Biochemistry, 4th Edition P73 pdf

These pentose phosphate pathway enzymes are located in the cytosol, which is the site of fatty acid synthesis, a pathway heavily dependent on NADPH for reductive reactions.. The reaction

turn activate some 800 molecules of phosphorylase Each of these catalyzes the

for-mation of many molecules of glucose-1-P

The Difference Between Epinephrine and Glucagon Although both epinephrine

and glucagon exert glycogenolytic effects, they do so for quite different reasons

Ep-inephrine is secreted as a response to anger or fear and may be viewed as an alarm

or danger signal for the organism Called the “fight or flight” hormone, it prepares

the organism for mobilization of large amounts of energy Among the many

physi-ological changes elicited by epinephrine, one is the initiation of the enzyme

cas-cade, as in Figure 15.17, which leads to rapid breakdown of glycogen, inhibition of

glycogen synthesis, stimulation of glycolysis, and production of energy The burst of

energy produced is the result of a 2000-fold amplification of the rate of glycolysis

Because a fear or anger response must include generation of energy (in the form

of glucose)—both immediately in localized sites (the muscles) and eventually

throughout the organism (as supplied by the liver)—epinephrine must be able to

activate glycogenolysis in both liver and muscles

Glucagon is involved in the long-term maintenance of steady-state levels of

cose in the blood It performs this function by stimulating the liver to release

glu-cose from glycogen stores into the bloodstream To further elevate gluglu-cose levels,

glucagon also stimulates liver gluconeogenesis by activating F-2,6-BPase activity (see

Figure 22.10) It is important to note, however, that stabilization of blood glucose

levels is managed almost entirely by the liver Glucagon does not activate the

phos-phorylase cascade in muscle (muscle membranes do not contain glucagon

recep-tors) Muscle glycogen breakdown occurs only in response to epinephrine release,

and muscle tissue does not participate in maintenance of steady-state glucose levels

in the blood

Glucagon and epinephrine both trigger glycogen breakdown and inhibit

glyco-gen synthesis (in liver and muscles, respectively), but their other effects on

meta-bolic pathways are adapted exquisitely to the needs of the tissues involved The liver

must export glucose to the bloodstream to support other tissues Thus, in the liver,

PFK-2 is phosphorylated and inhibited by protein kinase A (PKA), lowering

[fruc-tose-2,6-bisphosphate], inhibiting glycolysis, and activating gluconeogenesis (see

Figure 22.20) In muscles, the glucose provided by glycogen breakdown is used

im-mediately and locally to provide ATP energy for contraction Therefore, glycolysis

should be activated in concert with glycogen breakdown in muscles Activation of

glycolysis is accomplished in different ways, depending on the muscle Heart

mus-cle PFK-2 is activated upon phosphorylation at Ser466and Ser483by PKA in response

to epinephrine, thus activating glycolysis (see Figure 22.20) Skeletal muscle PFK-2,

however, is not a substrate for PKA Instead, skeletal muscle PFK-1 is phosphorylated

and activated by PKA (see Figure 22.20)

Cortisol and Glucocorticoid Effects on Glycogen Metabolism Glucocorticoids

are a class of steroid hormones that exert distinct effects on liver, skeletal muscle,

and adipose tissue The effects of cortisol, a typical glucocorticoid, are best

de-scribed as catabolic because cortisol promotes protein breakdown and decreases

protein synthesis in skeletal muscle In the liver, however, it stimulates

gluconeo-genesis and increases glycogen synthesis Cortisol-induced gluconeogluconeo-genesis results

primarily from increased conversion of amino acids into glucose (Figure 22.21)

Specific effects of cortisol in the liver include increased expression of several genes

encoding enzymes of the gluconeogenic pathway, activation of enzymes involved in

amino acid metabolism, and stimulation of the urea cycle, which disposes of

nitro-gen liberated during amino acid catabolism (see Chapter 25)

22.6 Can Glucose Provide Electrons for Biosynthesis?

Cells require a constant supply of NADPH for reductive reactions vital to biosynthetic

purposes Much of this requirement is met by a glucose-based metabolic sequence

variously called the pentose phosphate pathway, the hexose monophosphate shunt, or

the phosphogluconate pathway In addition to providing NADPH for biosynthetic

processes, this pathway produces ribose-5-phosphate, which is essential for nucleic acid

synthesis Several metabolites of the pentose phosphate pathway can also be shuttled into glycolysis

The Pentose Phosphate Pathway Operates Mainly in Liver and Adipose Cells

The pentose phosphate pathway begins with glucose-6-phosphate, a six-carbon sugar, and produces three-, four-, five-, six-, and seven-carbon sugars (Figure 22.22) As we will see, two successive oxidations lead to the reduction of NADPto NADPH and the re-lease of CO2 Five subsequent nonoxidative steps produce a variety of carbohydrates, some of which may enter the glycolytic pathway The enzymes of the pentose phosphate pathway are particularly abundant in the cytoplasm of liver and adipose cells These en-zymes are largely absent in muscle, where glucose-6-phosphate is utilized primarily for energy production via glycolysis and the TCA cycle These pentose phosphate pathway enzymes are located in the cytosol, which is the site of fatty acid synthesis, a pathway heavily dependent on NADPH for reductive reactions

The Pentose Phosphate Pathway Begins with Two Oxidative Steps

1 Glucose-6-Phosphate Dehydrogenase The pentose phosphate pathway begins with the oxidation of glucose-6-phosphate The products of the reaction are a cyclic

ester (the lactone of phosphogluconic acid) and NADPH (Figure 22.23) Glucose-6-phosphate dehydrogenase, which catalyzes this reaction, is highly specific for NADP As the first step of a major pathway, the reaction is irreversible and highly regulated Glucose-6-phosphate dehydrogenase is strongly inhibited by the product coenzyme, NADPH, and also by fatty acid esters of coenzyme A (which are inter-mediates of fatty acid biosynthesis) Inhibition due to NADPH depends upon the cytosolic NADP/NADPH ratio, which in the liver is about 0.015 (compared to about 725 for the NAD/NADH ratio in the cytosol)

2 Gluconolactonase The gluconolactone produced in step 1 is hydrolytically un-stable and readily undergoes a spontaneous ring-opening hydrolysis, although an enzyme, gluconolactonase, accelerates this reaction (Figure 22.24) The linear product, the sugar acid 6-phospho-D-gluconate, is further oxidized in step 3

3 6-Phosphogluconate Dehydrogenase The oxidative decarboxylation of

6-phosphogluconate by 6-6-phosphogluconate dehydrogenase yields D -ribulose-5-phosphate and another equivalent of NADPH There are two distinct steps in this

+

+

Glucose

Amino acids

Plasma Liver

Amino acid metabolizing enzymes

Gluconeogenesis

Nitrogen

Glycogen synthesis

Urea cycle

Cortisol

Urea

FIGURE 22.21 The effects of cortisol on carbohydrate

and protein metabolism in the liver.

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mecha-nism for 6-phosphogluconate dehydrogenase.

H2O

P

H

C

O

C

C

C

C

C

H2

H2

H2

H2

H2

H2

H2

O–

C

O

C

C

C

C

C

H

C O C

C

C O

H2 P

C

H

C O

C

C

C O

P

H

C

O

C

C

C

C

H

C O

C

C

C O

C

C

P

H

O

C

C

C

C O

P

C

H

C O

C

C O

C

P

H

O

C

C O

C

P

C

H

C O

C

C O

C

C

P

H

O

C

C O

C

4

5

4

5

CO2

Reductive anabolic pathways

Glucose-6-phosphate

6-Phospho-gluconate

Ribulose-5-phosphate

Ribulose-5-phosphate

Ribose-5-phosphate

Nucleic acid biosynthesis

Sedoheptulose-7-phosphate

Erythrose-4-phosphate

Another Xylulose-5-phosphate

Xylulose-5-phosphate

Glyceraldehyde-3-phosphate

Fructose-6-phosphate

Glyceraldehyde-3-phosphate

Glycolytic intermediates

ACTIVE FIGURE 22.22 The pentose phosphate pathway.The numerals in the blue circles indicate

the steps discussed in the text Test yourself on the concepts in this figure at www.cengage.com/login.

reaction (Figure 22.25): The initial NADP-dependent dehydrogenation yields a

-keto acid, 3-keto-6-phosphogluconate, which is very susceptible to

decarboxy-lation (the second step) The resulting product, D-ribulose-5-P, is the substrate for the nonoxidative reactions composing the rest of this pathway

There Are Four Nonoxidative Reactions in the Pentose Phosphate Pathway

This portion of the pathway begins with an isomerization and an epimerization, and

it leads to the formation of either D-ribose-5-phosphate or D-xylulose-5-phosphate These intermediates can then be converted into glycolytic intermediates or directed

to biosynthetic processes

4 Phosphopentose Isomerase This enzyme interconverts ribulose-5-P and ribose-5-P via an enediol intermediate (Figure 22.26) The reaction (and mechanism) is quite

+ H+

O

OH OH

OH HO

CH2

2 –O3PO

CH2

2 –O3PO

O

OH

OH HO

O

NADPH NADP+

-D -Glucose-6-phosphate

Glucose-6-P dehydrogenase

6-Phospho- D -gluconolactone

Step 1

FIGURE 22.23 The glucose-6-phosphate

dehydroge-nase reaction is the committed step in the pentose

phosphate pathway.

2 –O3POCH2

O

OH

OH HO

O

HCOH COO–

HOCH HCOH HCOH

CH2OPO3–

6-P- D -Gluconolactone

Gluconolactonase

6-P- D -Gluconate

Step 2

H +

H2O

FIGURE 22.24 The gluconolactonase reaction.

HCOH COO–

HOCH HCOH HCOH

CH2OPO3 –

HCOH COO–

C HCOH HCOH

CH2OPO3 –

O

CH2OH

HCOH HCOH

CH2OPO3 –

C O +

6-P- D -Gluconate

Step 3

6-Phosphogluconate dehydrogenase

H+

H +

3-Keto-6-P- D -Gluconate D -Ribulose-5-P

NADPH

2

FIGURE 22.25 The 6-phosphogluconate dehydrogenase

reaction.

similar to the phosphoglucoisomerase reaction of glycolysis, which interconverts

glucose-6-P and fructose-6-P The ribose-5-P produced in this reaction is utilized in the

biosynthesis of coenzymes (including NADH, NADPH, FAD, and B12), nucleotides,

and nucleic acids (DNA and RNA) The net reaction for the first four steps of the

pen-tose phosphate pathway is

Glucose-6-P  2 NADP H2O⎯⎯→ ribose-5-P  2 NADPH  2 H CO2

5 Phosphopentose Epimerase This reaction converts ribulose-5-P to another

ketose, namely, xylulose-5-P This reaction also proceeds by an enediol intermediate

but involves an inversion at C-3 (Figure 22.27) In the reaction, an acidic proton

located- to a carbonyl carbon is removed to generate the enediolate, but the

pro-ton is added back to the same carbon from the opposite side Note the distinction

in nomenclature here Interchange of groups on a single carbon is an

epimeriza-tion, and interchange of groups between carbons is an isomerization

To this point, the pathway has generated a pool of pentose phosphates The

G° for each of the last two reactions is small, and the three pentose-5-phosphates

CH2OH

HCOH

HCOH

CH2OPO3–

C O

HC

HCOH HCOH

CH2OPO3–

C

OH OH

HC

HCOH HCOH

CH2OPO3–

O HCOH

Step 4

D -Ribulose-5-P (ketose) Enediol Ribose-5-P (aldose)

FIGURE 22.26 The phosphopentose isomerase reaction involves an enediol intermediate.

HUMAN BIOCHEMISTRY

Aldose Reductase and Diabetic Cataract Formation

The complications of diabetes include a high propensity for cataract

formation in later life, both in type 1 and type 2 diabetics

Hyper-glycemia is the suspected cause, but by what mechanism? Several

lines of evidence point to the polyol pathway, in which glucose and

other simple sugars are reduced in NADPH-dependent reactions

Glucose, for example, is reduced by aldose reductase to sorbitol (see

accompanying figure), which accumulates in lens fiber cells,

in-creasing the intracellular osmotic pressure and eventually rupturing

the cells The involvement of aldose reductase in this process is supported by the fact that animals that have high levels of this en-zyme in their lenses (such as rats and dogs) are prone to develop diabetic cataracts, whereas mice that have low levels of lens aldose reductase activity are not Moreover, aldose reductase inhibitors

such as tolrestat and epalrestat suppress cataract formation These

drugs or derivatives from them may represent an effective preven-tive therapy against cataract formation in people with diabetes

CH2OH

H

CHO

OH

C

H C OH

H C OH

H

HO C

CH2OH

H

CH2OH OH C

H C OH

H C OH

H

HO C

H2C

CF3

CH3 C

O

H

COO–

CH2

CH3

N O

S COO–

(a)

NADPH + H+ NADP+

Aldose reductase

(b)

coexist at equilibrium The pathway has also produced two molecules of NADPH for each glucose-6-P converted to pentose-5-phosphate The next three steps rearrange the five-carbon skeletons of the pentoses to produce three-, four-, six-, and seven-carbon units, which can be used for various metabolic purposes Why should the cell do this? Very often, the cellular need for NADPH is considerably greater than the need for ribose-5-phosphate The next three steps thus return some of the five-carbon units to glyceraldehyde-3-phosphate and fructose-6-phosphate, which can enter the glycolytic pathway The advantage of this is that the cell has met its needs for NADPH and ribose-5-phosphate in a single pathway, yet at the same time it can return the excess carbon metabolites to glycolysis

6 and 8.Transketolase The transketolase enzyme acts at both steps 6 and 8 of the pentose phosphate pathway In both cases, the enzyme catalyzes the transfer of two-carbon units In these reactions (and also in step 7, the transaldolase reaction, which transfers three-carbon units), the donor molecule is a ketose and the recipient is an aldose In step 6, xylulose-5-phosphate transfers a two-carbon unit

to ribose-5-phosphate to form glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate (Figure 22.28) Step 8 involves a two-carbon transfer from xylulose-5-phosphate to erythrose-4-phosphate to produce another glyceraldehyde-3-phosphate and a fructose-6-glyceraldehyde-3-phosphate (Figure 22.29) Three of these products

CH2OH

COH COH

CH2OPO3–

C O

H H B

CH2OH

OH OH

CH2OPO3–

C O–

C HC

HB+

CH2OH

C C

CH2OPO3–

C O

HO H

H OH

E E

Phosphopentose epimerase

Ribulose-5-P

Step 5

Xylulose-5-P Enediolate

FIGURE 22.27 The phosphopentose epimerase reaction interconverts ribulose-5-P and xylulose-5-phosphate The mechanism involves an enediol intermediate and occurs with inversion at C-3.

CH2OH

CH

CH2OPO3–

C O

CHO

CH2OPO3–

HCOH HCOH HCOH HCOH

Transketolase

CH2OPO3–

CHO

CH2OH

CH2OPO3–

C O

HCOH HCOH

HCOH HOCH

Xylulose-5-P Ribose-5-P Glyceraldehyde-3-P Sedoheptulose-7-P

Step 6

FIGURE 22.28 The transketolase reaction of step 6 in the

pentose phosphate pathway.

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of the transketolase enzyme.

CH2OH

C

CH2OPO3–

C O

HO H HCOH

+ CHO

CH2OPO3–

HCOH HCOH

Transketolase

CH2OPO3–

CHO HCOH +

CH2OH

CH2OPO3–

C O

HCOH HCOH

CH HO

Xylulose-5-P

Step 8

Erythrose-4-P Glyceraldehyde-3-P Fructose-6-P

FIGURE 22.29 The transketolase reaction of step 8 in the

pentose phosphate pathway.

enter directly into the glycolytic pathway (The sedoheptulose-7-phosphate is taken

care of in step 7, as we shall see.) Transketolase is a thiamine pyrophosphate–

dependent enzyme, and the mechanism (Figure 22.30) involves abstraction of the

acidic thiazole proton of TPP, attack by the resulting carbanion at the carbonyl

carbon of the ketose phosphate substrate, expulsion of the

glyceraldehyde-3-phosphate product, and transfer of the two-carbon unit Transketolase can process

a variety of 2-keto sugar phosphates in a similar manner It is specific for ketose

substrates with the configuration shown but can accept a variety of aldose

phos-phate substrates

7 Transaldolase The transaldolase functions primarily to make a useful

gly-colytic substrate from the sedoheptulose-7-phosphate produced by the first

trans-ketolase reaction This reaction (Figure 22.31) is quite similar to the aldolase

re-action of glycolysis, involving formation of a Schiff base intermediate between the

C

CH2OH

HOCH

O S

N

R"

R

R'

+

HCOH

CH2OPO3–

S

N

R"

R +

C

CH2OH

HCOH

CH2OPO3–

OH

B

CHO HCOH

CH2OPO3–

S

N + C

CH2OH OH

HCOH HCOH

CH2OPO3–

HCOH

HC O

S

N C

CH2OH

OH

S

N

R

HCOH HCOH

CH2OPO3–

HCOH

O C

CH2OH

S

N

R +

HCOH HCOH

CH2OPO3–

HCOH

C

CH2OH

O H

–

E

–

R''

R"

R

R"

R

R"

R'

R'

R'

CH O H

B E

H

D -Xylulose-5-P

D -Ribose-5-P

Sedoheptulose-7-P

Glyceraldehyde-3-P

FIGURE 22.30 The mechanism of the TPP-dependent transketolase reaction Ironically, the group transferred

in the transketolase reaction might best be described

as an aldol, whereas the transferred group in the transaldolase reaction is actually a ketol Despite the irony, these names persist for historical reasons.

sedoheptulose-7-phosphate and an active-site lysine residue (Figure 22.32) Elim-ination of the erythrose-4-phosphate product leaves an enamine of dihydroxy-acetone, which remains stable at the active site (without imine hydrolysis) until the other substrate comes into position Attack of the enamine carbanion at the carbonyl carbon of glyceraldehyde-3-phosphate is followed by hydrolysis of the Schiff base (imine) to yield the product fructose-6-phosphate

Step 7

CH2OH

CH2OPO3–

C O

HCOH HCOH

CH HO

HCOH

+

CH2OPO3–

CHO HCOH

CH2OPO3– HCOH

CHO HCOH

+

CH2OH

CH2OPO3–

C O HOCH HCOH HCOH

Sedoheptulose-7-P Glyceraldehyde-3-P Erythrose-4-P Fructose-6-P

Transaldolase

FIGURE 22.31 The transaldolase reaction.

–

CH2OH

C O C HO

Lys NH2

H C

R

N H

CH2OH C +

+

C

C

R

H

N H

CH2OH C C

H N

CH2OH C

HO H C RCHO (Erythrose-4-P)

H C O C

CH2OH C N C

C

C

CH2OPO3–

CH2OH

C O C

C

C

CH2OPO3–

CH2OPO3–

E

H2O

Enamine

Glyceraldehyde-3-P

Fructose-6-P

ANIMATED FIGURE 22.32 The

trans-aldolase mechanism involves attack on the substrate by

an active-site lysine Departure of erythrose-4-P leaves

the reactive enamine, which attacks the aldehyde

car-bon of glyceraldehyde-3-P Schiff base hydrolysis yields

the second product, fructose-6-P See this figure

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Utilization of Glucose-6-P Depends on the Cell’s Need for ATP, NADPH,

and Ribose-5-P

It is clear that glucose-6-phosphate can be used as a substrate either for glycolysis or

for the pentose phosphate pathway The cell makes this choice on the basis of its

rel-ative needs for biosynthesis and for energy from metabolism ATP can be produced

in abundance if glucose-6-phosphate is channeled into glycolysis On the other hand,

if NADPH or ribose-5-phosphate is needed, glucose-6-phosphate can be directed to

the pentose phosphate pathway The molecular basis for this regulatory decision

de-pends on the enzymes that metabolize glucose-6-phosphate in glycolysis and the

pen-tose phosphate pathway In glycolysis, phosphoglucoisomerase converts

glucose-6-phosphate to fructose-glucose-6-phosphate, which is utilized by phosphofructokinase (a

highly regulated enzyme) to produce fructose-1,6-bisphosphate In the pentose

phosphate pathway, glucose-6-phosphate dehydrogenase (also highly regulated)

produces 6-phosphogluconolactone from glucose-6-phosphate Thus, the fate of

glucose-6-phosphate is determined to a large extent by the relative activities of

phos-phofructokinase and glucose-6-P dehydrogenase Recall from Chapter 18 that PFK is

inhibited when the ATP/AMP ratio increases and that it is inhibited by citrate but

ac-tivated by fructose-2,6-bisphosphate Thus, when the energy charge is high, glycolytic

flux decreases Glucose-6-P dehydrogenase, on the other hand, is inhibited by high

levels of NADPH and also by the acyl-CoA intermediates of fatty acid biosynthesis

Both of these are indicators that biosynthetic demands have been satisfied If that is

the case, glucose-6-phosphate dehydrogenase and the pentose phosphate pathway

are inhibited If NADPH levels drop, the pentose phosphate pathway turns on and

NADPH and ribose-5-phosphate are made for biosynthetic purposes

Even when the latter choice has been made, however, the cell must still be

re-sponsive to the relative needs for ribose-5-phosphate and NADPH (as well as ATP)

Depending on these relative needs, the reactions of glycolysis and the pentose

phos-phate pathway can be combined in novel ways to emphasize the synthesis of needed

metabolites There are four principal possibilities

1 Both Ribose-5-P and NADPH Are Needed by the Cell In this case, the first four

reac-tions of the pentose phosphate pathway predominate (Figure 22.33) NADPH is

pro-duced by the oxidative reactions of the pathway, and ribose-5-P is the principal

prod-uct of carbon metabolism As stated earlier, the net reaction for these processes is

Glucose-6-P  2 NADP H2O⎯⎯→ ribose-5-P  CO2 2 NADPH  2 H

2 More Ribose-5-P Than NADPH Is Needed by the Cell Synthesis of ribose-5-P can

be accomplished without production of NADPH if the oxidative steps of the

pen-tose phosphate pathway are bypassed The key to this route is the withdrawal of

fructose-6-P and glyceraldehyde-3-P, but not glucose-6-P, from glycolysis The

ac-tion of transketolase and transaldolase on fructose-6-P and glyceraldehyde-3-P

produces three molecules of ribose-5-P from two molecules of fructose-6-P and

one of glyceraldehyde-3-P In this route, as in case 1, no carbon metabolites are

re-turned to glycolysis The net reaction for this route is

5 Glucose-6-P  ATP ⎯⎯→ 6 ribose-5-P  ADP  H

3 More NADPH Than Ribose-5-P Is Needed by the Cell Large amounts of NADPH

can be supplied for biosynthesis without concomitant production of ribose-5-P if

ribose-5-P produced in the pentose phosphate pathway is recycled to produce

Glucose-6-P 6-Phosphogluconate

Reactions ,

Ribulose-5-phosphate Ribose-5-phosphate NADPH

NADP+

FIGURE 22.33 When biosynthetic demands dictate, the first four reactions of the pentose phosphate pathway

predominate and the principal products are ribose-5-P and NADPH.

glycolytic intermediates This alternative involves a complex interplay between the transketolase and transaldolase reactions to convert ribulose-5-P to fructose-6-P and glyceraldehyde-3-P, which can be recycled to glucose-6-P via gluconeogenesis The net reaction for this process is

6 Glucose-6-P  12 NADP 6 H2O⎯⎯→

6 ribulose-5-P  6 CO2 12 NADPH  12 H

6 Ribulose-5-P ⎯⎯→ 5 glucose-6-P  Pi Net: Glucose-6-P  12 NADP 6 H2O⎯⎯→ 6 CO2 12 NADPH  12 H Pi Note that in this scheme, the six hexose sugars have been converted to six pen-tose sugars with release of six molecules of CO2, and the six pentoses are recon-verted to five glucose molecules

4 Both NADPH and ATP Are Needed by the Cell, but Ribose-5-P Is Not Under some conditions, both NADPH and ATP must be provided in the cell This can

be accomplished in a series of reactions similar to case 3 if the fructose-6-P and glyceraldehyde-3-P produced in this way proceed through glycolysis to produce ATP and pyruvate, which itself can yield even more ATP by continuing on to the TCA cycle The net reaction for this alternative is

3 Glucose-6-P  5 NAD 6 NADP 8 ADP  5 Pi⎯⎯→

5 pyruvate  3 CO2 5 NADH  6 NADPH  8 ATP  2 H2O 8 H Note that, except for the three molecules of CO2, all the other carbon from glucose-6-P is recovered in pyruvate

Xylulose-5-Phosphate Is a Metabolic Regulator

In addition to its role in the pentose phosphate pathway, xylulose-5-phosphate serves as a signaling molecule When blood [glucose] rises (for example, follow-ing a carbohydrate-rich meal), glycolysis and the pentose phosphate pathway are activated in the liver, and xylulose-5-phosphate produced in the latter pathway

CH2OH

C O

HOCH

CH2OPO3– HOCH

Xylulose-5-P

Protein phosphatase 2A

2 H2O

2 ADP 2 ATP ChREBP ChREBP

2 Pi

Pyruvate

PDH

Acetyl-CoA

P P

Lipid synthesis

PKA

Glycolysis

+

PFK-2 F-2,6-BPase

+

FIGURE 22.34 Xylulose-5-phosphate is a regulator of multiple metabolic pathways Activation of PP2A triggers dephosphorylation of the bifunctional PFK-2/F2,6-BPase, which raises fructose-2,6-BP levels, in turn activating glycolysis and inhibiting gluconeogenesis Simultaneously, ChREBP is dephosphorylated, leading to elevated expression of genes encoding enzymes for lipogenesis These effects combine to trigger lipid biosynthesis in response to a carbohydrate-rich meal.