Pentose phosphate pathway

Pentose phosphate pathway has two phases

The main product of PPP is ribose 5-phosphate and NADPH

• PPP oxidizes glucose 6-phosphate, producing ribose 5-phosphate (precursor for nucleotides) and NADPH (reducing agent for lipid biosynthesis).

What type of tissues require PPP?

• Rapid dividing cells (bone marrow, skin, intestinal mucosa….)

• Tissues that carry out extensive fatty acid synthesis (liver, adipose, lactating mammary gland) or very active synthesis of cholesterol and steroid hormones (liver, adrenal glands, gonads).

• Erythrocytes, lens and cornea cells.

PPP is highly active in fatty acid- and steroid- synthesizing tissues

The oxidative phase of PPP

Products of this phase are ribose 5-phosphate and

NADPH

NADPH6-phospho-glucono--lactone

1. Glucose 6-phosphate dehydrogenase (G6PD) produces NADPH and 6-phosphoglucono-

d-lactone

• G6PD oxidize glucose 6-phosphate, producing NADPH and 6-phosphoglucono--lactone.

• Deficiency of G6PD causes favism.

G 6-P NADP+

Glucose 6-phosphatedehydrogenase

6-phospho-gluconate

2. Conversion of 6-phosphoglucono-d-lactone to 6-phosphogluconate

• Lactonase hydrolyzes 6-phosphoglucono--lactone, producing 6-phosphogluconate.

6-phospho-glucono--lactone

H2O

lactonase

3. Oxidation and decarboxylation of 6-phosphogluconate

• Oxidation and decarboxylation of 6-phosphogluconate is catalyzed by 6-phosphogluconate dehydrogenase. This reaction also produces NADPH.

6-phosphogluconate

NADP+

NADPHCO2D-ribulose5-phosphate

6-phosphogluconatedehydrogenase

4. Conversion of ribulose 5-phosphate to ribose 5-phosphate

• Ribulose 5-phosphate is converted to ribose 5-phosphate by phosphopentose isomerase.

• In some tissues, the PPP ends at this point.

D-ribulose5-phosphate

D-ribose5-phosphate

Phosphopentoseisomerase

The nonoxidative phase of PPP

Nonoxidative phase of PPP is very important for tissues that only require NADPH but not ribose 5-

phosphate

Nonoxidative phase is important for recycling ribose 5-phosphate

• For cells carrying out extensive fatty acid, cholesterol, or steroid hormone synthesis, only NADPH is required from PPP but not ribose 5-phosphate.

• In addition, erythrocytes, lens and cornea cells also do not need ribose 5-phosphate.

• In these tissues, ribose 5-phosphate produced by PPP must be recycled.

Nonoxidative phase starts with epimerization of ribulose 5-phosphate

• Ribulose 5-phosphate is epimerized to xylulose 5-phosphate by ribose 5-phosphate epimerase, which starts the nonoxidative phase of PPP.

CH2OH

C=O

H-C-OH

H-C-OH

CH2OPO32-

I

I

I

I

-HOH -

Ribulose5-phosphate

Ribose5-phosphate

epimerase

Xylulose5-phosphate

F 6-P

G 6-PG 6-PG 6-PG 6-P

F 6-P

G 3-P

F 6-PG 3-P

Erythrose4-phosphate

Fructose6-phosphate

Sedoheptulose7-phosphate

Xylulose5-phosphate

Transketolase and transaldolase rearrange the carbon skeleton, producing 5 fructose 6-pho

sphate from 6 ribose 5-phosphateRibose

5-phosphate

Xylulose5-phosphateepimerase

Ribose5-phosphate

transketolase

Sedoheptulose7-phosphate

G 3-P

transaldolase

Fructose6-phosphate

Erythrose4-phosphate

Xylulose5-phosphate

G 3-P

F 6-Ptransketolase

Phosphohexoseisomerase

Phosphohexose isomerase

FBPase-1AldolaseTriose phosphateisomerase

Transketolase

• Transketolase catalyzes the transfer of a two-carbon fragment from a ketose donor to an aldose acceptor.

• Transketolase need the coenzyme TPP. A mutation resulting in 1/10 affinity for TPP causes genetic disorder Wernicke-Korsakoff syndrome (p. 554): severe memory loss, mental confusion, and partial paralysis.

Transaldolase

• Transaldolase cleaves the ketose and transfer one of the fragment to a aldose.

• Both enzymes catalyze similar reaction.

Nonoxidative phase of PPP provides a means of converting hexose pho

sphates to pentose phosphates

• Nonoxidative phase of PPP is reversible and happens in cytosol.

• During photosynthetic assimilation of CO2, nonoxidative phase of PPP is very important in converting hexose phosphates to pentose phosphates.

Glucose 6-phosphate is partitioned between glycolysis and PPP

by [NADP+]

• NADP+ stimulate G6PD. When [NADP+] is high (meaning more NADPH is consumed), G6PD is stimulated and G-6-P is flowing toward PPP.

Glucose

G 6-P

6-phospho-gluconate

NADPH

NADPHPentose phosphates

G6PDG6PD

6-phospho-gluconate

NADPH

NADPHPentose

phosphates

G 6-P glycolysisATP

Favism is a deficiency of G6PD• Deficiency of G6PD

block the first step of PPP.

• However, because cells have other pathway to synthesize ribose 5-phosphate, G6PD deficiency is generally nonfatal and asymptomatic.

G6P

6-phospho-glucono--lactone

Glutathione reductase

NADPH

Glutathione peroxidase

GHS

GSH

H2O2

O2

O2-

O2-

Superoxide radical 2H+

e-

Mitochondrial respiration, ionizing radiation, sulfa drugs, herbicides, antimalarial

s, divicine

H2O2Hydrogen peroxideGlutathione peroxidase

GHS

GSH

H2OGlutathione peroxidase

SGGS

Glutathione reductase

NADPH

Glutathione reductase

NADP+

Glutathione reductase

NADP+

Glucose 6-phosphate dehydrogenase

NADPHNADP+NADPH

Glutathione peroxidase

GHS

GSH

Glutathione peroxidase

SGGS

Glutathione peroxidase

SGGS

H2O2

Glutathione peroxidase

GHS

GSH

H2O2

O2

O2-

O2-

Superoxide radical 2H+

e-

H2O2

Mitochondrial respiration, ionizing radiation, sulfa drugs, herbicides, antimalarial

s, divicine

Hydrogen peroxide H2O

Glutathione reductase

NADPH

Glutathione reductase

NADP+

Glutathione reductase

NADP+

H2O2

H2O

H+ e-

OH

Hydroxyl free radical