Chapter 14

Chapter-14b Takusagawas Note
!

1
1
Chapter 14b: Other Pathways of Carbohydrate Metabolism

1. GLUCONEOGENESIS
- is the biosynthesis of glucose from non-carbohydrate precursors at liver and kidney (very
small amount).
- Most excess glucose from diet is stored in liver as glycogen.
- However glycogen stored in liver is only a half day supply of glucose to the brain under
fasting or starvation conditions.
- Liver can send glucose to various tissues, but not ATP.
- Thus, when fasting, most glucose needs must be obtained by gluconeogenesis at liver, and the
produced glucose is sent to various tissues through bloodstream.

A. Gluconeogenesis Pathway
The first step of gluconeogenesis is conversion of various compounds to oxaloacetate
- Glycolysis products - lactate & pyruvate "
- Citric acid cycle intermediates # are converted to Oxaloacetate.
- Carbon skeletons of most amino acids $

!

2
2
- Leucine and lysine are not converted to oxaloacetate, these amino acids break down to acetyl-
CoA, likewise fatty acids.
- In plants, acetyl-CoA can convert to oxaloacetate by glyoxylate cycle, but not in animals.

Gluconeogenesis use the same glycolytic enzymes, except for hexokinase, phosphofructokinase
and pyruvate kinase
- Hexokinase (HK)
(glucose glucose-6-phosphate)

- Phosphofructokinase (PFK)
(fructose-6-phosphate
fructose-1,6-bisphosphate)

- Pyruvate kinase (PK)
(PEP pyruvate)

- These enzymes catalyze
reactions with large negative free energy changes (G < 0, exergonic reaction).

Energy
Glycolysis Products
Pyruvate
FBPDHAP/GAPGAPBPG3PG2PGPEP
G6PF6P
Glucose
G < 0
G < 0
G < 0
G 0
G 0

- Thus, these processes in gluconeogenesis must take different pathways.
Glycolysis pathway
Glucose
hexokinase (HK)
G6P
phosphoglucose isomerase (PGI)
F6P
phosphofructokinase (PFK)
FBP
aldolase
DHAP/GAP
triose phosphate isomerase (TIM)
GAP
glyceraldehyde-3-phosphate dehydrogenase
BPG (GAPDH)
phosphoglycerate kinase (PGK)
3PG
phosphoglycerate mutase (PGM)
2PG
enolase
PEP
pyruvate kinase (PK)
Pyruvate
pyruvate dehydrogenase
Oxaloacetate Citrate
!

3
3
Pyruvate is converted to oxaloacetate before conversion to phosphoenolpyruvate (PEP)
- As described in the previous page, pyruvate is not directly converted to PEP since the reverse
reaction is endergonic.
- Thus the pyruvate-PEP conversion takes the different pathway.
- Two enzymes are involved.
1. Pyruvate carboxylase driven by ATP catalyzes formation of oxaloacetate from pyruvate and
HCO
3
-
.
2. PEP carboxykinase (PEPCK) catalyzes decarboxylation of oxaloacetate to PEP by using
GTP hydrolysis energy.

Pyruvate carboxylase has a biotin prosthetic group
- Biotin is a CO
2
carrier, and is an essential human nutrient.
- Biotin is covalently bound to the enzyme by amide linkage between its carboxyl group and -
amino group of Lys residue of the enzyme.
- Biotin is therefore at the end of 14 long flexible arm so that CO
2
molecule can be
transported between the two relatively separated positions.
NH
C
HN
O
S
(CH
2
)
4
C
O
O
-
H
3
N (CH
2
)
4
CH
C
NH
O
Biotin
Lys residue
NH
C
N
O
S
(CH
2
)
4
C
O
NH
C
CH (CH
2
)
4
N
H
O
C
O
-
O
Carboxybiotinyl-enzyme
14 A long flexible arm

- Note: Biotinyl-enzyme is similar to lipoic acid + Lys-enzyme = lipoamide-enzyme, i.e.,
Pyruvate dehydrogenease multi-enzyme complex (Chapter 15).
!

4
4
Pyruvate carboxylase reaction
- occurs in two phases.
1. Carboxylation of biotin-Enzyme
- ATP reacts with carbonate (HCO
3
-
) to produce carboxyphosphate and ADP. The
hydrolysis of (ATP ADP + P
i
) provides free energy for carboxylation of biotin.
- Carboxyphosphate decomposes to P
i
and CO
2
.
- CO
2
carboxylates biotin to produce the very reactive carboxybiotinyl-enzyme.
2. The activated carboxyl group is transferred from carboxybiotin to pyruvate to form
oxaloacetate.

!

5
5
Oxaloacetate can be considered as activated pyruvate with CO
2

- Because oxaloacetate is synthesized with ATP hydrolysis energies from pyruvate and
CO
2
.
- Thus, it carries the ATP hydrolysis energy with CO
2
.

C
CH
2
C O
C
O O
-
O O
-
C O O
CH
3
C O
C
O O
-
+
Oxaloacetate Pyruvate + CO
2

Acetyl-CoA regulates pyruvate carboxylase
- In general, [oxaloacetate] is very low in cells. Thus oxaloacetate synthesis increases the
citric acid cycle activity, i.e., increases acetyl-CoA demand.
- Thus, acetyl-CoA is a powerful allosteric activator of pyruvate carboxylase.
- Gluconeogenesis only occurs when the citric acid cycle is inhibited by excess of ATP and/or
NADH.

PEP carboxykinase(PEPCK)
- catalyzes the GTP-driven decarboxylation of oxaloacetate to form PEP.

!

6
6
Gluconeogenesis requires metabolite transport between mitochondria and cytosol
- Since gluconeogenesis is carried out in cytosol, the mitochondrial products, PEP and
oxaloacetate, must be transported to cytosol.
- PEP is transported through the specific membrane transport proteins.
- Oxaloacetate does not have such transport proteins.
- Thus, oxaloacetate is transported by the malate-aspartate shuttle (remember: the cytosol
NADH transport in Chapter 17).
- There are two routes.
Gluconeogenesis
PEP PEP
Cytosol
Mitochondrion
Route-1: Oxaloacetate
Aspartate Aspartate
Oxaloacetate
aspartate
aminotransferae
aspartate
aminotransferae
malate
dehydrogenease
Oxaloacetate
Malate
Malate
Route-2: Oxaloacetate
malate
dehydrogenease
NADH + H
+
NAD
+
NAD
+
NADH + H
+

- Since NADH is utilized for gluconeogenesis, Route-2 is the major route since it transports
not only oxaloacetate but also NADH at the same time.
- If lactate is precursor, then both routes can be used since oxidation of lactate to pyruvate
produces NADH at cytosol (lactate + NAD
+
pyruvate + NADH + H
+
).

The other two highly unfavorable reverse reactions are bypassed by hydrolytic reactions
- The other two highly unfavorable reverse reactions are:
- PFK and hexokinase reactions whose reverse reaction produce ATPs, i.e.,
FBP + ADP + P
i
F6P + ATP
G6P + ADP + P
i
Glucose + ATP
- Instead the above reactions, FBP and G6P are directly hydrolyzed, and releasing P
i
in
exergonic process, i.e.,
FBP + H
2
O F6P + P
i
-- [1] catalyzed by fructose-1,6-bisphosphatase (FBPase)
G6P + H
2
O Glucose + P
i
-- [2] catalyzed by glucose-6-phosphatase (only present at liver
and kidney).
!

7
7
- Gluconeogenesis is accomplished by avoiding three energetically unfavorable reverse
reactions and by expensing hydrolysis of 4ATP, 2GTP and 2NADH per glucose.
2(Pyruvate) + 4ATP + 2GTP + 2NADH + 4H
+
+ 6H
2
O Glucose + 2NAD
+
+ 4ADP +
2GDP + 6P
i

- Note: Glycolysis produces 2ATP and 2NADH per glucose:
Glucose + 2NAD
+
+ 2ADP + 2P
i
2(Pyruvate) + 2ATP + 2NADH + 4H
+
+ 2H
2
O

- The overall reaction (a couple of glycolysis and gluconeogenesis) wastes 2ATP and 2GTP:
2ATP + 2GTP + 4H
2
O 2ADP + 2GDP + 4P
i

Glycolysis
Gluconeogenesis
!

8
8
B. Regulation of gluconeogenesis
- If glycolysis and gluconeogenesis were to proceed in uncontrolled manner, ATP and GTP
would be wasted.
- Thus, glycolysis and gluconeogenesis pathways are reciprocally regulated.

- Three independent pathways are regulated:
1. Glucose G6P (HK/glucose-6-phosphatase)
2. F6P FBP (PFK/FBPase)
3. PEP Pyruvate (PK/pyruvate carboxylase-PEPCK)

- Dominant mechanisms are:
1. Allosteric interactions (by F2,6P).
2. cAMP-dependent covalent modifications (cAMP levels are controlled by glucagon and
other hormones).

I mportant allosteric effector is fructose-2,6-bisphosphate (F2,6P)
- (see Chapter 14, page 18-19).
- F2,6P activates PFK (glycolysis) and inhibits FBPase.
- [F2,6P] is controlled by two enzyme activities:
1. Phosphofructokinase-2 (PFK-2) --- synthesis of F2,6P.
2. Fructose bisphosphatase-2 (FBPase-2) --- breakdown of F2,6P.
- Note: Phosphorylation inactivates liver PFK-2 and activates liver FBPase-2.
Phosphorylation activates heart PFK-2 and inactivates heart FBPase-2.
PFK-2 and FBPase-2 are not directly involved in glycolysis and gluconeogenesis.
- Low levels of [glucose] results in hormonal activation of gluconeogenesis through regulation
of [F2,6P].
Low blood [glucose]

Increased glucagon secretion from panceas

In Liver Increased [cAMP]

Increased enzyme phosphorylation

Activation of FBP-2 and inactivation of PFK-2

Decreased [F2,6P]

Inhibition of PFK and activation of FBPase

Increased gluconeogenesis
- Activation of gluconeogenesis in liver involves inhibition of glycolysis at the level of liver PK.
- Liver PK is inhibited allosterically by alanine (precursor of pyruvate) and phosphorylation.
- Muscle PK (isozyme of liver PK) is not subject to these control.
!

9
9

C. The Cori Cycle
- is discovered by Carl and Gerti Cori.
- Muscle contraction is powered by hydrolysis of ATP.
- ATP is regenerated either:
1. through oxidative phosphorylation in mitochondria of slow twitch (red) muscle fibers
(aerobic pathway, slow ATP production), or
2. by homolactic fermentation (pyruvate lactate) in fast-twitch (white) muscle fiber
(anaerobic pathway, fast ATP production).
- Lactate generated by homolactic fermentation is transferred via bloodstream to the liver, then
converted to pyruvate, then put into gluconeogenesis to produce glucose.
- The produced glucose is transferred from liver to muscle cells via bloodstream, and generate
ATP.
- This cycle is called Cori cycle.
- One cycle of Cori cycle wastes 2ATP and 2GTP per glucose.
- This Cori cycle is ATP/GTP-consuming glycolysis/gluconeogenesis futile cycle, but not in
the same cell.
- Thus, muscle cells can obtain ATP quickly by the Cori cycle.

blood
Muscle
Liver
blood
ATP
glycogenolysis
and glycolysis
P
i
+ ADP
ATP + GTP
gluconeogenesis
ADP + GDP
+ P
i
Glycogen
Lactate Lactate
Glucose
Glucose

Glycolysis
Gluconeogenesis
!

10
10
2. GLYOXYLATE PATHWAY
- Glyoxylate pathway occurs only in plants, but not in animals.
- converts acetyl-CoA to glyoxylate which condenses with malate to yield oxaloacetate.
- This oxaloacetate is used for production of glucose in gluconeogenesis.
- Thus, plants can convert acetyl-CoA to glucose by glyoxylate pathway.

Reaction pathway
1. Mitochondrial
oxaloacetate is converted
to aspartate, and
transported to
glyoxysome.
2. Aspartate in glyoxysome
is reconverted to
oxaloacetate.
3. Oxaloacetate is
condensed with acetyl-
CoA to form citrate,
which is isomerized to
isocitrate.
4. Isocitrate is cleaved to
succinate and glyoxylate
by glyoxysomal
isocitrate lyase.
5. Glyoxylate is condensed
with acetyl-CoA to
produce malate by
glyoxysomal malate
synthase.
6. Malate is transported in
cytosol, and is oxidized
by the cytosol malate
dehydrogenase to yield
oxaloacetate which enters
gluconeogenesis to
produce glucose.
7. Succinate is transported
to mitochondrion and is
entered into the citric acid
cycle.

Fig. 21-10.

!

11
11
- In the citric acid cycle, conversion of isocitrate (C
6
) to succinate (C
4
) produces two CO
2
.
- On the other hand, in the glyoxylate pathway, conversion of isocitrate to succinate produces
glyoxylate.
- Thus, glyoxylate pathway results in the net conversion of acetyl-CoA to glyoxylate instead of
2CO
2
.

glyoxylate pathway
citric acid cycle
Oxidative phosphorylation
Gluconeogenesis
2CO
2
2NADH+ GTP H C COO
-
O
H
3
C C
O
SCoA
Glyoxylate

- The net reaction of glyoxylate pathway is:
2(Acetyl-CoA) + 2NAD
+
+ 2FAD Oxaloacetate(C
4
) + 2CoA + 2NADH + FADH
2
+ 2H
+

- The net reaction of citric acid cycle is:
2(Acetyl-CoA) + 6NAD
+
+ 2FAD + 2GDP + P
i
4CO
2
+ 2CoA + 6NADH + 2FADH
2
+
2GTP + 6H
+

- Plants (germinating seeds) use the glyoxylate pathway to convert their stored triacylglycerols
to glucose.
Story of Jack and Bean Stalk

Seed
Triacylglycerol
Glucose
Cellulose (Glucose)
n
Short time

Note: Acetyl-CoA is not a precursor of gluconeogenesis in animal cells, i.e., animals cannot
produce glucose from acetyl-CoA ( fatty acid triacylglycerol).
!

12
12
Relation between the citric acid cycle and glyoxylate pathway

Two L-malates are
produced and one enters
gluconeogenesis to
produce glucose and the
other stays in the citric
acid cycle.
!

13
13
3. BIOSYNTHESIS OF OLIGOSACCHARIDES AND GLYCOPROTEINS
Glycosyl donors
- Glycosyl donors are nucleotide-sugars (such as UDP-glucose) which are synthesized by
condensation between monosaccharide-phosphate (such as G1P) and nucleosidetriphosphate
(such as UTP).
- Nucleotide-sugars contain a high energy bond between C1 and OP.
- Energy from hydrolysis of high energy bond is used to formation of glycosidic bond (G=
16 kJ/mol) between the two sugars.
- Oligosaccharide biosyntheses are catalyzed by glycosyl transferases.

A. Lactose synthesis
- The donor sugar is UDP-galactose and acceptor sugar is glucose.
- The reaction is catalyzed by lactose synthase.

!

14
14
B. Glycoprotein synthesis
- Proteins destined for secretion, incorporation into membranes, or localization inside
membranous organelles contain carbohydrates and therefore classified as glycoproteins.
- The oligosaccharide portions of glycoproteins are classified into three groups.
1. N-linked oligosaccharides
- linked by -N-glycosidic bond to Asn in Asn-X-Ser/Thr, X Pro.

- N-linked oligosaccharides are constructed on dolichol.
Dolichol (is hydrophobic, thus stays inside membrane = Ancho
Saturated -isoprene unit Isoprene unit
n
H CH
2
C CH
CH
3
CH
2
O carbohydrate
O
-
O
O
-
O
P O P CH
2
CH
2
O
CH
3
C CH
2

- All processes are carried out at rough endoplasmic reticulum.

!

15
15
The pathway of dolichol-PP-oligosaccharide synthesis
1. A dolichol phosphate anchors into the membrane of endoplasmic reticulum with the
phosphate group in cytosol.
2. A oligosaccharide is constructed on the dolichol phosphate.
3. The dolichol is flipped so that the oligosaccharide is moved from the cytosol side to the
rumen side.
4. Monosaccharides are attached on the other phosphate dolichols and are translocated into
rumen.
5. These monosaccharides are utilized to complete the oligosaccharide construction on the
dolichol.
6. After completion of oligosaccharide construction, the mature oligosaccharide is transferred to
the newly synthesized polypeptide at an Asn residue.

!

16
16
2. O-linked oligosaccharides
- are linked by -O-glycosidic bond to Ser or Thr.
- are posttranslationally formed in Golgi apparatus.
- Monosaccharide units are added one by one on a completed polypeptide chain.

3. GPI -linked proteins
- Glycosylphosphatidylinositol (GPI) groups are anchors of variety of proteins to the exterior
surface of eukaryotic plasma membrane.
- GPI core is synthesized inside of lumenal side of the ER membrane from
phosphatidylinositol, UDP-GlcNAc, and dolichol-P-mannose.
Mature polypeptide chain
!

17
17
4. PENTOSE PHOSPHATE PATHWAY
- Cells have two currencies:
1. Energy currency (ATP)
2. Reducing power currency (NADPH)

- Although NADH and NADPH are chemically resemblance, those are not metabolically
interchangeable.
- NADH participates in utilizing the free energy of the oxidation of (NADH NAD
+
) to
synthesize ATP.
- NADPH involves in utilizing the free energy of the oxidation of (NADPH NADP
+
) to
carry out endergonic reductive biosynthesis.

- In cells,
- [NAD
+
] / [NADH] 1000 (favors metabolite oxidation).
AH + NAD
+
A
+
+ NADH [oxidation reaction]
- [NADP
+
] / [NADPH] 0.01(favors metabolite reduction).
B
+
+ NADPH BH + NADP
+
[reduction reaction]

- NADPH is generated by the oxidation of G6P via an alternative pathway to glycolysis,
pentose phosphate pathway.

- ~30% of glucose oxidation in liver occurs via the pentose phosphate pathway.

The pentose phosphate pathway has three stages
1. Oxidative reactions, which yield NADPH and ribulose-5-phosphate (Ru5P)
3G6P + 6NADP
+
+ 3H
2
O 6NADPH + 6H
+
+ 3CO
2
+ 3Ru5P

2. Isomerization and epimerization reactions, which transfer Ru5P to ribose-5-phosphate(R5P)
[is an essential precursor in the biosynthesis of nucleotides] and xylulose-5-phosphate
(Xu5P).
3Ru5P R5P + 2Xu5P

3. A series of C-C bond cleavage and formation reactions, which convert (R5P + 2Xu5P) to
fructose-6-phosphate (F6P) and glyceraldehyde-3-phosphate (GAP).
R5P + 2Xu5P 2F6P + GAP

- Overall reaction of pentose phosphate pathway:
3G6P + 6NADP
+
+ 3H
2
O 6NADPH + 6H
+
+ 3CO
2
+ 2F6P + GAP

Note: Ribulose-5-phosphate (Ru5P)--- ketose
Ribose-5-phosphate (R5P)------ aldose

!

18
18
Pentose phosphate pathway

6: C
5
+ C
5

2
C
C
7
+ C
3

7: C
7
+ C
3

3 C
C
4
+ C
6

8: C
4
+ C
5

2
C
C
6
+ C
3

!

19
19
A. Oxidative reactions of NADPH production
- Only the first three reactions of the pentose phosphate pathway are involved in NADPH
production.
1. Glucose-6-phosphate dehydrogenase catalyzes net transfer of a hydride ion to NADP
+
from
C1 of G6P to form 6-phosphoglucono--lactone.
- This enzyme is the rate-determing enzyme of the pentose phosphate pathway.

2. 6-Phosphogluconolactonase increases the rate of hydrolysis of 6-phosphoglucono--lactone
to 6-phosphogluconate.
3. Phosphogluconate dehydrogenase catalyzes the oxidative decarboxylation of 6-
phosphogluconate to Ru5P and CO
2
. This oxidation reaction reduces the second NADP
+
to
NADPH.

This enzyme is the rate-determining enzyme
of pentose pathway.
!

20
20
B. I somerization and epimerization of ribulose-5-phosphate
- The produced Ru5P must subsequently be converted to R5P or Xu5P for further use.
- Ru5P is converted to R5P by ribulose-5-phosphate isomerase.
- R5P is an essential precursor in the biosynthesis of nucleotide.
- Ru5P is also converted to Xu5P by ribulose-5-phosphate epimerase.
- If more R5P is formed than the cell needs, the excess, along with Xu5P, is converted to F6P
and GAP which are glycolytic intermediates.

!

21
21
C. Carbon-Carbon bond cleavage and
formation reactions
- Excess of pentose cannot enter the
glycolysis, gluconeogenesis or pentose
phosphate pathway, thus they are
converted to hexoses (F6P) and trioses
(GAP) by C-C bond cleavage and
formation reactions.

- Two enzymes are involved:
1. Transketolase that catalyzes the
transfer of C
2
units (-CO-CH
2
OH).
- Transketolase has a thiamine
pyrophosphate cofactor (TPP).
- TPP forms a covalent adduct with Xu5P,
Xu5P-TPP.
- By releasing GAP, Xu5P-TPP becomes
dihydroxyethyl-TPP.
- Then the dihydroxyethyl group (C
2
unit)
is transferred to R5P at C1 to produce
sedoheptulose-7-phosphate (S7P).

1. ETPP + Xu5P ETPP-Xu5P
2. ETPP-Xu5P ETPP-C
2
+ GAP
3. ETPP-C
2
+ R5P ETPP-S7P
4. ETPP-S7P ETPP + S7P

- The overall reaction is to transfer a C
2

unit from Xu5P to R5P to yield GAP and
S7P: Xu5P + R5P GAP + S7P
C
5
+ C
5

C
2
C
3
+ C
7

!

22
22
2. Transaldolase catalyzes the transfer
of C
3
units (-CHOH-CO-CH
2
OH).
- Transaldolase catalyzes the transfer of
C
3
unit from S7P to GAP yielding
erythrose-4-phosphate (E4P) and F6P.
- This is an aldol cleavage reaction.
- The enzyme has an essential Lys residue
whose -amino group forms a Schiff
base with the carbonyl group of S7P.

1. E-Lys + S7P E-Lys-S7P
2. E-Lys-S7P E-Lys-C
3
+ E4P
3. E-Lys-C
3
+ GAP E-Lys-F6P
4. E-Lys-F6P E-Lys + F6P

- The overall reaction is to transfer a C
3

unit from S7P to GAP to yield E4P and
F6P: S7P + GAP E4P + F6P
C
7
+ C
3

C
3
C
4
+ C
6

!

23
23
A second transketolase reaction yields GAP and a second F6P
- The C
2
unit of Xu5P is transferred to E4P to form GAP and F6P.
- The third phase of the pentose phosphate pathway is therefore transformation of two
molecules of Xu5P and one of R5P to form two molecules of F6P and one molecule of GAP.
2Xu5P + R5P 2F6P + GAP
- The summary of the third phase reactions is:
1st: C
5
+ C
5
C
7
+ C
3
[C
2
transfer by transketolase]
2nd: C
7
+ C
3
C
6
+ C
4
[C
3
transfer by transaldolase]
3rd: C
5
+ C
4
C
6
+ C
3
[C
2
transfer by transketolase]
Sum: 3C
5
2C
6
+ C
3

D. Control of the pentose phosphate pathway
- Principal products of pentose phosphate pathway are: NADPH and R5P (processor of
nucleotide biosynthesis).
- The excess of pentoses are converted to F6P and GAP which can enter either glycolysis or
gluconeogenesis to the pentose phosphate pathway.
- In the latter case, one G6P molecule can be converted to 6CO
2
via 6 cycles of the pentose
phosphate pathway and gluconeogenesis, and produces 12NADPH molecules.
- Proof:
6G6P 4F6P + 2GAP + 12NADPH + 6CO
2

%
5G6P 4G6P + G6P

____________________________________________________________
G6P 12NADPH + 6CO
2

- The pentose phosphate pathway and thus the rate of NADPH production are controlled by
the rate of the glucose-6-phosphate dehydrogenase reaction (first committed step with
G = -17.6 kJ/mol in liver).
- The enzyme is regulated by [NADP
+
], i.e., the substrate availability.
[NADP ]
[NADPH]
0.01
+

Example of NADPH usage
- Erythrocyte membrane integrity requires a plentiful supply of reduced glutathione (GSH) to
eliminate H
2
O
2
and R-O-O-H.
- These hydroperoxides are toxic products that can react with double bonds in the fatty acid
residues, and consequently the C-C bonds in fatty acids are cleaved, thereby damaging the
erythrocyte membrane.
- These hydroperoxides must be eliminated through the action of glutathione peroxidase.
2GSH + R-O-O-H
glutathione peroxidase
GSSG + ROH + H
2
O

- Then GSH is subsequently regenerated by the NADPH reduction of GSSG.
GSSG + NADPH
glutathione reductase
2GSH + NADP
+

- Thus, a steady supply of NADPH is vital for erythrocyte membrane integrity.

Chapter 14

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Chapter-14b Takusagawas Note

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