
Respiration:
8 NADH + FADH + 4.5 O2 + 18 ADP → 8 NAD + FAD + 18 ATP
Total:
3 Ethanol + 4.5 O2 + 15 ADP → Itaconate + CO2 + 15 ATP
Yield = 0.83 Cmol/Cmol, oxygen consumption = 4.5 mol O2/mol product
Synthesis of C6 compounds
Citric acid production from glucose as a substrate first involves conversion of glucose into two PEP
moieties, of which one is carboxylated to oxaloacetate and the other decarboxylated to acetyl-CoA,
and subsequently both compounds merge to form citric acid. The generated reducing power is
converted via respiration into metabolic energy in the form of ATP. With ethanol as substrate,
ethanol molecules are converted into acetyl-CoA and via the glyoxylate route two of them are
converted into oxaloacetate. The oxaloacetate is used to merge with another acetyl-CoA to form
citric acid.
L-Lysine is synthesized from glucose along a similar route involving the conversion of glucose into
two PEP moieties. One PEP molecule is carboxylated into oxaloacetate, the other converted into
pyruvate. Pyruvate and oxaloacetate are then used as building blocks for the synthesis of lysine.
Starting from ethanol, the substrate is converted into two malic acid molecules by the glyoxylate
pathway. One is converted into oxaloacetate, the other into pyruvate by NADP-dependent malic
enzyme. From that point onwards the same route is used as for glucose.
Citric acid
With glucose as substrate
Biosynthesis:
Glucose + ADP + 3 NAD → Citrate + ATP + 3 NADH
Respiration:
3 NADH + 1.5 O2 + 6 ADP → 3 NAD + 6 ATP
Total:
Glucose + 1.5 O2 + 7 ADP → Citrate + 7 ATP
Yield = 1 Cmol/Cmol, oxygen consumption = 1.5 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
3 Ethanol + 8 NAD + FAD + 3 ATP → Citrate + 8 NADH + FADH + 3 ADP
Respiration:
8 NADH + FADH + 4.5 O2 + 18 ADP → 8 NAD + FAD + 18 ATP
Total:
3 Ethanol + 4.5 O2 + 15 ADP → Citrate + 15 ATP
Yield = 1 Cmol/Cmol, oxygen consumption = 4.5 mol O 2/mol product
L-Lysine
With glucose as substrate
Biosynthesis:
Glucose + 2 NAD + 4 NADPH + ATP → Lysine + 2 NADH + 4 NADP
Respiration:
2 NADH + O2 + 4 ADP → 2 NAD + 4 ATP
NADPH regen.:
1/3 Glucose + 1/3 ATP + 4 NADP → 1/3 ADP + 2 CO 2 + 4 NADPH
Total:
4/3 Glucose + 8/3 ADP + O2 → Lysine + 8/3 ATP + 2 CO2
Yield = 0.75 Cmol/Cmol, oxygen consumption = 1 mol O 2/mol product
With ethanol as substrate
Biosynthesis:
4 Ethanol + 6 NAD + 6 ATP + 2FAD → Lysine + 2 CO 2 + 6 NADH + 6 ADP+ 2 FADH
Respiration:
6 NADH + 2 FADH + 4 O2 + 16 ADP → 6 NAD + 2 FAD + 16 ATP
Total:
4 Ethanol + 4 O2 + 10 ADP → lysine + 2 CO2 + 10 ATP
Yield = 0.75 Cmol/Cmol, oxygen consumption = 4 mol O 2/mol product
Table 2. Calculated theoretical maximum yields and oxygen utilization of a number of biobased
platform chemicals based on glucose or ethanol as a fermentation substrate.
Glucose
Ethanol
Y
O2
Y
O2
Product
CP/Cs /mol P
CP/Cs /mol P
Lactic acid
1.00
0.00
0.75
3.00
Lactic acid
1.00
0.00
1.20
0.75
3-hydroxypropanoate
1.00
0.00
0.75
3.00
3-hydroxypropanoate
1.00
0.00
1.29
0.50
1,3-propanediol
0.71
0.20
0.75
2.00
C4
Succinic acid
1.14
0.00
1.00
2.50
Fumaric/malic acid
1.33
0.00
1.00
3.00
1,4-butanediamine
0.57
1.50
0.67
3.50
Aspartic acid
1.14
0.50
1.00
3.00
3-hydroxybutyrolactone 0.62
2.50
1.00
1.50
C5
L-Glutamic acid
0.83
1.50
0.83
4.50
Itaconic acid
0.83
1.50
0.83
4.50
C6
Citric acid
1.00
1.50
1.00
4.50
L-Lysine
0.75
1.00
0.75
4.00
Mol P = mol product
CP/Cs: Carbon yield, ratio of C atoms in product and C atoms in substrate
C-atoms
in product
C3
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