Pentose Phosphate

CH339K

Pentose Phosphate

An example of a pathway that can be both:• Anabolic

– Generates ribose-5-phosphate for nucleotide synthesis

– Metabolizes dietary pentoses into glycolytic/gluconeogenic intermediates.

• Catabolic– Generates reducing power (NADPH)– Can completely oxidize glucose– Can carry on into glycolysis

Aka Hexose Monophosphate Shunt

NADH vs NADPH

As a general rule of thumb:• NAD+/NADH is used in catabolic processes• NADP+/NADPH is used in anabolic processes

G3P to

Glycolysis

Oxidative Phase

1)Lose a carbon2)Reduce 2 NADP+

lactonase

H2O

O

OH

HH

H

OH

OH

H OH

H

CH2OPO3-2

O

OHH

H

OH

OH

H OH

CH2OPO3-2

Glucose-6-phosphate 6-Phosphpgluconolactone

Glucose-6-Phosphate dehydrogenase

NADP+

NADPH, H+

O

OHH

H

OH

OH

H OH

CH2OPO3-2

6-Phosphpgluconolactone

C

HC

CH

HC

HC

CH2OPO3-2

O OH

OH

OH

OH

OH

6-Phosphogluconate

6-Phosphogluconolactonase

C

HC

CH

HC

HC

CH2OPO3-2

O OH

OH

OH

OH

OH

6-Phosphogluconate

H2C

C

HC

HC

CH2OPO3-2

OH

OH

OH

OPhosphogluconate Dehydrogenase

NADP+

NADPH, H+

Ribulose-5-phosphate

+ CO2

H2O H+

1)

2)

3)

Better Picture

Glutathione

-SH containing tripeptideGlu-Cys-GlyAmino of Cysteine linked to -carboxyl of glutamateCommonly used for reducing agent in cellsOxidizes to for disulfide-linked GSSGRereduced to GSH using NADPH

2

NADPH + H+

NADP+

GSH

GSSG

GlutathioneReductase

Making Glutathione

• For the Reaction to form GSH:GSSG + 2e- + 2H+ ⇄ 2GSH -0.23 V

NADPH + H+ ⇄ NADP+ + 2e- + 2 H+ +0.32 V

GSSG + NADPH + H+ ⇄ 2GSH + NADP+ +0.09 V

We can figure out Go from what we learned about redox reactions

o' o'

o' -1 -1

o' -1

ΔG = -nFΔE

ΔG = -2(96480 JV mol )(0.09 V)

ΔG = -17.37 kJmol

Divicine is found in fava beans and some other legumes

Favas (broad beans) are common foodstuffs in the old world.Largest production in Europe and China.

The parent plant, Vicia faba, is among the oldest cultivated plants - ~6,000 years.

For what it’s worth…

Glucose-6-P Dehydrogenase Deficiency

• Effects ~ 4*108 people worldwide• Most common human genetic disease• X-linked• Lack of G-6PD means lack of NADPH• Lack of NADPH means lack of GSH• Lack of GSH means excess of peroxides• RBC membranes particularly susceptible to

peroxides• Hemolytic Anemia

Glucose-6-Phosphate Dehydrogenase Deficiency

Cappellini, M.D., and Fiorelli, G. (2008) Glucose-6-phosphate dehydrogenase deficiency, Lancet 371: 64-74.

Harmful Agents for G6PDD Sufferers

Antimalarials Analgesics Antibiotics Anthelmintics Miscellaneous

Primaquine

Pamaquine

Chloroquine

Aspirin

Bufferin

Anacin

Excedrin

Empirin

APC Tablets

Darvon Compound

Coricidin

Sulfanilamide

Sulfapyridine

Sulfadimidine

Sulfacetamide

Glucosulfone sodium

Nitrofurantoin

Furazolidone

Nitrofurazone

Dapsone

Sulfoxone

Sulfisoxazole

B-Naphthol

Stibophen

Niridazole

Probenecid

Thiazide Diuretics

Phenothiazine

Chloramphenicol

Orinase

Dimercaprol

Methylene blue

Naphthalene (moth balls)

Vitamin K

Fava beans

G3P to

Glycolysis

H2C

C

HC

HC

CH2OPO3-2

OH

OH

OH

O

Ribulose-5-phosphate

H2C

C

CH

HC

CH2OPO3-2

OH

OH

O

OH

HC

HC

HC

HC

CH2OPO3-2

O

OH

OH

OH

Xylulose-5-Phosphate Ribose-5-Phosphate

Epimerase Isomerase

CH

HC

HC

HC

CH2OPO3-2

OH

OH

OH

OH

C O

H2C OH

CH

HC

CH2OPO3-2

OH

O

+

Transketolase

HC

HC

HC

CH2OPO3-2

OH

OH

OH

CHOH

C O

H2C OH

HC

HC

CH2OPO3-2

OH

OH

CH

HC

CH2OPO3-2

OH

O

CHOH

C O

H2C OH

HC

HC

CH3

OH

OH

Sedoheptulose-7-Phosphate

Glyceraldehyde- 3-Phosphate

Erythrose-4-Phosphate

Fructose-6-Phosphate

Glyceraldehyde- 3-Phosphate

Fructose-6-Phosphate

Transketolase

Transaldolase

Non-oxidative phase

phosphopentose isomerase

Ribulose can be used to make ribose•enediol intermediate

Transketolase moves 2-carbon units

Transaldolase moves 3-carbon units

Lack of transketolase can cause hepatosplenomegaly and liver cirrhosis in childhood.

Verhoeven, N. M. et al (2001) Transaldolase Deficiency: Liver Cirrhosis Associated with a New Inborn Error in the Pentose Phosphate Pathway , Amer. J. Hum. Gen. 68(5): 1086-1092.

1.

2.

Transketolase uses a TPP cofactor

Transaldolase forms a protonated Schiff base

Control• Conversion of glucose-6-Pi to the lactone is

essentially irreversible. • The enzyme, glucose-6-phosphate

dehydrogenase, controls the rate of the pathway. – NADPH competes with NADP for binding in he

active site; – ATP competes with glucose-6-phosphate.

• At high [NADPH] and/or high [ATP], entrance into the pathway is restricted.

Multiple Functions of Pentose Phosphate Pathway

Products in the pathway can be withdrawn at several points